Bonica’s Management of Pain [5th Edition] 9781496349064

Table of contents :
Cover......Page 1
Copyright......Page 4
Section Editors......Page 9
Contributing Authors......Page 12
Foreword......Page 55
Preface to the Fifth Edition (2019)......Page 57
Preface to the First Edition (1953)......Page 61
Acknowledgments......Page 66
Contents......Page 67
CHAPTER 1: Intellectual Milestones in Our Understanding and Treatment of Pain......Page 195
Pain Understood as Part of a Larger Philosophy or Worldview......Page 196
Mechanistic Views of Pain......Page 200
19TH CENTURY—PAIN AS A SPECIFIC SENSE......Page 202
AFFERENT SIGNALING......Page 207
GATE CONTROL THEORY......Page 209
Treatments for Pain......Page 211
Cognitive Treatment for Pain......Page 212
Pharmacologic Treatment of Pain......Page 214
Anatomically Specific Treatments for Pain......Page 215
The Specialty of Pain Medicine......Page 218
ACKNOWLEDGMENTS......Page 219
Definition of Commonly Used Pain Terms......Page 223
Taxonomies......Page 236
EXPERT-BASED CLASSIFICATIONS OF PAIN......Page 237
CLASSIFICATION BASED ON DURATION......Page 239
CLASSIFICATION BASED ON THE ETIOLOGY OF PAIN......Page 240
CLASSIFICATION BASED ON SEVERITY......Page 241
CLASSIFICATION BASED ON INTENSITY AND FUNCTIONING......Page 242
MECHANISM-BASED CLASSIFICATION OF PAIN......Page 244
Empirically Based Classification of the Psychological Components of Pain......Page 246
COMPREHENSIVE, MULTIDIMENSIONAL CLASSIFICATION OF PAIN: INTERNATIONAL ASSOCIATION FOR THE STUDY OF PAIN TAXONOMY......Page 249
COMPREHENSIVE, MULTIDIMENSIONAL CLASSIFICATION OF PAIN: ACTTION-AMERICAN PAIN SOCIETY AND ACTTION-AMERICAN PAIN SOCIETY-AMERICAN ACADEMY OF PAIN MEDICINE......Page 254
INDUCTIVE EMPIRICALLY BASED CLASSIFICATIONS OF PAIN......Page 257
PSYCHOMETRIC CONSIDERATIONS......Page 258
Conclusion......Page 259
CHAPTER 3: Peripheral Pain Mechanisms and Nociceptor Sensitization......Page 263
Functional Characterization of Nociceptors......Page 264
Identification of Putative Nociceptors......Page 267
ANATOMY OF THE NOCICEPTOR......Page 270
STIMULUS TRANSDUCTION......Page 276
PASSIVE ELECTROPHYSIOLOGIC PROPERTIES AND THE SPREAD OF THE GENERATOR POTENTIAL......Page 279
ACTION POTENTIAL GENERATION......Page 280
ACTION POTENTIAL PROPAGATION......Page 283
TRANSMITTER RELEASE......Page 284
Nociceptor Sensitization......Page 286
Clinical Implications of Nociceptor Function......Page 291
CHAPTER 4: Substrates of Spinal Cord Nociceptive Processing......Page 305
MODELS OF PAIN PROCESSING......Page 306
METHODS OF NEURONAL CHARACTERIZATION......Page 307
DEFINING NOCICEPTIVE SECOND-ORDER NEURONS......Page 308
DEVELOPMENT OF SENSORY SYSTEMS......Page 309
GROSS ANATOMY OF THE SPINAL CORD......Page 310
SPINAL LAMINAE......Page 312
FUNCTIONAL CHARACTERIZATION OF NOCICEPTIVE NEURONS......Page 316
INTRASPINAL PATHWAYS......Page 318
Ventrolateral (Anterolateral) Axonal Pathways......Page 319
Laminar Distribution of Spinothalamic Tract Neurons......Page 320
Dorsolateral and Ventromedial Axonal Pathways......Page 322
Ventrolateral (Anterolateral) Axonal Pathways......Page 323
POSTSYNAPTIC DORSAL COLUMN NEURONS......Page 324
OTHER ASCENDING PATHWAYS......Page 325
NEUROTRANSMITTERS FROM PRIMARY AFFERENTS......Page 326
Excitatory Amino Acids: Ionotropic Receptor/Channels......Page 329
Substance P......Page 330
Calcitonin Gene-Related Peptide......Page 331
Adenosine Triphosphate......Page 332
Inhibitory Amino Acids......Page 333
Opioids......Page 334
Acetylcholine......Page 335
Serotonin (5-Hydroxytryptamine)......Page 336
Other Neurotransmitters in Descending Systems......Page 337
NEUROTRANSMITTERS FROM GLIA OR UNKNOWN SOURCES......Page 338
OTHER IMPORTANT RECEPTORS/CHANNELS......Page 339
ACKNOWLEDGMENTS......Page 340
CHAPTER 5: Modulation of Spinal Nociceptive Processing......Page 345
ACUTE SEGMENTAL MODULATORY EFFECTS......Page 346
HETEROSEGMENTAL MODULATORY SYSTEMS......Page 347
C-FIBER WIND-UP AND CENTRAL SENSITIZATION......Page 349
TONIC DESCENDING INFLUENCES......Page 351
Periaqueductal Grey of the Mesencephalon and the Rostral Ventral Medulla......Page 353
Other Deep Brain Sites......Page 358
Cortical Structures......Page 360
SUMMARY OF SUPRASPINAL INFLUENCES......Page 362
ON, OFF, AND NEUTRAL CELLS......Page 363
ALLODYNIA AND HYPERALGESIA......Page 364
INFLAMMATION-INDUCED HYPERSENSITIVITY AND INHIBITORY SYSTEMS......Page 365
STRESS-INDUCED ANALGESIA AND HYPERALGESIA......Page 367
NEUROPATHIC PAIN......Page 368
OPIOID-INDUCED HYPERALGESIA......Page 369
Conclusion......Page 370
CHAPTER 6: Supraspinal Mechanisms of Pain and Nociception......Page 377
METHODOLOGIES OF NONINVASIVE AND INVASIVE FUNCTIONAL BRAIN IMAGING IN PAIN......Page 378
Brainstem......Page 380
PERIAQUEDUCTAL GRAY MATTER—A KEY STRUCTURE OF ENDOGENOUS ANALGESIA......Page 382
Hypothalamus......Page 385
THE LATERAL PAIN SYSTEM—THE SENSORY-DISCRIMINATIVE PATHWAY......Page 386
SPINAL CONNECTIONS TO BRAINSTEM AND MEDIAL THALAMUS—THE AFFECTIVE PATHWAY......Page 387
Cortex......Page 388
Primary Somatosensory Cortex......Page 389
Secondary Somatosensory Cortex......Page 391
Insular Cortex......Page 392
Cingulate Cortex......Page 394
Prefrontal Cortex......Page 396
Amygdala......Page 399
Hippocampus......Page 400
Vigilance, Arousal, and Attention in Pain Processing......Page 401
Pain Plasticity......Page 404
Summary and Conclusion......Page 406
CHAPTER 7: Psychological Aspects of Pain......Page 416
Cognitive Factors: Predispositions, Appraisals, Beliefs, Perceived Control, and Self-efficacy......Page 418
PREDISPOSITIONS......Page 419
APPRAISAL AND BELIEFS......Page 422
CATASTROPHIZING AND FEAR-AVOIDANCE BELIEFS......Page 423
PERCEIVED CONTROL AND SELF-EFFICACY......Page 425
COPING......Page 426
Stress and Autonomic Responses: Hypothalamic-Pituitary-Adrenal Axis Dysregulation......Page 427
Emotion......Page 428
ANXIETY......Page 429
DEPRESSION......Page 432
ANGER AND HOSTILITY......Page 433
PSYCHOGENIC VIEW......Page 437
OPERANT CONDITIONING......Page 438
SOCIAL (OBSERVATIONAL) LEARNING......Page 440
GATE CONTROL THEORY......Page 441
Cognitive-Behavioral Perspective......Page 442
Biopsychosocial, Contextual Model......Page 446
Families and Family Systems Perspective......Page 447
Conclusion......Page 448
CHAPTER 8: Individual Differences in Pain: The Roles of Gender, Ethnicity, and Genetics......Page 460
CLINICAL PAIN......Page 464
EXPERIMENTAL PAIN......Page 468
RESPONSES TO PAIN TREATMENT......Page 470
BIOPSYCHOSOCIAL MECHANISMS......Page 473
Ethnic Group Differences in Pain......Page 474
CLINICAL PAIN......Page 475
EXPERIMENTAL PAIN......Page 476
RESPONSES TO PAIN TREATMENT......Page 477
BIOPSYCHOSOCIAL MECHANISMS......Page 479
CLINICAL PAIN......Page 480
EXPERIMENTAL PAIN......Page 481
Interactions among Individual Difference Factors......Page 483
Conclusion......Page 485
ACKNOWLEDGMENTS......Page 486
CHAPTER 9: Functional Neuroanatomy of the Nociceptive System......Page 500
Organization of the Peripheral Nociceptive System......Page 501
Peripheral Nervous System Structures of Pain Sensation......Page 507
Functional Anatomy of the Central Nervous System......Page 508
DORSAL HORN......Page 509
SPINOTHALAMIC TRACT......Page 511
THALAMUS......Page 513
SENSORY CORTEX......Page 514
DESCENDING PATHWAYS OF THE CENTRAL NERVOUS SYSTEM......Page 515
CENTRAL PAIN......Page 516
CENTRAL PAIN AFTER SPINAL CORD INJURY......Page 517
PERIPHERAL AUTONOMIC NERVOUS SYSTEM......Page 519
PARASYMPATHETIC DIVISION......Page 520
CRANIAL PARASYMPATHETICS......Page 522
SACRAL PARASYMPATHETICS......Page 524
SYMPATHETIC (THORACOLUMBAR) DIVISION......Page 525
Sympathetic Preganglionic Neurons......Page 526
Sympathetic Postganglionic Neurons......Page 527
SENSATION IN VISCERAL ORGANS......Page 534
AUTONOMIC CENTERS IN THE CENTRAL NERVOUS SYSTEM......Page 535
TRANSMISSION IN THE PERIPHERAL AUTONOMIC NERVOUS SYSTEM......Page 537
PHYSIOLOGY OF THE AUTONOMIC NERVOUS SYSTEM......Page 538
ENTERIC NERVOUS SYSTEM......Page 540
Conclusion......Page 541
CHAPTER 10: Clinical Trials......Page 547
Uncontrolled Studies Paradigm......Page 548
CONTROL GROUPS: AN IMPROVEMENT OVER THE CASE SERIES......Page 552
Randomized Allocation of Treatment and Control Groups......Page 557
Other Methods for Reducing Bias in Clinical Trials......Page 559
BASELINE SIMILARITY OF STUDY GROUPS......Page 560
BLINDING......Page 561
WERE GROUPS TREATED EQUALLY EXCEPT FOR THE EXPERIMENTAL TREATMENT?......Page 562
LOW LOSS TO FOLLOW-UP AND INTENTION-TO-TREAT ANALYSIS......Page 563
MEASUREMENT OF OUTCOMES......Page 565
REPORTING THE RESULTS......Page 567
STATISTICAL POWER......Page 568
GENERALIZABILITY OF RESULTS AND EFFICACY VERSUS EFFECTIVENESS......Page 569
EFFECTS OF FUNDING SOURCE......Page 570
ASSESSMENT OF HARMS......Page 572
CLUSTER TRIALS......Page 573
CROSSOVER TRIALS......Page 574
PRAGMATIC TRIALS......Page 575
EXPERTISE-BASED TRIALS......Page 576
COMPARATIVE EFFECTIVENESS......Page 577
STEPPED WEDGE DESIGN......Page 578
Systematic Reviews......Page 579
Conclusion......Page 581
CHAPTER 11: Transdermal Pain: A Sociocultural Perspective......Page 589
What Is Transdermal Pain?......Page 592
Ethnicity, Race, Sex, Gender, Age: Whose Pain?......Page 595
Across Cultures: Beliefs, Attitudes, Perceptions, Behaviors......Page 602
Pain and Narrative: Culture, Meaning, Ethics......Page 607
Beyond the Gate: Consciousness and the Limits of a Molecular Gaze......Page 610
Pain and Globalization: Power, Money, Systems......Page 613
Conclusion: Summary and Synthesis......Page 619
ACKNOWLEDGMENT......Page 621
CHAPTER 12: Ethical Issues in Pain Management......Page 631
Pain, Suffering, and the Core Values of Health Care......Page 632
CURATIVE VERSUS PALLIATIVE PARADIGMS OF PATIENT CARE......Page 634
The Phenomenon of Undertreated Pain......Page 636
Professional Barriers......Page 637
Patient Barriers......Page 644
Societal Barriers......Page 645
Ethical Implications of the Barriers......Page 646
Embracing a New Ethic of Pain Relief......Page 647
Conclusion......Page 653
THE QUEST FOR MORAL ORDER AMID EXISTENTIAL DISORDER......Page 658
THE CONTRIBUTIONS AND LIMITATIONS OF ETHICAL ANALYSIS IN END-OF-LIFE CARE......Page 659
The Transition from Curative to Palliative and End-of-Life Care......Page 662
NEGOTIATING TREATMENT PREFERENCES: THE IDEAL DECISION-MAKING PROCESS......Page 663
Prognosis and Clinical Judgment......Page 664
Patients’ Attitudes and Values......Page 665
Physicians’ Attitudes and Values......Page 666
COMMUNICATION WITH PATIENTS ABOUT TREATMENT PREFERENCES NEAR THE END OF LIFE......Page 668
Surrogate Decision Making......Page 671
ASSESSING DECISIONAL CAPACITY......Page 672
IDENTIFYING A SURROGATE......Page 673
THE SURROGATE’S ROLES AND RESPONSIBILITIES......Page 675
A REALISTIC PROCESS OF ADVANCE CARE PLANNING......Page 676
Three Basic Problems......Page 677
A Realistic Approach......Page 678
THE ETHICAL BASIS OF THE CONFLICT......Page 681
THE CLINICAL CONTEXT OF THE CONFLICT......Page 683
DIFFERENTIAL DIAGNOSIS OF THE CONFLICT......Page 684
Physician-Assisted Death......Page 688
TERMINOLOGY......Page 689
ETHICAL CONSIDERATIONS ALONG THE CLINICAL SPECTRUM......Page 690
TWO LEVELS OF RESPONSE: SOCIAL POLICY AND CLINICAL CARE......Page 692
Social Policy......Page 693
Clinical Care......Page 694
Conclusion: Beyond the Patient–Physician Dyad......Page 695
PREVALENCE OF UNRELIEVED PAIN IS A PUBLIC HEALTH PROBLEM......Page 700
BARRIERS TO THE SAFE AND EFFECTIVE USE OF OPIOID ANALGESICS FOR PAIN MANAGEMENT......Page 702
POLICIES GOVERNING THE USE OF OPIOID ANALGESICS FOR PAIN MANAGEMENT......Page 703
International Treaties: Establishing Balance between Drug Control and Medical Use......Page 706
THE FEDERAL FOOD, DRUG, AND COSMETIC ACT......Page 710
US FEDERAL CONTROLLED SUBSTANCES LAW......Page 715
The Controlled Substances Act Ensures Availability of Controlled Substances for Medical Purposes......Page 718
The Controlled Substances Act Does Not Regulate Medical Practice......Page 719
The Controlled Substances Act Distinguishes Treatment of Addiction from Treatment of Pain, but Legal Definitions Create Confusion......Page 722
The Controlled Substances Act and Regulations Do Not Limit Prescription Amount or Duration......Page 724
Regulations Implementing the Controlled Substances Act Now Authorize a Greater Variety of Secure Disposal Opportunities for Controlled Substances......Page 726
US State Laws: Striving for Balance between Drug Control and Medical Use......Page 727
STATE PAIN POLICY DEVELOPMENT: AN EMERGING TREND......Page 728
Policy Evaluation Findings......Page 731
Progress Report Card Findings......Page 739
THE IMPORTANCE OF IMPROVING STATE PAIN POLICY......Page 743
The Need to Implement and Communicate Policy......Page 744
Considering Additional US Policies......Page 745
Taking Diversion into Account......Page 748
Conclusions......Page 751
CHAPTER 15: Litigation Involving Pain Management......Page 768
Administrative Proceedings......Page 770
IN THE MATTER OF DILEO......Page 771
HOOVER V AGENCY FOR HEALTH CARE ADMINISTRATION......Page 772
OREGON BOARD OF MEDICAL EXAMINERS V BILDER......Page 774
ACCUSATION OF EUGENE WHITNEY, MD......Page 775
Civil Litigation......Page 777
ESTATE OF HENRY JAMES V HILLHAVEN CORPORATION......Page 778
BERGMAN V CHIN, MD, AND EDEN MEDICAL CENTER......Page 780
TOMLINSON V BAYBERRY CARE CENTER, ET AL.......Page 783
Criminal Litigation......Page 785
STATE V NARAMORE......Page 786
UNITED STATES V ROSEN (1978)......Page 791
UNITED STATES V HURWITZ......Page 793
UNITED STATES V MCIVER......Page 795
Constitutional Cases......Page 797
Lessons from the Litigation......Page 801
CHAPTER 16: International Access to Therapeutic Opioids......Page 806
Pain Relief Is Part of Cancer and HIV/AIDS Control......Page 807
PAIN AND PALLIATIVE CARE......Page 808
Opioids Are Essential Medicines and Controlled Substances......Page 809
GOVERNMENTS MUST ENSURE ADEQUATE OPIOID AVAILABILITY......Page 811
Disparities in Opioid Consumption......Page 814
MORPHINE EQUIVALENCE METRIC......Page 816
GLOBAL OPIOID CONSUMPTION TRENDS......Page 817
Regional Opioid Consumption Trends......Page 819
WORLD HEALTH ORGANIZATION REGION FOR THE AMERICAS (AMRO)......Page 822
WORLD HEALTH ORGANIZATION REGION FOR THE EASTERN MEDITERRANEAN (EMRO)......Page 823
WORLD HEALTH ORGANIZATION REGION FOR EUROPE (EURO)......Page 824
WORLD HEALTH ORGANIZATION REGION FOR SOUTHEAST ASIA (SEARO)......Page 825
WORLD HEALTH ORGANIZATION REGIONS FOR THE WESTERN PACIFIC (WPRO)......Page 826
Barriers to Opioid Availability and Accessibility......Page 827
Concerns about Dependence Syndrome (Addiction)......Page 830
Health Care Professionals’ Fear of Prosecution or Sanction......Page 832
EXCESSIVELY STRICT LAWS OR REGULATORY POLICIES......Page 833
MEDICATION DISTRIBUTION SYSTEM BARRIERS......Page 835
ECONOMIC FACTORS INCLUDING AFFORDABILITY......Page 837
United Nations’ Recommendations......Page 838
Efforts to Address Barriers and Improve Opioid Availability and Accessibility......Page 842
Conclusion......Page 847
Introduction......Page 856
GENERAL GUIDELINES FOR ASSESSMENT OF PERSISTENT PAIN......Page 861
Outline of a Multidimensional Assessment Questionnaire for Persistent Pain History......Page 862
SUMMARY OF PROPRIETARY QUESTIONNAIRES TO CONSIDER......Page 864
The Pain History......Page 865
O: ONSET OF PAIN......Page 866
R: REGION/RADIATION......Page 867
S: SEVERITY/INTENSITY OF PAIN......Page 868
ALTERED PERCEPTION......Page 869
MOOD ASSESSMENT......Page 870
PSYCHOSOCIAL FACTORS......Page 871
SLEEP DISORDERS......Page 873
COGNITIVE IMPAIRMENT......Page 874
HABITS......Page 875
Risk of Opioid Misuse, Abuse, or Dependence......Page 876
Assessment of Function......Page 878
Current and Past Treatments......Page 879
Goals......Page 880
Physical Examination......Page 881
Observe......Page 882
Observe or Ask About......Page 883
Test......Page 884
BEDSIDE METHOD FOR QUANTITATIVE SENSORY TESTING......Page 887
Vibration......Page 888
Grading the Tests......Page 889
CAVEATS TO QUANTITATIVE SENSORY TESTING INTERPRETATION......Page 891
Follow-up Visits......Page 892
Conclusion......Page 893
Appendix 17.3: Goal Setting......Page 903
Appendix 17.1: Initial Visit Questionnaire......Page 894
Appendix 17.2: Pain Diagram......Page 902
Appendix 17.4: Follow-up Questionnaire......Page 905
The Electrodiagnostic Laboratory......Page 910
NERVE CONDUCTION STUDIES......Page 912
NEEDLE ELECTROMYOGRAPHY......Page 919
Application in Selected Conditions......Page 925
Conclusion......Page 928
CHAPTER 19: Diagnostic Imaging of Pain......Page 932
Headache......Page 933
ACUTE HEADACHE......Page 934
Computed Tomography Angiography and Magnetic Resonance Angiography......Page 940
CHRONIC HEADACHE......Page 941
INTRACRANIAL HYPOTENSION......Page 944
INTRACRANIAL HYPERTENSION (PSEUDOTUMOR CEREBRI)......Page 945
Facial Pain......Page 946
OVERVIEW......Page 948
BENIGN VERSUS MALIGNANT; INFECTION/INFLAMMATION......Page 950
DISCOGENIC PAIN......Page 952
MAGNETIC RESONANCE NEUROGRAPHY......Page 955
THORACIC OUTLET SYNDROME......Page 961
PIRIFORMIS SYNDROME......Page 962
PERIPHERAL NERVE ENTRAPMENT SYNDROMES......Page 963
Imaging Guided Injection......Page 964
Future Application of Pain Imaging......Page 965
Conclusion......Page 967
Introduction......Page 974
Validity......Page 975
Reliability......Page 977
Utility......Page 978
HOW MANY PAIN PROBLEMS SHOULD BE ASSESSED?......Page 979
WHICH PAIN DOMAIN(S) SHOULD BE ASSESSED?......Page 980
RECALL RATINGS VERSUS SUMMARY SCORES FROM MULTIPLE RATINGS USING DIARIES......Page 982
MEASURING PAIN INTENSITY......Page 987
Recommendations for Assessing Pain Intensity......Page 988
MEASURING PAIN AFFECT......Page 989
MEASURING PAIN QUALITY......Page 992
Using Pain Quality Measures as Diagnostic Aides......Page 993
Strengths and Weaknesses of Pain Quality Measures as Diagnostic Aids......Page 995
Pain Quality Scales as Descriptive and Outcome Measures......Page 996
Strengths and Weakness of Descriptive and Outcome Measures of Pain Quality......Page 1009
MEASURING PAIN’S SPATIAL CHARACTERISTICS......Page 1010
MEASURING PAIN’S TEMPORAL CHARACTERISTICS......Page 1012
Brief Pain Inventory Pain Interference Scale......Page 1014
Patient-Reported Outcomes Measurement Information System Pain Interference Item Bank and Short Forms......Page 1017
Recommendations for Assessing Pain Interference......Page 1018
Simple Pain Measures to Consider......Page 1019
Selecting the Best Measure for a Patient or Population......Page 1021
BEHAVIOR OBSERVATION MEASURES......Page 1023
Summary and Conclusions......Page 1024
Psychosocial History......Page 1038
VOCATIONAL HISTORY......Page 1039
EDUCATIONAL HISTORY......Page 1040
BELIEF STRUCTURES......Page 1041
SOCIAL SUPPORT......Page 1043
Substance Use......Page 1044
NICOTINE......Page 1045
ALCOHOL......Page 1046
PRESCRIBED AND NONPRESCRIBED DRUG USE......Page 1047
Psychiatric Functioning......Page 1048
DEPRESSION......Page 1049
ANXIETY......Page 1050
POSTTRAUMATIC STRESS DISORDER......Page 1051
Psychological Screening for Advanced Interventional Procedures......Page 1052
Conclusion......Page 1053
Basic Concepts......Page 1060
Conceptual and Empirical Issues......Page 1061
Disability......Page 1062
ASSOCIATIONS BETWEEN IMPAIRMENT AND DISABILITY......Page 1064
THE “EMBEDDEDNESS” PROBLEM......Page 1065
PRACTICAL PROBLEMS IN IDENTIFYING THE ROLE OF PAIN IN DISABILITY DETERMINATIONS......Page 1066
EVALUATION METHODS IN THE SOCIAL SECURITY ADMINISTRATION......Page 1068
OUTCOMES OF SOCIAL SECURITY ADMINISTRATION EVALUATIONS......Page 1073
DISABILITY EVALUATION AND DISABILITY MANAGEMENT IN THE WASHINGTON STATE DEPARTMENT OF LABOR AND INDUSTRIES......Page 1074
WASHINGTON STATE DEPARTMENT OF LABOR AND INDUSTRIES PROGRAMS TO REDUCE DISABILITY......Page 1077
METHODS USED BY WASHINGTON STATE DEPARTMENT OF LABOR AND INDUSTRIES TO EVALUATE INJURED WORKERS FOR PERMANENT DISABILITY BENEFITS......Page 1087
OUTCOMES OF WASHINGTON STATE DEPARTMENT OF LABOR AND INDUSTRIES EVALUATIONS......Page 1089
Conclusion......Page 1090
CONUNDRUMS IN THE ASSESSMENT OF PAIN......Page 1094
A CONCEPTUAL MODEL FOR ASSESSING PAIN......Page 1095
Classes of Variables Underlying Pain Behavior......Page 1096
Assessment of Medical Factors......Page 1097
ARE THERE RED FLAGS?......Page 1099
ARE THERE RISK FACTORS FOR DELAYED RECOVERY?......Page 1104
History......Page 1105
Ancillary Studies......Page 1106
CONCLUSION......Page 1107
Assessment of Central Nervous System Sensitization......Page 1108
Psychological Factors as Causal Agents in Development of Chronic Pain......Page 1110
Psychological Consequences of Chronic Pain......Page 1111
ELEMENTS OF THE PSYCHOLOGICAL EVALUATION......Page 1112
Interviews......Page 1114
Self-report Inventories......Page 1116
Assessment of Pain......Page 1117
Assessment of Overt Expressions of Pain......Page 1119
Assessment of Emotional Distress......Page 1121
Assessment of Fear......Page 1122
Assessment of Beliefs, Coping, and Psychosocial Adaptation to Pain......Page 1123
Assessing Functional Impact......Page 1124
SELF-REPORT MEASURES OF FUNCTION......Page 1125
Assessment of Physical Capacity......Page 1126
Assessment of Social Factors......Page 1127
Conclusion......Page 1128
NEUROPATHY CLASSIFICATION......Page 1138
HISTORY, EXAMINATION, AND DIAGNOSTIC STUDIES......Page 1141
Metabolic Causes......Page 1144
Infectious Causes......Page 1145
Toxic Neuropathies......Page 1146
Nutritional Neuropathies......Page 1147
Hereditary Neuropathies......Page 1149
Neuropathy with Paraproteinemia......Page 1152
Autoimmune Demyelinating Neuropathies......Page 1153
Vasculitic Neuropathy......Page 1156
Neuralgic Amyotrophy......Page 1157
Diabetic Amyotrophy......Page 1158
Postherpetic Neuralgia......Page 1159
Sjögren’s Syndrome......Page 1160
ANALGESIA THERAPY: GUIDELINES FOR PHARMACOTHERAPY......Page 1161
Tricyclic Agents......Page 1163
α2δ Ligands......Page 1164
Opioids......Page 1165
Other Pharmacologic Agents......Page 1166
Cannabinoids......Page 1167
Principles of Pharmacotherapy for Pain from Neuropathy......Page 1168
Unresolved Questions......Page 1169
Epidemiology......Page 1177
ANIMAL MODELS......Page 1179
HUMAN MODELS......Page 1180
INFLAMMATION......Page 1181
IMMUNOLOGIC FACTORS......Page 1183
Afferent Dysfunction......Page 1184
CENTRAL DYSFUNCTION......Page 1185
SYMPATHETIC DYSFUNCTION......Page 1186
TROPHIC, DYSTROPHIC, AND NUTRITIONAL ABNORMALITIES......Page 1189
MOTOR AND MOVEMENT DISORDERS......Page 1190
Genetics......Page 1192
A Convergent Pathophysiologic Theory......Page 1193
THE INTERNATIONAL ASSOCIATION FOR THE STUDY OF PAIN CRITERIA......Page 1194
THE BUDAPEST CRITERIA......Page 1197
SEQUENTIAL STAGES AND SUBSETS OF COMPLEX REGIONAL PAIN SYNDROME......Page 1200
PSYCHOLOGICAL FACTORS IN COMPLEX REGIONAL PAIN SYNDROME......Page 1202
Treatment......Page 1206
THE RATIONALE FOR FUNCTIONAL RESTORATION......Page 1207
REHABILITATION-BASED TREATMENT MODALITIES......Page 1210
PHARMACOTHERAPY......Page 1213
PSYCHOLOGICAL INTERVENTIONS......Page 1218
INTERVENTIONAL THERAPIES......Page 1221
OTHER THERAPEUTIC MODALITIES......Page 1224
CHAPTER 26: Phantom Pain......Page 1246
Epidemiology......Page 1247
Pathophysiology of Phantom Pain......Page 1248
Treatment of Phantom Pain......Page 1252
ANTIDEPRESSANTS......Page 1253
ANTIEPILEPTIC DRUGS......Page 1254
OPIOIDS......Page 1255
NMDA RECEPTOR ANTAGONISTS......Page 1256
TRANSIENT RECEPTOR POTENTIAL CATION CHANNEL SUBFAMILY V MEMBER 1 (TRPV1) MODULATORS......Page 1257
INTERVENTIONAL THERAPY......Page 1258
NEUROMODULATION......Page 1260
SURGICAL INTERVENTIONS......Page 1262
BEHAVIORAL MEDICINE INTERVENTIONS......Page 1263
MISCELLANEOUS TREATMENTS FOR RESIDUAL LIMB PAIN......Page 1265
Summary......Page 1266
CHAPTER 27: Herpes Zoster and Postherpetic Neuralgia......Page 1274
RASH......Page 1275
PAIN......Page 1276
DISTRIBUTION OF HERPES ZOSTER......Page 1277
Herpes Zoster Oticus (Ramsay-Hunt Syndrome)......Page 1278
Diagnosis of Herpes Zoster......Page 1279
Viral DNA Testing......Page 1280
Epidemiology of Herpes Zoster......Page 1281
Pathophysiology of Herpes Zoster and Mechanisms of Acute Pain......Page 1283
MOTOR NEUROPATHY......Page 1285
RARE NEUROLOGIC COMPLICATIONS......Page 1286
PATIENT EDUCATION......Page 1287
ANTIVIRAL THERAPY......Page 1288
ANALGESIC TREATMENT......Page 1291
CORTICOSTEROIDS......Page 1294
NEURAL BLOCKADE......Page 1295
COMPLEMENTARY AND ALTERNATIVE MEDICINE......Page 1296
CHILDHOOD VACCINATION......Page 1297
HERPES ZOSTER VACCINATION FOR ADULTS......Page 1298
Clinical Picture of Postherpetic Neuralgia......Page 1300
DIAGNOSIS AND ASSESSMENT OF POSTHERPETIC NEURALGIA......Page 1301
Laboratory Diagnosis......Page 1302
RISK FACTORS FOR POSTHERPETIC NEURALGIA......Page 1303
Pathophysiology of Postherpetic Neuralgia......Page 1304
Treatment of Postherpetic Neuralgia......Page 1308
ANTICONVULSANTS: GABAPENTIN AND PREGABALIN......Page 1311
Tricyclic Antidepressants......Page 1315
OPIOID ANALGESICS......Page 1316
TAPENTADOL......Page 1318
TOPICAL THERAPIES......Page 1319
Topical Capsaicin......Page 1320
COMBINATION THERAPY......Page 1322
INVASIVE TREATMENTS FOR POSTHERPETIC NEURALGIA......Page 1323
Botulinum Toxin......Page 1324
Peripheral Nerve Blocks......Page 1325
Neuroaugmentive Techniques......Page 1326
Neuraxial Blocks......Page 1327
Scrambler Therapy......Page 1328
Prevention of Postherpetic Neuralgia......Page 1329
Conclusions......Page 1331
Diagnosis......Page 1344
Clinical Characteristics......Page 1347
Clinical Assessment......Page 1349
CENTRAL POSTSTROKE PAIN......Page 1350
CENTRAL PAIN IN SPINAL CORD INJURY......Page 1351
OTHER CENTRAL PAIN CONDITIONS......Page 1352
Preclinical Models......Page 1353
Mechanisms......Page 1354
Treatment of Central Pain......Page 1357
PHARMACOLOGIC TREATMENT......Page 1358
First-line Pharmacologic Treatments......Page 1360
Second- and Third-Line Pharmacologic Treatments......Page 1363
Other Drugs, Combination Therapy, and Intrathecal Drug Administration......Page 1364
PSYCHOLOGICAL AND PHYSIOTHERAPY TREATMENT......Page 1365
Targeted Drug Delivery......Page 1366
Neuromodulation......Page 1367
CHAPTER 29: The Psychophysiology of Pain......Page 1384
Historical Perspective: Mind–Body Issues......Page 1386
WHAT ARE EMOTIONS?......Page 1387
ADAPTIVE FUNCTIONS OF EMOTION......Page 1388
EMOTIONS AND BEHAVIOR......Page 1389
THE CENTRAL NEUROANATOMY OF EMOTION: LIMBIC STRUCTURES......Page 1390
PERIPHERAL NEUROANATOMY OF EMOTION: THE AUTONOMIC NERVOUS SYSTEM......Page 1392
The Role of Feedback......Page 1393
Relationship of Central and Peripheral Mechanisms......Page 1395
NOXIOUS SIGNALING AND CENTRAL LIMBIC PROCESSING......Page 1396
Central Neurotransmitter Systems......Page 1397
LOCUS COERULEUS AND THE DORSAL NORADRENERGIC BUNDLE......Page 1398
THE VENTRAL NORADRENERGIC BUNDLE AND THE HYPOTHALAMO-PITUITARY-ADRENOCORTICAL AXIS......Page 1402
PRIMARY AND SECONDARY FEATURES OF THE AFFECTIVE DIMENSION OF PAIN......Page 1405
SUMMARY OF THE CONSTRUCTION AND MODULATION OF PAIN......Page 1406
Emotion and Cognition......Page 1408
MULTIPLE PERSPECTIVES ON THE SELF......Page 1409
BASIC DEFINITIONS: STRESS, HOMEOSTASIS, AND ALLOSTASIS......Page 1411
PHYSIOLOGIC MECHANISMS OF STRESS......Page 1413
Neural Substrates......Page 1414
Immune Mechanisms......Page 1415
The Sickness Response......Page 1416
SUMMARY OF THE PHYSIOLOGIC MECHANISMS OF STRESS......Page 1417
STRESS AND CHRONIC PAIN......Page 1418
Future Directions......Page 1419
CLASSICAL CONDITIONING......Page 1429
OPERANT CONDITIONING......Page 1431
OBSERVATIONAL LEARNING......Page 1432
THE HALLMARK WORK OF WILBERT FORDYCE......Page 1433
OPERANT CONDITIONING AND CHRONIC PAIN: THE BASICS......Page 1436
CLASSICALLY CONDITIONED FEAR/AVOIDANCE AND PAIN......Page 1437
Observational Learning and Pain......Page 1438
COGNITIVE-BEHAVIORAL THERAPY AND PAIN......Page 1440
COGNITIVE-BEHAVIORAL THERAPY AS AN ESSENTIAL COMPONENT OF A COMPREHENSIVE INTERDISCIPLINARY APPROACH TO PAIN MANAGEMENT......Page 1441
Conclusion......Page 1442
CHAPTER 31: Psychiatric Illness, Depression, Anxiety, and Somatic Symptom Disorder......Page 1445
Psychiatric Nosology and Diagnostic and Treatment Approaches......Page 1446
Framework for Describing Psychiatric Symptoms......Page 1452
Depression......Page 1455
SUICIDAL IDEATION AND BEHAVIOR......Page 1456
WHICH CAME FIRST, DEPRESSION OR PAIN?......Page 1458
BIOLOGIC TESTS FOR DEPRESSION......Page 1460
EPIDEMIOLOGY OF DEPRESSION......Page 1461
Biologic Theories......Page 1463
Psychological Theories......Page 1467
Anthropologic Theories......Page 1471
Pharmacologic Agents......Page 1472
Behavioral Model......Page 1476
Cognitive Model......Page 1477
Cognitive-Behavioral Model......Page 1478
Anxiety Disorders......Page 1479
GENERALIZED ANXIETY DISORDER......Page 1480
PANIC DISORDER......Page 1482
EPIDEMIOLOGY......Page 1483
TREATMENT......Page 1485
DIAGNOSIS......Page 1486
EPIDEMIOLOGY OF POSTTRAUMATIC STRESS DISORDER IN CHRONIC PAIN PATIENTS......Page 1488
TREATMENT......Page 1489
EPIDEMIOLOGY......Page 1490
OVERVIEW OF PERSONALITY DISORDERS......Page 1491
PERSONALITY AND PAIN TREATMENT OUTCOME......Page 1493
DEFINITIONS......Page 1494
OVERVIEW OF SOMATOFORM DISORDERS AND SOMATIC SYMPTOM DISORDERS......Page 1496
Somatic Symptom Disorder......Page 1498
Conversion Disorder (Functional Neurologic Symptom Disorder)......Page 1499
ILLNESS ANXIETY DISORDER......Page 1502
Conclusion: Pain and Suffering and Psychiatry......Page 1503
CHAPTER 32: Treatment of Pain in Patients with Addiction......Page 1517
Substance Use Disorder......Page 1518
NEUROBIOLOGIC OVERLAP BETWEEN PAIN AND ADDICTION SYSTEMS......Page 1521
Tolerance......Page 1522
Dependence......Page 1523
Analgesic Effects of Drugs of Abuse......Page 1524
EFFECTS OF SUBSTANCE USE DISORDER ON PAIN......Page 1525
EFFECTS OF OPIOID USE DISORDER ON PAIN......Page 1526
Genetics of Pain and Opioid Use Disorder......Page 1527
Tolerance......Page 1528
Physical Dependence......Page 1529
Opioid-Induced Hyperalgesia......Page 1530
Pain Management in Persons with Substance Use Disorder......Page 1542
PREVALENCE OF SUBSTANCE USE DISORDERS IN PATIENTS WITH PAIN......Page 1543
Provide Effective Pain Relief......Page 1546
Reinforce or Introduce Substance Use Disorder Treatment......Page 1560
Pain, Substance Use Disorder, and Suicide......Page 1562
Conclusions......Page 1571
CHAPTER 33: The Doctor–Patient Relationship in Pain Management: Dealing with Difficult Clinician–Patient Interactions......Page 1590
Difficult Patients and Difficult Doctor–Patient Relationships......Page 1591
PSYCHIATRIC AND PERSONALITY ISSUES......Page 1592
OPIOID THERAPY......Page 1594
COMORBID MEDICAL CONDITIONS......Page 1595
SUBSTANCE USE DISORDERS......Page 1596
Physician Factors......Page 1597
Health Care System Factors......Page 1598
Patient Interaction Strategies......Page 1599
PATIENT-FOCUSED CARE......Page 1600
Communication Framework: WIPS and E’s......Page 1602
SCENARIO 1......Page 1604
SCENARIO 2......Page 1605
SCENARIO 4......Page 1606
SCENARIO 5......Page 1607
SCENARIO 6......Page 1608
SCENARIO 7......Page 1609
ACKNOWLEDGMENT......Page 1610
PROBLEM IN PERSPECTIVE......Page 1615
JOINT ANATOMY......Page 1616
Nerve and Blood Supply......Page 1618
HISTORY......Page 1619
Number of Joints Affected......Page 1620
Systemic Features of Arthritis......Page 1622
EXAMINATION OF SYNOVIAL FLUID......Page 1623
Epidemiology and Pathophysiology......Page 1624
Symptoms and Signs......Page 1627
SECONDARY OSTEOARTHRITIS......Page 1630
Treatment......Page 1631
Etiology and Pathophysiology......Page 1634
Symptoms and Signs......Page 1635
Laboratory Findings......Page 1637
Treatment Philosophy......Page 1638
Current Management of Rheumatoid Arthritis......Page 1639
Important Complications of Rheumatoid Arthritis Presenting with Pain......Page 1643
Ankylosing Spondylitis......Page 1644
Spondylodiskitis......Page 1648
REACTIVE ARTHRITIS......Page 1649
Symptoms and Signs......Page 1650
Complications of Reactive Arthritis Associated with Chronic Pain......Page 1651
Symptoms and Signs......Page 1652
Treatment......Page 1653
ARTHRITIS ASSOCIATED WITH INFLAMMATORY BOWEL DISEASE......Page 1654
Pathophysiology......Page 1655
Symptoms and Signs......Page 1656
Treatment......Page 1657
Etiology and Pathophysiology......Page 1658
Pathophysiology of Acute Gouty Arthritis......Page 1660
Signs and Symptoms......Page 1662
Treatment......Page 1664
Nongonococcal Bacterial Arthritis......Page 1667
Gonococcal Arthritis......Page 1670
POLYMYALGIA RHEUMATICA......Page 1671
CHAPTER 35: Myofascial Pain Syndrome......Page 1677
Brief Historical Overview......Page 1678
Basic Myofascial Pain Concepts......Page 1680
Muscle Physiology......Page 1683
The Motor Endplate......Page 1685
Sensitization and Activation of Muscle Nociceptors......Page 1689
Central Sensitization......Page 1691
pH and Muscle Pain......Page 1698
Neuropeptides, Inflammatory Mediators, and Tissue Injury and Pain......Page 1699
Cytokines and Pain......Page 1701
TRIGGER POINT DIAGNOSIS......Page 1703
PHYSICAL EXAMINATION AND DIAGNOSIS......Page 1705
Patient Education......Page 1710
Physical Therapy......Page 1711
Needling Therapies......Page 1712
NONINVASIVE TREATMENT OPTIONS......Page 1717
Summary......Page 1718
CHAPTER 36: Fibromyalgia: A Discrete Disease or the End of the Continuum......Page 1739
Historical Perspective......Page 1741
FIBROMYALGIA......Page 1743
SIGNIFICANCE OF TENDER POINTS......Page 1744
OTHER FEATURES OF FIBROMYALGIA GLEANED FROM EPIDEMIOLOGIC OR OBSERVATIONAL STUDIES......Page 1745
GENETIC FACTORS......Page 1750
EVIDENCE OF A GLOBAL INCREASE IN SENSORY PROCESSING OF NONPAINFUL STIMULI......Page 1752
BRAIN IMAGING STUDIES......Page 1753
THE ROLE OF NEUROENDOCRINE OR AUTONOMIC ABNORMALITIES......Page 1757
THE ROLE OF PERIPHERAL FACTORS IN FIBROMYALGIA......Page 1758
THE ROLE OF “SMALL FIBER NEUROPATHY” IN FIBROMYALGIA......Page 1759
DIAGNOSIS OF FIBROMYALGIA......Page 1760
GENERAL APPROACH......Page 1768
PHARMACOLOGIC THERAPY......Page 1772
Serotonin and Norepinephrine Reuptake Inhibitors......Page 1773
Anticonvulsants......Page 1775
Other Central Nervous System–Acting Drugs......Page 1776
Classic Analgesics......Page 1777
NEUROSTIMULATORY THERAPIES......Page 1778
NONPHARMACOLOGIC THERAPIES......Page 1779
Prognosis......Page 1780
Key Points......Page 1781
CHAPTER 37: Pain of Dermatologic Disorders......Page 1793
Basic Considerations: Anatomy and Physiology of the Skin......Page 1796
LEUKOCYTOCLASTIC VASCULITIS......Page 1799
Pathogenesis......Page 1800
Symptoms and Signs......Page 1801
ANTINEUTROPHILIC CYTOPLASMIC ANTIBODIES-ASSOCIATED VASCULITIDES: GRANULOMATOSIS WITH POLYANGIITIS (FORMERLY KNOWN AS WEGENER’S GRANULOMATOSIS)......Page 1802
MICROSCOPIC POLYANGIITIS......Page 1803
Symptoms and Signs......Page 1804
LIVEDOID VASCULOPATHY......Page 1805
ANTIPHOSPHOLIPID SYNDROME......Page 1807
Treatment......Page 1808
Treatment......Page 1809
COCAINE LEVAMISOLE TOXICITY......Page 1810
CALCINOSIS CUTIS......Page 1811
CALCIPHYLAXIS......Page 1812
Ulcers......Page 1813
Treatment......Page 1814
VENOUS ULCERS......Page 1815
Treatment......Page 1816
PYODERMA GANGRENOSUM......Page 1817
NECROTIZING SOFT TISSUE INFECTION/NECROTIZING FASCIITIS......Page 1819
Symptoms and Signs......Page 1820
Treatment......Page 1821
ERYSIPELAS AND CELLULITIS......Page 1822
Treatment......Page 1823
Treatment......Page 1824
PANNICULITIS......Page 1825
Erythema Nodosum......Page 1826
DERCUM DISEASE (ADIPOSA DOLOROSA)......Page 1827
HIDRADENITIS SUPPURATIVA......Page 1828
Diagnosis......Page 1829
INFLAMED EPIDERMAL CYST......Page 1830
Stevens-Johnson/Toxic Epidermal Necrolysis Syndrome......Page 1832
Pemphigus Vulgaris......Page 1834
Bullous Pemphigoid......Page 1836
Epidermolysis Bullosa......Page 1838
RELAPSING POLYCHONDRITIS......Page 1839
Treatment......Page 1840
SENSORY MONONEUROPATHIES......Page 1841
ERYTHROMELALGIA......Page 1842
FABRY’S DISEASE......Page 1843
Treatment......Page 1844
PAINFUL NEOPLASMS......Page 1845
ACKNOWLEDGMENTS......Page 1847
Basic Neuroanatomic and Neurophysiologic Considerations......Page 1860
INTERMITTENT CLAUDICATION......Page 1863
AORTIC AND OTHER LARGE ARTERY PAIN......Page 1869
REST PAIN, ULCERS, AND GANGRENE......Page 1870
PAIN SYNDROMES FOLLOWING STROKE......Page 1872
PAIN ASSOCIATED WITH DISEASES INVOLVING SMALL ARTERIES......Page 1873
PAIN ASSOCIATED WITH VENOUS DISORDERS......Page 1875
PAIN ASSOCIATED WITH AMPUTATION......Page 1876
Differentiating Vascular from Nonvascular Pain......Page 1877
The Relief of Vascular Pain......Page 1878
Conclusion......Page 1882
Anatomy and Pathophysiology......Page 1885
Clinical Presentation: Symptoms and Signs......Page 1887
Diagnostic Tests......Page 1891
Differential Diagnosis......Page 1894
Management......Page 1895
Outcomes......Page 1899
Extent and Impact of the Problem......Page 1902
Assessment and Classification of Pain Following Spinal Cord Injury......Page 1903
MUSCULOSKELETAL PAIN......Page 1907
Shoulder Pain......Page 1908
Back Pain......Page 1909
VISCERAL PAIN......Page 1910
OTHER NOCICEPTIVE PAIN......Page 1911
AT- AND BELOW-LEVEL SPINAL CORD INJURY PAIN......Page 1912
OTHER NEUROPATHIC PAIN......Page 1918
Psychological Factors......Page 1919
Social and Environmental Factors......Page 1920
Musculoskeletal Pain......Page 1921
Management of Spasticity-Related Pain......Page 1924
VISCERAL PAIN......Page 1926
Anticonvulsants......Page 1927
Antidepressants......Page 1930
N-Methyl-D-Aspartate Receptor Antagonists......Page 1932
Opioids......Page 1933
Cannabinoids......Page 1934
Spinal Drug Administration......Page 1935
PSYCHOLOGICAL AND ENVIRONMENTAL MANAGEMENT......Page 1936
OTHER NONPHARMACOLOGIC MANAGEMENT OF PAIN IN PEOPLE WITH SPINAL CORD INJURY......Page 1937
Neurostimulation......Page 1938
Physical Therapy and Exercise......Page 1939
SURGICAL INTERVENTIONS......Page 1940
Conclusion......Page 1941
CHAPTER 41: Epidemiology, Prevalence, and Cancer Pain Syndromes......Page 1953
Epidemiology of Cancer Pain......Page 1954
SPECIAL NEEDS OF PARTICULAR AGE GROUPS: PEDIATRIC, YOUNG ADULT, ADULT, GERIATRIC......Page 1955
SPECIAL NEEDS OF PARTICULAR ETHNIC GROUPS: COMMUNICATION STYLES, COMMON PREFERENCES, AND MANAGING TABOOS......Page 1957
COMORBIDITIES ASSOCIATED WITH SPECIFIC CANCERS: LUNG DISEASE, LIVER DISEASE, RENAL DISEASE, AND NEUROLOGIC DISEASE......Page 1959
CANCER PAIN AND SUBSTANCE ABUSE......Page 1961
CANCER PAIN IN INMATES......Page 1962
Components of the Comprehensive Medical Evaluation of a Patient with Chronic Cancer Pain......Page 1963
DEFINITION OF PAIN......Page 1964
DEFINITION OF SUFFERING......Page 1965
VALIDATED ASSESSMENT TOOLS......Page 1966
TYPES OF PAIN......Page 1971
PRESENTING COMPLAINT......Page 1973
Pain Onset......Page 1974
Pain Progression......Page 1975
Focality......Page 1976
Formulating the Presenting Complaint......Page 1977
DETAILS OF THE PAIN HISTORY......Page 1978
THE REGIONAL PAIN PHYSICAL EXAMINATION......Page 1982
BEDSIDE PROVOCATIVE MANEUVERS......Page 1984
Spurling’s Test......Page 1986
Dermatomal Pain......Page 1987
Myotomal Pain......Page 1988
Back Pain......Page 1989
Retroperitoneal Pain Stretch Maneuver......Page 1990
Abdominal Wall Pain......Page 1991
Formulating a Cancer Pain Diagnosis......Page 1992
SYNDROME DIAGNOSIS......Page 1993
PATHOPHYSIOLOGIC DIAGNOSIS......Page 1994
THE MEDICAL MODEL: PAIN IS A MANIFESTATION OF DISEASE......Page 1995
REHABILITATIVE (“CHRONIC NONMALIGNANT PAIN”) MODEL: FOCUS ON DYSFUNCTIONAL PAIN BEHAVIOR AND PAIN-RELATED DECONDITIONING......Page 1996
ANESTHETIC MODEL: DIAGNOSTIC AND THERAPEUTIC BLOCKS......Page 1997
BONE PAIN......Page 1998
PAIN AND DELIRIUM......Page 1999
PAIN AND BOWEL DISEASE......Page 2000
MANAGING CANCER PAIN IN THE ADDICT......Page 2001
SAFE PRESCRIBING PRACTICES: UNIVERSAL PRECAUTIONS......Page 2003
SYMPTOM CLUSTERS......Page 2004
PAIN AT THE END OF LIFE......Page 2005
CANCER PAIN EMERGENCIES......Page 2006
Conclusion......Page 2007
CHAPTER 42: Assessment and Diagnosis of the Cancer Patient with Pain......Page 2011
Issues in Assessment and Diagnosis of Cancer Pain......Page 2018
Pain and the Cancer Patient......Page 2020
MOLECULAR MECHANISM OF TUMOR PAIN......Page 2023
SOMATIC PAIN......Page 2025
VISCERAL PAIN......Page 2027
AFFECTIVE PROCESSING AND SUFFERING......Page 2029
PSYCHOLOGICAL FACTORS AND THE COMPLEXITIES OF CANCER PAIN......Page 2031
Depression in Cancer Patients......Page 2033
DETECTING AND ASSESSING DEPRESSION IN THE CANCER PATIENT......Page 2035
Cancer-Related Fatigue......Page 2040
Sleep Disturbance in Cancer......Page 2042
Sources of Pain in the Cancer Patient......Page 2045
Classification of Cancer Pain by Feature......Page 2051
CHRONICITY......Page 2052
INTENSITY/SEVERITY......Page 2053
Tumor Involvement of Encapsulated Organs......Page 2055
Tumor Infiltration of Peripheral Nerves......Page 2057
Tumor Infiltration of Abdominal Hollow Organs......Page 2058
TUMOR TYPE AND STAGE OF DISEASE......Page 2059
Pancreatic Cancer......Page 2060
Ovarian Cancer......Page 2063
Cervical Cancer......Page 2065
Prostate Cancer......Page 2066
Breast Cancer......Page 2069
Lung Cancer......Page 2072
Renal Cell Cancers......Page 2074
Colorectal Cancer......Page 2075
Leukemias and Lymphomas......Page 2076
Multiple Myeloma......Page 2077
Tumor Markers......Page 2078
PATTERNS OF CANCER PAIN......Page 2079
CANCER PAIN SYNDROMES......Page 2081
Bone Metastases......Page 2088
CHARACTERISTICS OF METASTATIC BONE PAIN......Page 2093
PROGNOSIS......Page 2095
SACRAL INSUFFICIENCY FRACTURES......Page 2097
Visceral Pain......Page 2100
MECHANISM......Page 2101
VISCERAL PAIN DESCRIPTIONS BY SITE......Page 2104
NEUROPATHIC PAIN SECONDARY TO CANCER-RELATED PATHOLOGY IN CRANIAL NERVES......Page 2105
Cervical Plexopathy......Page 2106
Radicular Pain/Radiculopathy......Page 2107
Leptomeningeal Metastases......Page 2108
Myelopathies in Cancer......Page 2109
Brachial Plexopathy......Page 2110
Lumbosacral Plexopathy......Page 2113
Spinal and Radicular Pain......Page 2115
Paraneoplastic Peripheral Neuropathy......Page 2116
NEUROPATHIC PAIN SECONDARY TO THERAPEUTIC INTERVENTIONS......Page 2118
Postsurgical Neuropathic Pain......Page 2119
Radiation Myelopathy, Plexopathy, and Neuropathy......Page 2123
Chemotherapy-Induced Peripheral Neuropathy......Page 2126
ORAL MUCOSITIS......Page 2129
GRAFT-VERSUS-HOST DISEASE......Page 2131
MECHANISM......Page 2132
PATTERN OF PAIN......Page 2133
PRESENTATION AND PHYSICAL FINDINGS......Page 2135
INVESTIGATIONS......Page 2136
Stepwise Approach to Pain Assessment......Page 2137
FEATURES OF PAIN HISTORY......Page 2138
Quality......Page 2139
Impact of Pain......Page 2140
Effects of Pain on Activities of Daily Living......Page 2141
QUALITY OF LIFE ASSESSMENT......Page 2143
GENERAL ASSESSMENT......Page 2145
ASSOCIATED SYMPTOMS......Page 2148
LABORATORY AND IMAGING DATA......Page 2149
Summary......Page 2150
CHAPTER 43: Cancer Pain: Principles of Management and Pharmacotherapy......Page 2175
Cancer Pain Management Overview......Page 2180
Surgery......Page 2183
Stenting, Drainage Procedures, and Antibiotics......Page 2184
Symptomatic Cancer Pain Management......Page 2186
WORLD HEALTH ORGANIZATION ANALGESIC LADDER......Page 2187
For the Individual......Page 2190
Nonsteroidal Anti-Inflammatory Drugs......Page 2191
EFFICACY IN CANCER PAIN......Page 2192
Acetaminophen......Page 2193
Opioid-Induced Bowel Dysfunction......Page 2194
Antiemetics......Page 2198
Adjuvant Analgesics......Page 2202
GENERAL PURPOSE ADJUVANTS......Page 2203
MUSCULOSKELETAL PAIN ADJUVANTS......Page 2204
NEUROPATHIC PAIN ADJUVANTS......Page 2205
BONE PAIN ADJUVANTS......Page 2208
Psychotropic Drugs......Page 2209
Cannabinoids......Page 2210
SELECTION OF OPIOID THERAPY IN CANCER PAIN MANAGEMENT......Page 2212
TOLERANCE AND HYPERALGESIA......Page 2221
OXYCODONE......Page 2223
OXYMORPHONE......Page 2224
METHADONE......Page 2225
LEVORPHANOL......Page 2228
FENTANYL......Page 2229
Transdermal Fentanyl......Page 2230
Oral Transmucosal/Intranasal/Sublingual Fentanyl......Page 2234
Fentanyl-Associated Deaths......Page 2235
BUPRENORPHINE......Page 2236
HYDROCODONE......Page 2237
CODEINE......Page 2238
TRAMADOL......Page 2239
TAPENTADOL......Page 2240
Prevention or Minimizing Opioid-Related Side Effects......Page 2241
OPIOID EFFECTS ON COGNITION, MOTOR SKILLS, AND DRIVING ABILITY......Page 2243
OPIOID ROTATION IN CANCER PAIN......Page 2247
PARENTERAL OPIOID THERAPY......Page 2248
INTRACEREBROVENTRICULAR OPIOIDS......Page 2250
Substance Abuse in Oncology......Page 2252
Home Infusion Therapy......Page 2255
Integrative Oncology......Page 2257
Summary......Page 2259
CHAPTER 44: Interventional Pain Therapies......Page 2283
Intrathecal Drug Therapy......Page 2285
Tunneled Intrathecal Catheter......Page 2286
Implantable Drug Delivery Systems......Page 2287
INTRATHECAL VERSUS EPIDURAL DRUG DELIVERY......Page 2290
OUTCOME STUDIES......Page 2291
PATIENT-CONTROLLED INTRATHECAL ANALGESIA......Page 2293
PHARMACOLOGY......Page 2294
Ziconotide......Page 2295
Local Anesthetics......Page 2296
CONTRAINDICATIONS AND RISK MANAGEMENT......Page 2297
COMPLICATIONS AND SIDE EFFECTS......Page 2298
Spinal Chemoneurolysis......Page 2299
SPINAL CHEMONEUROLYSIS TECHNIQUE......Page 2300
Cervical and Thoracic Neurolysis......Page 2302
INDICATIONS......Page 2303
ANATOMY OF THE CELIAC PLEXUS......Page 2304
ADVERSE EFFECTS......Page 2305
Posterior Approach to the Splanchnic Nerves and Celiac Plexus......Page 2306
Anterior Approaches......Page 2308
OUTCOME STUDIES......Page 2309
INDICATIONS......Page 2310
TECHNIQUES......Page 2311
OUTCOME STUDIES......Page 2312
Ganglion of Impar Block......Page 2313
TECHNIQUE......Page 2314
Intercostal Nerve Block......Page 2315
ADVERSE EFFECTS......Page 2316
TECHNIQUE......Page 2317
OUTCOME STUDIES......Page 2319
ANATOMY OF THE TRIGEMINAL NERVE AND ITS BRANCHES......Page 2321
TECHNIQUES......Page 2323
OTHER HEAD AND NECK INTERVENTIONAL TARGETS......Page 2327
Spinal Cord Stimulation......Page 2328
Vertebral Augmentation......Page 2329
INDICATIONS......Page 2330
OUTCOMES......Page 2331
Spinal Cord Ablation......Page 2332
SURGICAL TECHNIQUES......Page 2333
COMPLICATIONS......Page 2335
PERCUTANEOUS RADIOFREQUENCY LESIONING......Page 2336
OPEN LIMITED MYELOTOMY......Page 2337
COMPLICATIONS......Page 2338
IMAGE-GUIDED ABLATION OF PAINFUL BONE METASTASES......Page 2339
Summary......Page 2340
CHAPTER 45: Pain Caused by Cancer of the Head and Neck and Oral and Oropharynx......Page 2347
TUMOR-INDUCED ALGESIA......Page 2348
Pain Mechanisms Due to Chemotherapy and/or Radiotherapy......Page 2351
Pain Due to Surgery......Page 2352
EPIDEMIOLOGY......Page 2353
PATHOGENESIS......Page 2355
HEMATOPOIETIC CELL TRANSPLANTATION......Page 2357
HEAD AND NECK RADIATION THERAPY......Page 2358
COMBINED RADIATION THERAPY, SURGERY, AND/OR CHEMOTHERAPY......Page 2361
Management of Oral Mucositis......Page 2362
BLAND ORAL RINSES......Page 2364
TOPICAL ANTIMICROBIALS......Page 2365
SYSTEMIC ANALGESICS......Page 2366
ANTI-INFECTIVE APPROACHES......Page 2367
Hyposalivation......Page 2368
COGNITIVE AND BEHAVIORAL INTERVENTIONS......Page 2369
Conclusion......Page 2370
Epidemiology Review......Page 2382
PATHOPHYSIOLOGY......Page 2384
18F-FDG-PET-CT......Page 2387
TREATMENT......Page 2388
CYCLOOXYGENASE-2-SPECIFIC INHIBITORS......Page 2389
BISPHOSPHONATES......Page 2390
OPIOIDS/OPIATE ANTAGONISTS......Page 2392
HORMONAL THERAPY......Page 2393
PROCEDURAL INTERVENTIONS......Page 2394
Percutaneous Vertebroplasty/Kyphoplasty......Page 2395
GRANULOCYTE COLONY-STIMULATING FACTOR RELATED PAIN......Page 2396
Conclusion......Page 2397
Epidemiology Review......Page 2402
ANATOMY AND PHYSIOLOGY......Page 2403
SENSITIZATION......Page 2407
LOCALIZATION......Page 2408
VISCERAL AFFERENTATION......Page 2410
ASCENDING PATHWAYS......Page 2411
Paraneoplastic Pemphigus......Page 2412
Pleura......Page 2413
Midline Retroperitoneal Syndrome......Page 2414
Hepatic Distension Syndrome......Page 2415
Peritoneal Carcinomatosis......Page 2416
Malignant Perineal Pain......Page 2417
Tumor-Related Gynecomastia......Page 2418
Vascular Obstruction......Page 2419
Superior Vena Cava Obstruction......Page 2420
COMPLEX VISCERAL PAIN SYNDROMES......Page 2421
Burning Perineum Syndrome......Page 2422
Treatment......Page 2423
SHORT INTERFERING RNA THERAPEUTICS......Page 2424
T-TYPE CALCIUM CHANNEL ANTAGONISTS......Page 2425
P38 KINASE INHIBITORS......Page 2426
P2X PURINOCEPTOR 3 ANTAGONISTS......Page 2427
Cebranopadol......Page 2429
Thoracic Sympathetic Ganglion Block......Page 2430
Interpleural Catheters......Page 2431
Surgery......Page 2432
Hypophysectomy and Cancer Pain......Page 2434
Conclusion......Page 2435
Introduction......Page 2442
BONE DISEASE......Page 2449
CLINICAL APPLICATIONS OF RADIATION THERAPY......Page 2450
TRACHEA, BRONCHI, AND LUNGS......Page 2452
PELVIS......Page 2453
BRAIN METASTASES......Page 2455
Bone Metastases......Page 2456
Single-Fraction Radiation......Page 2459
Stereotactic Radiation for Nonspine Bone Metastases......Page 2462
Reirradiation......Page 2463
Pathologic Fracture......Page 2465
Spinal Cord Compression......Page 2468
RADIATION TOLERANCE OF THE SPINAL CORD......Page 2477
CLINICAL MANAGEMENT......Page 2478
Treatment of Diffuse Bone Metastases......Page 2480
WIDE-FIELD RADIOTHERAPY......Page 2481
RADIOPHARMACEUTICALS......Page 2482
Role of Palliative Chemotherapy......Page 2486
PALLIATIVE CHEMOTHERAPY......Page 2491
BREAST CANCER......Page 2492
OVARIAN CANCER......Page 2494
GASTROINTESTINAL CANCERS......Page 2495
PROSTATE CANCER......Page 2496
DECISION MAKING ABOUT CHEMOTHERAPY......Page 2497
Endocrine Therapy......Page 2499
ENDOCRINE THERAPY FOR RELIEF OF CANCER PAIN......Page 2500
Summary......Page 2501
EPIDEMIOLOGY......Page 2516
Pain in Children: How Does This Differ from That in Adults?......Page 2517
INFANTS–PRESCHOOL......Page 2518
Pediatric Cancer Pain......Page 2519
EPIDEMIOLOGY OF PEDIATRIC CANCER PAIN......Page 2520
UNDERTREATMENT AND IMPACT OF PEDIATRIC CANCER PAIN......Page 2521
Evaluation of Pediatric Cancer Pain......Page 2522
HISTORY AND PHYSICAL EXAM......Page 2523
SENSORY EXPERIENCE—OBSERVATION......Page 2524
EMOTIONAL AND COGNITIVE EXPERIENCE......Page 2525
FUNCTIONAL AND QUALITY OF LIFE ASSESSMENT......Page 2526
CANCER HISTORY—DIAGNOSIS......Page 2527
CANCER HISTORY—TREATMENTS......Page 2529
PROXY REPORTS......Page 2530
INTEGRATING DATA IN EVALUATION OF THE WHOLE CHILD......Page 2531
Etiologies of Cancer Pain......Page 2532
Brain and Spinal Tumors......Page 2533
Bone Tumors......Page 2535
PROCEDURE-RELATED PAIN......Page 2536
Postlumbar Puncture Headache......Page 2539
Postoperative Pain......Page 2540
Phantom Limb Pain......Page 2541
Mucositis......Page 2542
Neuropathic Pain......Page 2545
Infection......Page 2546
Graft-versus-host Disease......Page 2547
PAIN IN SURVIVORSHIP......Page 2548
Management of Pain......Page 2549
Pharmacologic Management of Cancer-Related Pain in Children......Page 2550
Overview of Opioid Analgesia in Children......Page 2552
ADVERSE EFFECTS......Page 2553
TOLERANCE TO OPIOIDS......Page 2554
ADJUVANT THERAPIES FOR NEUROPATHIC PAIN......Page 2555
Physical and Psychological Therapies for Pain in the Pediatric Cancer Patient......Page 2556
ACUPUNCTURE......Page 2557
HYPNOTHERAPY......Page 2558
EXPRESSIVE ARTS THERAPIES......Page 2559
MASSAGE......Page 2560
BIOFEEDBACK......Page 2561
BOTANICALS......Page 2562
CANNABIS......Page 2563
SPIRITUALITY/RELIGIOSITY......Page 2564
THERAPEUTIC YOGA......Page 2565
Palliative Care for Children with Cancer......Page 2566
Summary......Page 2567
CHAPTER 50: Acute Pain Management in Children......Page 2583
Pain Assessment in Infants and Children......Page 2584
Nonopioid Analgesics......Page 2587
ACETAMINOPHEN......Page 2588
NONSTEROIDAL ANTI-INFLAMMATORY DRUGS......Page 2589
KETAMINE......Page 2592
Opioids......Page 2593
ONTOGENY OF OPIOID ACTIONS......Page 2594
CODEINE......Page 2595
OXYCODONE......Page 2596
MORPHINE......Page 2597
HYDROMORPHONE......Page 2599
METHADONE......Page 2600
FENTANYL......Page 2601
Opioid Administration in Infants and Children......Page 2603
INTERMITTENT INTRAVENOUS BOLUS DOSING......Page 2604
PATIENT-, NURSE-, AND PARENT-CONTROLLED ANALGESIA......Page 2605
TREATMENT OF OPIOID SIDE EFFECTS......Page 2607
LOCAL ANESTHETICS AND REGIONAL ANESTHESIA IN INFANTS AND CHILDREN......Page 2610
Epidural Analgesia in Infants and Children......Page 2611
DRUGS AND DRUG DOSING USED FOR EPIDURAL ANALGESIA......Page 2613
Peripheral Nerve Blocks in Children......Page 2617
INFRACLAVICULAR......Page 2619
Sciatic-Subgluteal Approach......Page 2620
Popliteal Approach......Page 2621
FEMORAL BLOCK......Page 2622
CANCER PAIN......Page 2623
CHILDREN WITH TRAUMA......Page 2626
Conclusions......Page 2627
CHAPTER 51: Acute Pain in Adults......Page 2637
Acute and Chronic Effects of Acute Pain......Page 2638
PRIMARY AFFERENTS AND PERIPHERAL NERVE NEUROTRANSMITTERS......Page 2640
SPINAL CORD AND SUPRASPINAL STRUCTURES......Page 2641
PREVENTIVE ANALGESIA......Page 2642
Treatment Methods......Page 2644
Opioids......Page 2645
Nonsteroidal Anti-inflammatory Agents......Page 2648
Excitatory Amino Acids......Page 2652
Anticonvulsants......Page 2653
α-Adrenergic Medications......Page 2654
Steroids......Page 2655
NONSELECTIVE NORADRENERGIC AND SEROTONINERGIC MEDICATIONS......Page 2656
INTRAVENOUS PATIENT-CONTROLLED ANALGESIA......Page 2658
Single-Dose Neuraxial Opioids......Page 2661
Continuous Epidural Analgesia......Page 2663
PERIPHERAL REGIONAL ANALGESIA......Page 2673
Intra-articular Analgesia......Page 2675
ENHANCED RECOVERY AFTER SURGERY PATHWAYS......Page 2676
WAR TRAUMA......Page 2677
AMBULATORY SURGICAL PATIENTS......Page 2681
ELDERLY PATIENTS......Page 2682
OPIOID-TOLERANT PATIENTS......Page 2684
OBESITY, OBSTRUCTIVE SLEEP APNEA, AND SLEEP......Page 2688
Gender or Sex Differences in Analgesia......Page 2690
Inpatient Pain Services......Page 2695
Long-term Impact of Acute Pain......Page 2696
Continuous Epidural Analgesia......Page 2714
THORACIC EPIDURAL ANALGESIA......Page 2715
BLOCK TECHNIQUE: EPIDURAL......Page 2717
TECHNIQUE......Page 2718
Opioids......Page 2720
Combined Spinal and Epidural......Page 2721
Separate Needles Techniques......Page 2722
Contraindications of Neuraxial Techniques......Page 2723
COAGULOPATHY, THROMBOCYTOPENIA, AND BLEEDING DISORDERS......Page 2724
CENTRAL NERVOUS SYSTEM DISORDERS......Page 2725
INTRODUCTION......Page 2726
PERINEURAL OPIOIDS......Page 2727
PERINEURAL CLONIDINE AND DEXMEDETOMIDINE......Page 2728
PERINEURAL DEXAMETHASONE......Page 2729
Landmark Technique......Page 2730
Ultrasound-Guided Transversus Abdominis Plane......Page 2731
ILIOHYPOGASTRIC AND ILIOINGUINAL BLOCK......Page 2732
RECTUS SHEATH BLOCK......Page 2733
Peripheral Nerve Blocks and Catheters......Page 2734
Nerve Stimulation......Page 2736
Ultrasound Guidance......Page 2737
CLINICAL EFFECTS......Page 2738
INDICATIONS......Page 2739
ULTRASOUND TECHNIQUE......Page 2740
CLINICAL EFFECTS......Page 2741
LANDMARKS......Page 2742
TECHNIQUE......Page 2743
CLINICAL EFFECTS......Page 2744
LANDMARKS......Page 2745
Ultrasound Guidance......Page 2746
ULTRASOUND TECHNIQUE......Page 2748
Axillary Nerve Block......Page 2749
INDICATIONS......Page 2750
Ultrasound Guidance......Page 2751
CLINICAL EFFECTS......Page 2754
TECHNIQUES......Page 2755
Ultrasound Technique......Page 2756
CLINICAL EFFECTS......Page 2758
INDICATIONS AND LANDMARKS......Page 2759
Landmark Technique......Page 2760
Ultrasound Guidance......Page 2762
COMPLICATIONS......Page 2763
INDICATIONS......Page 2764
Nerve Stimulator-Guided Femoral Block......Page 2765
Ultrasound Technique......Page 2766
CLINICAL EFFECTS......Page 2767
INDICATIONS......Page 2768
Ultrasound Guidance......Page 2771
Landmark Approach......Page 2772
INDICATIONS......Page 2773
Ultrasound Guidance......Page 2774
CLINICAL EFFECTS......Page 2776
INDICATIONS AND LANDMARKS......Page 2777
Ultrasound Guidance......Page 2778
Obturator Nerve......Page 2779
Landmark Technique......Page 2780
Ultrasound Guidance......Page 2781
INDICATIONS......Page 2782
Landmark Technique......Page 2783
Ultrasound Technique......Page 2787
CLINICAL EFFECTS......Page 2790
TECHNIQUES......Page 2791
Landmark Technique......Page 2792
Classic Ultrasound Technique......Page 2793
CLINICAL EFFECTS......Page 2794
INDICATIONS......Page 2795
Quadratus Lumborum 1......Page 2797
COMPLICATIONS......Page 2798
INDICATIONS......Page 2799
PECS I and PECS II......Page 2800
Serratus Anterior Plane Block......Page 2801
Complications of Peripheral Nerve Blocks......Page 2802
NEUROLOGIC COMPLICATIONS......Page 2803
NONNEUROLOGIC COMPLICATIONS......Page 2805
SUMMARY OF TREATMENT OF LOCAL ANESTHETIC SYSTEMIC TOXICITY......Page 2806
Summary......Page 2808
CHAPTER 53: Burn Pain......Page 2832
The Nature of Burn Pain......Page 2833
Psychological Factors......Page 2837
Generalized Treatment Paradigm for Burn Pain......Page 2840
OPIOIDS......Page 2845
NONOPIOIDS......Page 2847
ANESTHETICS......Page 2848
PHARMACOLOGIC OPTIONS FOR BACKGROUND PAIN MANAGEMENT......Page 2850
PHARMACOLOGIC OPTIONS FOR PROCEDURAL PAIN MANAGEMENT......Page 2851
COGNITIVE INTERVENTIONS AND COPING STYLES......Page 2852
PREPARATORY INFORMATION......Page 2854
BEHAVIORAL INTERVENTIONS......Page 2855
HYPNOSIS......Page 2858
VIRTUAL REALITY......Page 2859
Conclusion......Page 2860
ACKNOWLEDGMENT......Page 2861
Epidemiology of Chronic Pain in Children......Page 2868
MUSCULOSKELETAL PAIN......Page 2869
Nonrheumatologic Musculoskeletal Pain......Page 2870
Fibromyalgia Syndrome......Page 2871
Back Pain......Page 2872
HEADACHE......Page 2873
CHRONIC ABDOMINAL PAIN......Page 2874
Sickle Cell Disease......Page 2875
ADDITIONAL CONSIDERATIONS......Page 2876
Impact of Persistent Pain on Children and Families......Page 2877
BACKGROUND......Page 2880
HISTORY......Page 2882
MEASUREMENT OF PAIN AND FUNCTIONING......Page 2884
CLINICAL FORMULATION......Page 2889
FEEDBACK WITH THE FAMILY......Page 2890
GENERAL PRINCIPLES OF TREATMENT......Page 2892
Pharmacologic Interventions......Page 2894
Psychological Interventions......Page 2899
School and Social Reintegration......Page 2902
Sleep......Page 2905
Intensive Rehabilitation Therapy......Page 2907
MUSCULOSKELETAL PAIN......Page 2908
COMPLEX REGIONAL PAIN SYNDROMES......Page 2909
BACK PAIN......Page 2911
HEADACHE......Page 2912
FUNCTIONAL GASTROINTESTINAL PAIN......Page 2915
Barriers to Care......Page 2916
Conclusion......Page 2917
THE PREVALENCE OF PAIN IN OLDER ADULTS......Page 2933
IMPACT OF PAIN ON FUNCTIONING AND QUALITY OF LIFE......Page 2934
UNDERTREATMENT OF PAIN IN OLDER PERSONS......Page 2935
CHANGE IN PAIN PROCESSING AND MODULATION......Page 2936
CLINICAL EVALUATION OF PAIN......Page 2937
NONVERBAL, COGNITIVELY IMPAIRED OLDER ADULTS......Page 2939
PHARMACOKINETICS AND PHARMACODYNAMICS ASSOCIATED WITH AGING......Page 2940
Acetaminophen......Page 2941
Nonsteroidal Anti-inflammatory Drugs......Page 2942
Safe Nonsteroidal Anti-inflammatory Drug Product Selection and Monitoring Use......Page 2943
SAFE, EFFECTIVE USE OF OPIOIDS IN THE OLDER PERSON POTENTIAL RISKS OF OPIOID ANALGESICS......Page 2944
Potential Safety Concerns with Opioids......Page 2945
Prudent Product Selection and Use......Page 2946
SAFE, EFFECTIVE USE OF ADJUVANTS IN THE OLDER PERSON......Page 2948
INTERVENTIONAL APPROACHES......Page 2950
PHYSICAL MODALITIES......Page 2951
PSYCHOSOCIAL MODALITIES......Page 2952
COMPLEMENTARY AND INTEGRATIVE HEALTH......Page 2953
MULTIDISCIPLINARY PAIN TREATMENTS......Page 2954
Summary......Page 2955
Historical Notes......Page 2967
Pain of Childbirth......Page 2968
CHILDBIRTH PAIN MECHANISMS AND PATHWAYS......Page 2970
EFFECTS OF PAIN ON THE MOTHER AND FETUS......Page 2973
Physiologic Changes of Pregnancy......Page 2976
RESPIRATORY CHANGES......Page 2977
CARDIOVASCULAR CHANGES......Page 2978
Aortocaval Compression......Page 2979
Implications for Labor Analgesia......Page 2980
Anatomy of the Spinal Column and Analgesic Implications......Page 2981
UTEROPLACENTAL UNIT......Page 2982
Transfer of Drugs across the Placenta......Page 2983
LABOR SUPPORT......Page 2984
INTRADERMAL WATER INJECTIONS......Page 2985
Systemic Analgesia......Page 2986
PARENTERAL OPIOID ANALGESIA......Page 2987
Neuraxial Analgesia......Page 2988
EPIDURAL ANALGESIA......Page 2990
Drugs for Initiation of Epidural Analgesia......Page 2991
COMBINED SPINAL-EPIDURAL ANALGESIA......Page 2993
Drugs for Initiation of Combined Spinal-Epidural Analgesia......Page 2995
MAINTENANCE OF EPIDURAL ANALGESIA......Page 2996
Dural Puncture Epidural Analgesia......Page 2998
Hypotension......Page 2999
Maternal Hyperthermia......Page 3000
Respiratory Depression......Page 3001
LUMBAR SYMPATHETIC BLOCK......Page 3002
Effects of Analgesia on the Progress of Labor......Page 3003
Nonobstetric Drug Therapy during Pregnancy and Lactation......Page 3004
Analgesic Drugs during Pregnancy and Lactation......Page 3006
HISTORY......Page 3014
CLASSIFICATION OF SICKLE CELL SYNDROMES......Page 3016
GENOTYPES......Page 3018
Pathophysiology......Page 3019
VASO-OCCLUSION......Page 3020
CELLULAR DEHYDRATION......Page 3023
INFLAMMATION AND REPERFUSION INJURY......Page 3024
GENETIC MARKERS......Page 3025
OTHER FACTORS......Page 3027
Classification of Sickle Cell Pain Syndromes......Page 3028
THE VASCULAR OCCLUSIVE CRISIS......Page 3030
Predisposing Factors......Page 3031
Precipitating Factors......Page 3032
Phases of the Acute Vaso-occlusive Crisis......Page 3033
The Prodromal Phase......Page 3035
The Established Phase......Page 3036
The Relapsing or Postdromal Phase......Page 3037
ACUTE CHEST SYNDROME......Page 3041
ACUTE ABDOMINAL PAIN SYNDROMES......Page 3047
Right Upper Quadrant Pain Syndromes......Page 3048
Left Upper Quadrant Syndrome......Page 3052
Other Acute Abdominal Painful Episodes......Page 3054
PRIAPISM......Page 3055
AVASCULAR NECROSIS......Page 3059
LEG ULCERS......Page 3063
NEUROPATHIC PAIN......Page 3067
Management of Sickle Cell Pain......Page 3068
NONPHARMACOLOGIC MANAGEMENT OF PAIN......Page 3069
Nonopioids and Sickle Cell Disease......Page 3070
Adjuvants and Sickle Cell Disease......Page 3071
Management of Pain at Home......Page 3072
Outpatient Management of Sickle Cell Pain......Page 3073
Pain Management in the Day Unit......Page 3074
Management of Sickle Cell Pain in the Hospital......Page 3075
Specific Approaches to Treatment......Page 3077
Induction of Fetal Hemoglobin......Page 3078
Hydroxyurea......Page 3079
Hydroxyurea and the HUG Trials......Page 3080
Benefits and Side Effects of Hydroxyurea......Page 3081
Other Novel Approaches to Therapy......Page 3083
Allogeneic Hematopoietic Stem Cell Transplant......Page 3084
Gene Therapy......Page 3085
Conclusion......Page 3087
CHAPTER 58: Pain in HIV......Page 3106
Prevalence of Pain in HIV/AIDS......Page 3107
Pain in Children with HIV/AIDS......Page 3108
OROPHARYNGEAL PAIN......Page 3109
ABDOMINAL PAIN......Page 3110
Chest Pain Syndromes......Page 3112
PULMONARY/PLEURITIC PAIN......Page 3113
ARTHROPATHY......Page 3114
PERIPHERAL NEUROPATHY......Page 3115
DISTAL SYMMETRIC POLYNEUROPATHY......Page 3117
TREATMENT OF HIV-ASSOCIATED SENSORY NEUROPATHY......Page 3118
INFLAMMATORY DEMYELINATING POLYNEUROPATHY......Page 3119
PROGRESSIVE POLYRADICULOPATHY......Page 3120
PRIMARY HEADACHES......Page 3121
SECONDARY HEADACHES......Page 3125
PAIN MEASUREMENT/ASSESSMENT TOOLS......Page 3127
PHARMACOLOGIC TREATMENT......Page 3128
Nonsteroidal Anti-inflammatory Drugs......Page 3133
Opioid Analgesics......Page 3134
Antidepressant Agents......Page 3136
Anticonvulsants......Page 3138
Topical Capsaicin......Page 3139
Combination Pharmacotherapy......Page 3140
NONPHARMACOLOGIC THERAPIES......Page 3141
UNDERTREATMENT OF PAIN......Page 3142
Summary......Page 3143
CHAPTER 59: The Treatment of Chronic Pain in Patients with History of Substance Abuse......Page 3153
Principle of Balance......Page 3155
THE IMPORTANCE OF THE DEFINITIONS......Page 3156
Basic Science of the Disease of Addiction......Page 3158
BINARY CONCEPT OF PAIN AND ADDICTION......Page 3161
PAIN AND OPIOID ADDICTION—A CONTINUUM APPROACH......Page 3163
SEPARATING THE “MOTIVE” FROM “BEHAVIOR” WHEN DEALING WITH PAIN AND ADDICTION......Page 3164
OPIOIDS FOR ANALGESIA OR OPIOID-STABILIZING EFFECT?......Page 3166
Recommendations for Terminating Opioid Therapy......Page 3167
Assessment Tools......Page 3169
Universal Precautions in Pain Medicine......Page 3171
THE 10 PRINCIPLES OF UNIVERSAL PRECAUTIONS IN PAIN MEDICINE......Page 3172
PATIENT TRIAGE......Page 3176
Treating the Pain Patient on Opioid Agonist Treatment......Page 3177
The Treatment of Pain and Suffering in Our Society......Page 3179
Conclusion......Page 3181
How Communication Influences Compliance Assessment......Page 3186
Interpreting Aberrant Behavior......Page 3189
Borrowing from Tomorrow to Pay for Today......Page 3190
Avoiding Excessive Pill Loads......Page 3191
Compliance Monitoring Tips and Traps......Page 3193
Urine Drug Testing in Pain Medicine......Page 3194
WHOM TO TEST......Page 3195
TESTING STRATEGIES......Page 3196
PRESUMPTIVE VERSUS DEFINITIVE TESTING......Page 3198
LIMITATIONS OF TEST INTERPRETATION......Page 3200
Dealing with Unexpected Urine Toxicology Results......Page 3201
Decision to Terminate Opioid Therapy......Page 3202
FUTURE CONSIDERATIONS......Page 3204
General Principles......Page 3209
ANATOMY AND PHYSIOLOGY......Page 3210
SECONDARY HEADACHE......Page 3213
Clinical Features......Page 3215
Frequent Migraine......Page 3216
Principles of Management of Migraine......Page 3217
Preventive Treatments of Migraine......Page 3218
Acute Attack Therapies of Migraine......Page 3220
Medication Overuse......Page 3224
Pathophysiology......Page 3225
Cluster Headache......Page 3226
Managing Cluster Headache......Page 3229
PAROXYSMAL HEMICRANIA......Page 3231
SHORT-LASTING UNILATERAL NEURALGIFORM HEADACHE ATTACKS WITH CONJUNCTIVAL INJECTION AND TEARING OR CRANIAL AUTONOMIC ACTIVATION......Page 3232
Primary Stabbing Headache......Page 3233
Primary Exertional Headache......Page 3234
Primary Sex Headache......Page 3235
Hypnic Headache......Page 3236
Primary Thunderclap Headache......Page 3237
Hemicrania Continua......Page 3238
New Daily Persistent Headache......Page 3239
Low Cerebrospinal Fluid Volume Headache......Page 3240
Raised Cerebrospinal Fluid Pressure Headache......Page 3243
Giant Cell Arteritis......Page 3244
ACKNOWLEDGMENT......Page 3245
CHAPTER 62: Noncardiac Chest Pain......Page 3253
Epidemiology......Page 3256
Natural History......Page 3259
GASTROESOPHAGEAL REFLUX DISEASE......Page 3260
LINKED ANGINA......Page 3264
ESOPHAGEAL DYSMOTILITY......Page 3265
SUSTAINED ESOPHAGEAL CONTRACTIONS......Page 3267
ESOPHAGEAL HYPERSENSITIVITY......Page 3268
PSYCHOLOGICAL COMORBIDITY......Page 3273
CARDIOLOGY EVALUATION......Page 3276
BARIUM ESOPHAGRAM......Page 3277
UPPER ENDOSCOPY......Page 3278
AMBULATORY 24-HOUR ESOPHAGEAL pH MONITORING......Page 3280
THE WIRELESS pH SYSTEM......Page 3281
THE PROTON PUMP INHIBITOR TEST......Page 3283
MULTICHANNEL INTRALUMINAL IMPEDANCE......Page 3287
ESOPHAGEAL MANOMETRY......Page 3288
EDROPHONIUM (TENSILON) TEST......Page 3290
Sensory Testing of the Esophagus......Page 3291
ACID PERFUSION TEST (BERNSTEIN TEST)......Page 3295
ELECTRICAL STIMULATION......Page 3296
INTRALUMINAL ULTRASONOGRAPHY......Page 3297
BALLOON DISTENSION......Page 3298
ESOPHAGEAL EVOKED POTENTIALS......Page 3303
BRAIN IMAGING......Page 3304
SENSORY TESTING—PITFALLS IN STUDY DESIGN......Page 3305
PSYCHOLOGICAL EVALUATION......Page 3306
GERD-RELATED NCCP......Page 3307
NON–GERD-RELATED NCCP......Page 3310
PAIN MODULATORS......Page 3313
Serotonin Norepinephrine Reuptake Inhibitors......Page 3315
Selective Serotonin Reuptake Inhibitors......Page 3316
Adenosine Antagonists......Page 3317
Octreotide......Page 3318
ENDOSCOPIC TREATMENT AND SURGERY FOR NCCP......Page 3319
PSYCHOLOGICAL TREATMENT......Page 3321
FUTURE THERAPY......Page 3323
CHAPTER 63: Abdominal, Peritoneal, and Retroperitoneal Pain......Page 3341
Clinical Approach to Abdominal Pain......Page 3342
PAIN LOCALIZATION AND CHARACTER......Page 3343
TIME COURSE......Page 3344
CONTEXTUAL INFORMATION......Page 3345
PHYSICAL EXAMINATION......Page 3348
Mechanisms of Visceral Pain......Page 3349
VISCERAL NOCICEPTION......Page 3350
CENTRAL PROCESSING OF SOMATIC AND VISCERAL PAIN......Page 3352
SENSITIZATION AND VISCERAL HYPERSENSITIVITY......Page 3353
GENETIC FACTORS......Page 3355
ADVERSE LIFE EVENTS AND STRESS......Page 3356
PSYCHIATRIC DISEASES......Page 3357
Biomarkers of Abdominal Pain......Page 3358
LIFESTYLE MODIFICATIONS......Page 3360
PLACEBO RESPONSE......Page 3362
OPIOIDS......Page 3363
NONOPIOID ANALGESICS......Page 3364
ANTIDEPRESSANTS......Page 3365
PSYCHOLOGICAL THERAPIES......Page 3366
BLOCKING AFFERENT PATHWAYS......Page 3367
SMOOTH MUSCLE RELAXANTS......Page 3369
ALTERING THE MICROBIOME......Page 3370
SEROTONIN......Page 3371
COMPLEMENTARY AND ALTERNATIVE MEDICINE THERAPY......Page 3372
Conclusion......Page 3374
CHAPTER 64: Pelvic Pain in Females......Page 3392
INTRODUCTION......Page 3393
OVERVIEW OF ASSESSMENT......Page 3394
Pelvic Inflammatory Disease......Page 3395
Adnexal Pathology......Page 3397
Acute Exacerbation of Chronic Pelvic Pain......Page 3398
COMPLICATIONS SPECIFIC TO PREGNANCY......Page 3399
Ectopic Pregnancy......Page 3400
Miscarriage......Page 3401
Fibroid Degeneration......Page 3402
Urinary Retention and Uterine Incarceration......Page 3403
Ovarian Hyperstimulation Syndrome......Page 3404
Dysmenorrhea......Page 3406
NONSTEROIDAL ANTI-INFLAMMATORY DRUGS......Page 3407
SURGICAL TREATMENTS......Page 3408
Mittelschmerz......Page 3409
Abuse......Page 3410
Personality......Page 3411
History......Page 3412
Investigations......Page 3413
Therapeutic Trial......Page 3414
Empirical Treatment......Page 3415
Endometriosis......Page 3416
Adenomyosis......Page 3420
Adhesions......Page 3421
Pelvic Venous Congestion......Page 3422
Constipation......Page 3423
Interstitial Cystitis/Bladder Pain Syndrome......Page 3424
MUSCULOSKELETAL FACTORS IN CHRONIC PELVIC PAIN......Page 3425
Pelvic Floor Abnormalities......Page 3426
Sacroiliac Joint Pain......Page 3427
Pudendal Neuropathy......Page 3428
Neuropathy Secondary to a Pfannenstiel Incision......Page 3429
OVERVIEW......Page 3430
Vaginismus......Page 3432
Vulval Pain Syndromes......Page 3433
Conclusion......Page 3436
CHAPTER 65: Pelvic Pain in Males......Page 3445
Taxonomy and Phenotyping Chronic Pelvic Pain......Page 3446
PELVIC PAIN SYNDROMES AND NONPELVIC PAIN SYNDROMES......Page 3447
Male Urogenital Pain Syndromes......Page 3449
SUBCLASSIFICATION OF THE PELVIC PAIN SYNDROMES BY ORGAN......Page 3450
THE IMPORTANCE OF TAXONOMY AND PHENOTYPING......Page 3451
Prostate Pain Syndrome......Page 3452
Penile Pain Syndrome......Page 3453
PRECIPITATING FACTORS......Page 3454
DIFFERENCES BETWEEN VISCERAL AND NONVISCERAL SOMATIC PAINS......Page 3455
CENTRAL MECHANISMS......Page 3457
Pelvic Muscle Pain Syndromes......Page 3458
Spinal and Abdominal Muscle Pain Syndromes......Page 3460
Peripheral Nerve Pain Syndromes......Page 3461
Functional Problems and Male Pelvic Pain......Page 3464
Psychological Consequences of Male Pelvic Pain......Page 3465
Prostate Pain Syndrome......Page 3466
Scrotal/Testicular/Epididymal Pain Syndromes......Page 3468
Psychology and Sexual Counseling......Page 3469
Surgery......Page 3470
Neuromodulation......Page 3471
Overview and Conclusion......Page 3472
CHAPTER 66: Cranial Neuralgias......Page 3480
HISTORY......Page 3482
EPIDEMIOLOGY......Page 3485
ETIOLOGY AND PATHOPHYSIOLOGY......Page 3486
SYMPTOMS AND SIGNS......Page 3488
DIFFERENTIAL DIAGNOSIS......Page 3491
Treatment—Medical Management......Page 3496
Treatment—Nerve and Neurolytic Blockade......Page 3500
Treatment—Surgical......Page 3502
MULTIPLE SCLEROSIS......Page 3507
NEOPLASM......Page 3508
Epidemiology......Page 3510
Symptoms and Signs......Page 3511
Treatment......Page 3512
Nervus Intermedius Neuralgia......Page 3514
SYMPTOMS AND SIGNS......Page 3516
Glossopharyngeal Neuralgia......Page 3517
DIAGNOSIS......Page 3519
Vagal Neuralgia......Page 3520
SYMPTOMS AND SIGNS......Page 3521
Other Terminal Branch Neuralgias......Page 3522
DIAGNOSIS......Page 3524
Conclusion......Page 3525
CHAPTER 67: Facial Pain......Page 3538
TRIGEMINAL NEUROPATHY......Page 3539
Trigeminal Neuralgia Type 2......Page 3540
Neuropathic Trigeminal Neuralgia......Page 3541
GLOSSOPHARYNGEAL NEURALGIA......Page 3542
NERVUS INTERMEDIUS NEURALGIA......Page 3543
ODONTOGENIC PAIN......Page 3544
Dental Findings......Page 3546
Radiographic Examination......Page 3549
TEMPOROMANDIBULAR DISORDERS......Page 3550
Migraine Headache......Page 3554
Tension Headache......Page 3556
Cluster Headache......Page 3557
Exertional Headache......Page 3558
MEDICATION OVERUSE HEADACHE......Page 3559
SINUS HEADACHES......Page 3560
SHORT-LASTING, UNILATERAL, NEURALGIFORM HEADACHE ATTACKS WITH CONJUNCTIVAL INJECTION AND TEARING......Page 3561
PAROXYSMAL HEMICRANIAS......Page 3562
CONTACT POINT HEADACHE......Page 3563
CHAPTER 68: Neck and Arm Pain......Page 3568
CERVICAL SPINE......Page 3569
Ligaments of the Cervical Spine......Page 3576
MUSCULATURE OF THE NECK......Page 3578
THE VERTEBRAL CANAL......Page 3579
VERTEBRAL ARTERIES......Page 3582
CERVICAL NERVES......Page 3583
THE CERVICAL AND BRACHIAL PLEXUS......Page 3586
PECTORAL GIRDLE AND SHOULDER ANATOMY......Page 3601
Epidemiology of Neck and Arm Pain......Page 3609
HISTORY AND PHYSICAL EXAMINATION......Page 3611
Location/Radiation......Page 3612
Onset......Page 3614
Associated Symptoms......Page 3615
Age and Psychosocial History......Page 3616
Past Medical History and Review of Systems......Page 3617
Surgical History......Page 3618
Physical Examination......Page 3619
LABORATORY EVALUATION......Page 3638
RADIOGRAPHIC STUDIES......Page 3639
Cervical Spondylosis and Radiculopathy......Page 3642
Cervicogenic Headache......Page 3648
DIFFUSE IDIOPATHIC SKELETAL HYPEROSTOSIS......Page 3652
CERVICAL RADICULOPATHIES......Page 3653
UPPER EXTREMITY PERIPHERAL NERVE ENTRAPMENT SYNDROMES AND BRACHIAL PLEXUS NEUROPATHY......Page 3659
Carpal Tunnel Syndrome......Page 3661
Cubital Tunnel Syndrome......Page 3662
LESIONS OF THE BRACHIAL PLEXUS......Page 3664
Acute Brachial Plexus Neuritis......Page 3665
Thoracic Outlet Syndrome......Page 3667
General Considerations......Page 3679
SKELETAL STRUCTURES OF THE CHEST WALL......Page 3680
Thoracic Spine......Page 3681
Sternum......Page 3683
INTERCOSTAL SPACES......Page 3684
INTERCOSTAL NERVES......Page 3685
Neoplastic Chest Wall Pain......Page 3686
SUPERIOR VENA CAVA SYNDROME......Page 3687
COSTOPLEURAL SYNDROME......Page 3688
NEUROPATHIC PAIN......Page 3689
Neuropathic Pain of Central Origin......Page 3690
Peripheral Neuropathic Chest Wall Pain......Page 3691
Abnormalities of the Thoracic Spine......Page 3695
Chest Wall Pain of Sternal Origin......Page 3703
Chest Wall Pain of Myofascial Origin......Page 3704
Breast Pain......Page 3705
Postsurgical Chest Wall Pain......Page 3706
CHEST PAIN AND PSYCHOLOGICAL FACTORS......Page 3709
Conclusion......Page 3710
Lumbosacral Plexopathy......Page 3750
NEOPLASMS......Page 3753
RADIATION-INDUCED PLEXOPATHY......Page 3755
ABSCESS......Page 3756
ANEURYSMS......Page 3757
OBSTETRIC-RELATED PLEXOPATHY......Page 3758
LATERAL FEMORAL CUTANEOUS NERVE ENTRAPMENT......Page 3759
Symptoms and Signs......Page 3761
Diagnosis......Page 3762
Treatment......Page 3763
FEMORAL NERVE ENTRAPMENT......Page 3764
Etiology......Page 3766
Diagnosis......Page 3767
Treatment......Page 3768
SAPHENOUS NERVE ENTRAPMENT......Page 3769
Etiology......Page 3770
Diagnosis......Page 3771
OBTURATOR NERVE ENTRAPMENT......Page 3772
Etiology......Page 3773
Symptoms and Signs......Page 3774
Treatment......Page 3775
SCIATIC NERVE ENTRAPMENT......Page 3776
Etiology......Page 3778
Symptoms and Signs......Page 3779
Treatment......Page 3781
FIBULAR (PERONEAL) NERVE ENTRAPMENT......Page 3782
Etiology......Page 3784
Symptoms and Signs......Page 3785
Treatment......Page 3786
Etiology......Page 3787
Etiology......Page 3788
Diagnosis and Treatment......Page 3789
Diagnosis and Treatment......Page 3790
Symptoms and Signs......Page 3791
Etiology......Page 3792
Diagnosis......Page 3793
Etiology......Page 3794
Etiology......Page 3795
Symptoms and Signs......Page 3796
Symptoms and Signs......Page 3797
Etiology......Page 3798
Diagnosis......Page 3799
Etiology......Page 3800
Treatment......Page 3801
Etiology and Pathophysiology......Page 3802
Symptoms and Signs......Page 3803
Treatment......Page 3804
Symptoms and Signs......Page 3805
Diagnosis......Page 3806
Treatment......Page 3808
Treatment......Page 3809
Treatment......Page 3810
Treatment......Page 3811
Definition......Page 3820
Referred Pain......Page 3821
CERVICOGENIC HEADACHE......Page 3823
Pursuing Diagnosis......Page 3824
TRAUMA......Page 3825
ACUTE NECK PAIN......Page 3826
Serious Conditions......Page 3827
Inflammatory Disorders......Page 3828
Spurious Conditions......Page 3829
CHRONIC NECK PAIN......Page 3830
Cervical Disk Stimulation......Page 3831
Medial Branch Blocks......Page 3833
WHIPLASH......Page 3834
Clinical Features......Page 3835
Diagnosis......Page 3837
Diagnosis......Page 3838
Minimally Invasive Tests......Page 3839
Prevalence......Page 3841
Conservative Therapy......Page 3842
Injections......Page 3843
Interventional Pain Medicine......Page 3844
CERVICOGENIC HEADACHE......Page 3846
Summary......Page 3849
DEFINITION......Page 3859
REFERRED PAIN......Page 3860
CAUSES......Page 3862
Management Algorithm......Page 3864
TRIAGE......Page 3866
Medical History......Page 3868
Psychological and Social History......Page 3875
Physical Examination......Page 3876
Other Examination......Page 3877
Ancillary Investigations......Page 3878
Formulation......Page 3880
INITIAL MANAGEMENT......Page 3881
Pain......Page 3882
REVIEW......Page 3890
Yellow Flags......Page 3891
Discussion......Page 3893
Conclusion......Page 3894
Introduction......Page 3900
REFERRED PAIN......Page 3901
Lumbar Intervertebral Disks......Page 3903
PREVALENCE......Page 3904
ACCEPTED CAUSES......Page 3907
Assessment......Page 3908
MEDICAL HISTORY......Page 3911
PHYSICAL EXAMINATION......Page 3917
REVIEW OF PREVIOUS INVESTIGATIONS......Page 3919
Provisional Diagnosis......Page 3920
CLEARANCE......Page 3922
NOT INDICATED......Page 3923
MAGNETIC RESONANCE IMAGING......Page 3924
DISK STIMULATION......Page 3926
SINUVERTEBRAL NERVE BLOCKS......Page 3928
LUMBAR MEDIAL BRANCH BLOCKS......Page 3929
SACROILIAC JOINT BLOCKS......Page 3930
SACRAL LATERAL BRANCH BLOCKS......Page 3932
Treatment......Page 3933
Paracetamol (Acetaminophen)......Page 3934
Antidepressants......Page 3935
Massage......Page 3936
McKenzie Therapy......Page 3937
Exercise Therapy......Page 3938
Acupuncture......Page 3939
BACK SCHOOL......Page 3940
MULTIDISCIPLINARY PAIN MANAGEMENT......Page 3941
FUNCTIONAL RESTORATION......Page 3944
Discogenic Pain......Page 3945
Zygapophysial Joint Pain......Page 3948
Sacroiliac Pain......Page 3952
Spinal Surgery......Page 3956
Conclusion......Page 3957
CHAPTER 74: Surgery for Low Back Pain......Page 3971
Rationale......Page 3972
BEFORE EVIDENCE-BASED MEDICINE......Page 3973
ADVENT OF EVIDENCE-BASED MEDICINE......Page 3975
SINCE EVIDENCE-BASED MEDICINE......Page 3978
Discussion......Page 3980
CHAPTER 75: Failed Back Surgery......Page 3984
MISMATCH: SURGERY NEEDED VERSUS SURGERY PERFORMED (“WRONG SURGERY”)......Page 3985
INCOMPLETE EVALUATION AND/OR DIAGNOSIS (“RESIDUAL PATHOLOGY”)......Page 3987
COMPLICATIONS......Page 3988
Extraspinal Pathology......Page 3989
Structural Etiologies of Failed Back Surgery......Page 3991
FORAMINAL STENOSIS......Page 3993
PAINFUL DISK (DISCOGENIC PAIN)......Page 3994
FACET JOINT PAIN......Page 3995
SPINAL STENOSIS AND AXIAL LOW BACK PAIN......Page 3996
NEUROPATHIC PAIN......Page 3997
DECONDITIONING......Page 3998
Psychological Factors in Failed Back Surgery (“Right Patient”)......Page 3999
ROLE OF THE HISTORY......Page 4001
Response to Mechanical Changes......Page 4002
Pain Improves but Recurs 1 to 6 Months after Surgery......Page 4003
ROLE OF RADIOLOGIC EVALUATION OF FAILED BACK SURGERY......Page 4004
Treatments......Page 4005
Rehabilitation and Exercise......Page 4006
Medications......Page 4007
Sacroiliac Joint Pain......Page 4008
Lysis of Adhesions......Page 4009
Reoperation......Page 4010
Introduction......Page 4017
SPINAL SURGERY......Page 4019
SPINAL CORD STIMULATION AND INTRATHECAL DRUG DELIVERY SYSTEMS......Page 4021
AFFECTIVE DISORDERS AS PREDICTORS OF OUTCOME......Page 4023
SOMATIZATION......Page 4026
PAIN SENSITIVITY......Page 4027
ANGER......Page 4028
Cognitive Factors......Page 4029
COPING STRATEGIES......Page 4030
Behavioral Factors......Page 4031
SUBSTANCE ABUSE......Page 4032
COMPONENTS OF PSYCHOLOGICAL EVALUATIONS......Page 4033
Pain Intensity Measures......Page 4036
Mood and Personality......Page 4038
Functional Capacity and Activity Interference Measures......Page 4039
Pain Beliefs......Page 4040
ELECTRONIC PAIN ASSESSMENT PROGRAMS......Page 4042
Conclusion......Page 4043
CHAPTER 77: Rational Pharmacotherapy for Pain......Page 4056
Drugs Are Both Underused and Overused in Pain Management......Page 4057
Pharmacotherapy Alone Is Rarely Optimal Therapy for Chronic Pain......Page 4058
EVERY USE OF MEDICATION FOR PAIN IS AN EXPERIMENT......Page 4059
PATIENT PREFERENCE: SYMPTOM CONTROL VERSUS SIDE EFFECTS......Page 4060
SYNERGISM AND POTENTIATION......Page 4061
OUTCOMES ANALYSES OF PAIN PHARMACOTHERAPY......Page 4062
APPROVED DRUGS AND DRUGS FOR NONAPPROVED USES......Page 4064
RATIONAL PHARMACOTHERAPY......Page 4066
Conclusion......Page 4067
CHAPTER 78: Nonsteroidal Anti-inflammatory Drugs and Acetaminophen......Page 4069
CENTRAL SITES OF ACTION......Page 4073
COX-1 AND COX-2 SELECTIVITY......Page 4074
Induction of COX-2......Page 4076
Oral......Page 4077
Topical......Page 4078
DISTRIBUTION......Page 4081
Renal Failure......Page 4082
Specific Drugs......Page 4083
Indomethacin......Page 4084
Tolmetin and Etodolac......Page 4085
Ketorolac......Page 4086
Diclofenac......Page 4088
Ibuprofen......Page 4089
Naproxen......Page 4090
Oxaprozin......Page 4091
Meloxicam......Page 4092
Celecoxib......Page 4093
Valdecoxib and Parecoxib......Page 4094
ACETAMINOPHEN......Page 4095
NSAID Combination Medications......Page 4097
Cardiovascular Effects......Page 4099
Allergy and Hypersensitivity......Page 4102
Gastrointestinal Toxicity......Page 4103
Hematologic Effects......Page 4105
Renal Toxicity......Page 4107
Hepatic Toxicity......Page 4108
Surgical Complications......Page 4109
DEDICATION......Page 4110
CHAPTER 79: Opioid Analgesics......Page 4120
Classification Based on Interactions with an Opioid Receptor......Page 4121
Classification Based on Opioid Agonist or Antagonist Activity......Page 4128
The Pharmacodynamic Effects of Opioids......Page 4129
ANALGESIA......Page 4130
MOOD EFFECTS......Page 4131
NAUSEA AND VOMITING......Page 4132
RESPIRATORY DEPRESSION......Page 4133
HYPOTHALAMIC EFFECTS......Page 4135
OPIOID TOLERANCE, DEPENDENCE, AND ADDICTION......Page 4136
Clinically Observable Tolerance......Page 4137
Proposed Mechanisms of Tolerance......Page 4138
THE OPIOID-DEPENDENT PATIENT......Page 4142
PERIPHERAL EFFECTS OF OPIOIDS......Page 4144
EFFECTS ON SMOOTH MUSCLE AND THE CARDIOVASCULAR SYSTEM......Page 4145
OPIOID EFFECTS IN PREGNANCY AND ON THE NEONATE......Page 4146
ROUTES FOR OPIOID ADMINISTRATION......Page 4147
SUBLINGUAL ADMINISTRATION......Page 4149
EPIDURAL, INTRATHECAL, AND INTRAVENTRICULAR ADMINISTRATION......Page 4152
MORPHINE......Page 4154
METHADONE......Page 4156
OXYCODONE......Page 4158
FENTANYL......Page 4159
CODEINE......Page 4160
TRAMADOL......Page 4161
PENTAZOCINE, NALBUPHINE, AND BUTORPHANOL......Page 4162
BUPRENORPHINE......Page 4163
Abuse-Deterrent Opioid Formulations......Page 4168
Conclusions and Insights into the Future of Opioids for Pain......Page 4171
DEDICATION......Page 4172
Skeletal Muscle Relaxants......Page 4178
MECHANISM OF ACTION......Page 4182
Methocarbamol......Page 4184
Cyclobenzaprine......Page 4185
Tizanidine......Page 4187
Acute Low Back Pain......Page 4188
Chronic Low Back Pain......Page 4189
Topical Analgesic Balms......Page 4190
TOPICAL COUNTERIRRITANTS......Page 4192
Conclusion......Page 4193
CHAPTER 81: Neuropathic Pain Pharmacotherapy......Page 4197
Antidepressants......Page 4199
TRICYCLIC ANTIDEPRESSANTS......Page 4201
SELECTIVE SEROTONIN AND NOREPINEPHRINE REUPTAKE INHIBITORS......Page 4205
Antiepileptics......Page 4206
GABAPENTIN......Page 4213
CARBAMAZEPINE......Page 4214
OXCARBAZEPINE......Page 4215
VALPROATE......Page 4216
Opioids......Page 4217
Tramadol......Page 4220
NMDA Receptor Antagonists......Page 4221
Systemic Sodium Channel Blockers......Page 4224
Nonsteroidal Anti-inflammatory Agents......Page 4225
CAPSAICIN......Page 4226
TOPICAL LIDOCAINE PATCHES......Page 4227
TOPICAL KETAMINE......Page 4229
Cannabinoids......Page 4230
Drug Combinations......Page 4234
Future Drugs......Page 4239
Evidence-Based Recommendations for Drug Therapy in Neuropathic Pain......Page 4240
Intrathecal Drugs for Neuropathic Pain......Page 4241
Neuropathic Pain—Not Only Pharmacotherapy......Page 4242
MOLECULAR STRUCTURE......Page 4260
CHIRALITY......Page 4261
ACID–BASE BALANCE......Page 4262
LIPOPHILIC–HYDROPHILIC BALANCE......Page 4263
PHARMACODYNAMICS......Page 4264
Absorption......Page 4265
Effects of Disease States on Local Anesthetic Pharmacokinetics......Page 4267
DIFFERENTIAL BLOCKADE......Page 4268
Neuraxial Anesthesia......Page 4269
Intravenous Regional Anesthesia......Page 4271
Topical Anesthesia......Page 4272
POTENCY, ONSET, AND DURATION......Page 4273
pH ADJUSTMENT OF LOCAL ANESTHETICS......Page 4274
MIXTURES OF LOCAL ANESTHETICS......Page 4275
SPECIAL STATES: PREGNANCY......Page 4276
INTRAVENOUS LIDOCAINE FOR ACUTE POSTOPERATIVE PAIN......Page 4277
INTRAVENOUS LIDOCAINE FOR CHRONIC NEUROPATHIC PAIN......Page 4278
SYSTEMIC TOXICITY......Page 4280
ALLERGIES......Page 4281
Prolonged-Duration Local Anesthetics......Page 4282
Cultural Background......Page 4289
Psychoanalytic Background......Page 4290
PHYSIOLOGIC MECHANISMS IN ANGER AND PAIN RESEARCH......Page 4295
PSYCHOLOGICAL CONSTRUCTS IN ANGER AND PAIN RESEARCH......Page 4299
ANGER MANAGEMENT STYLE......Page 4301
Anger-In......Page 4303
Anger-Out......Page 4305
Opioid Deficit Hypothesis and the Role of Endogenous Opioid Functioning......Page 4307
Measurement of Anger......Page 4309
STATE-TRAIT ANGER EXPRESSION INVENTORY-2......Page 4311
MULTIDIMENSIONAL ANGER INVENTORY......Page 4312
NOVACO ANGER SCALE AND PROVOCATION INVENTORY......Page 4313
Psychotherapeutic Management......Page 4314
CONSIDERATIONS IN THE SELECTION OF PSYCHOTHERAPY......Page 4317
BEHAVIORAL AND COGNITIVE-BEHAVIORAL THERAPIES......Page 4319
Summary......Page 4322
Introduction......Page 4331
HISTORY AND DEVELOPMENT OF COGNITIVE-BEHAVIORAL THERAPY FOR PAIN......Page 4332
EVIDENCE FOR COGNITIVE-BEHAVIORAL THERAPY FOR CHRONIC PAIN......Page 4333
Components of Cognitive-Behavioral Therapy for Chronic Pain......Page 4334
CHRONIC PAIN PSYCHOEDUCATION......Page 4335
Resetting Expectations about the Outcomes of Chronic Pain—the A-B-C Model......Page 4336
RELAXATION TECHNIQUES......Page 4338
BEHAVIORAL ACTIVATION AND TIME-BASED PACING......Page 4341
SLEEP HYGIENE......Page 4343
COGNITIVE RESTRUCTURING......Page 4344
COMMUNICATION SKILLS......Page 4346
Maintaining Treatment Gains......Page 4347
THIRD-WAVE THERAPIES—ACCEPTANCE AND COMMITMENT THERAPY......Page 4349
Depression and Anxiety......Page 4350
Posttraumatic Stress Disorder......Page 4351
Effectiveness of Interprofessional Pain Management Programs and Pain Rehabilitation Programs......Page 4352
COGNITIVE-BEHAVIORAL THERAPY TO PREVENT THE TRANSITION FROM ACUTE TO CHRONIC PAIN......Page 4353
Summary......Page 4354
Prevalence of Anxiety and Depressive Disorders in Chronic Pain......Page 4360
Impact of Anxiety and Depressive Disorders on Functioning......Page 4362
The Interaction of Anxiety, Depression, and Chronic Pain......Page 4365
THE FEAR-AVOIDANCE MODEL......Page 4366
A Contextual Behavioral Approach to Anxiety and Depressive Disorders......Page 4367
EVIDENCE FROM PHARMACOLOGIC APPROACHES......Page 4369
EVIDENCE FROM PSYCHOLOGICAL APPROACHES......Page 4371
COGNITIVE-BEHAVIORAL THERAPY FOR CHRONIC PAIN: EFFECTS ON DEPRESSION AND ANXIETY......Page 4372
Developments in Cognitive Behavioral Therapy......Page 4373
Summary......Page 4376
History of Hypnosis in Pain and Symptom Control......Page 4383
Hypnosis by Definition......Page 4386
CONSCIOUS, UNCONSCIOUS, AND CONTENT OF CONSCIOUSNESS......Page 4387
CENTRAL MECHANISMS OF HYPNOSIS......Page 4389
HIGH AND LOW HYPNOTIZABILITY......Page 4390
CENTRAL MECHANISMS OF HYPNOTIC ANALGESIA......Page 4391
Pain as a Plastic Experience......Page 4394
Testing Hypnotizability......Page 4396
Current Research and Applications of Medical Hypnosis for Pain......Page 4398
EFFICACY AND EFFECTIVENESS......Page 4400
REVIEW OF RESEARCH STUDIES ACCORDING TO PAIN PROBLEMS OR SITUATIONS......Page 4403
Perioperative and Procedural Uses......Page 4404
Complex Regional Pain Syndrome......Page 4406
Phantom Limb Pain......Page 4407
Burns......Page 4409
Dentistry......Page 4410
Pediatric Pain......Page 4412
Irritable Bowel Syndrome......Page 4414
Headaches......Page 4415
Cancer......Page 4416
PRINCIPLES OF PREPARATION, INDUCTION, AND SUGGESTIONS......Page 4418
COMMON INDUCTION PROCEDURES......Page 4421
SUGGESTIONS AND IMAGERY......Page 4423
Chronic Pain Management......Page 4426
ERICKSONIAN NATURALISTIC APPROACHES TO PAIN AND SYMPTOM MANAGEMENT......Page 4429
Conclusions......Page 4431
CHAPTER 87: Group Therapy for Chronic Pain......Page 4441
GROUP VERSUS INDIVIDUAL TREATMENT......Page 4442
GROUP COGNITIVE-BEHAVIORAL THERAPY VERSUS WAIT-LIST, TREATMENT AS USUAL, OR OTHER GROUP TREATMENTS......Page 4447
BEHAVIORAL VERSUS EXERCISE AND PHYSICAL THERAPY GROUP TREATMENTS......Page 4467
MINDFULNESS-BASED APPROACHES TO PAIN MANAGEMENT......Page 4468
ACCEPTANCE-BASED APPROACHES TO PAIN MANAGEMENT......Page 4473
Factors Affecting Psychotherapeutic Outcome......Page 4476
THE IMPORTANCE OF COGNITIVE CHANGE......Page 4477
COMPLIANCE WITH HOMEWORK AND SKILLS PRACTICE TO MAINTAIN TREATMENT GAINS......Page 4479
IMPORTANCE OF THERAPIST SKILL AND ADEQUATE TIME WITH THERAPIST......Page 4480
IMPORTANCE OF GROUP PROCESS......Page 4481
EFFICIENCY AND COST-EFFECTIVENESS......Page 4482
VICARIOUS LEARNING AND MODELING OF COLLABORATIVE APPROACH......Page 4483
INTERPERSONAL GROUP PROCESS......Page 4484
LENGTH OF GROUP......Page 4485
NUMBER OF PARTICIPANTS......Page 4486
Summary and Conclusions......Page 4487
Future Directions......Page 4488
Appendix 87.1: Search Strategies......Page 4490
CHAPTER 88: Motivating Chronic Pain Patients for Behavioral Change......Page 4500
Neural Mechanisms of Motivation......Page 4502
Concept of Readiness to Change: Transtheoretical Model of Behavior Change......Page 4503
MOTIVATION ENHANCEMENT THERAPY......Page 4507
Help Patients Recognize the Problems and Goals......Page 4508
DECISIONAL BALANCE......Page 4510
SELF-MOTIVATIONAL STATEMENTS......Page 4511
What Not to Do in Motivation Enhancement Therapy......Page 4513
Dealing with Setbacks and Resistance......Page 4514
SIMPLE REFLECTION......Page 4515
DOUBLE-SIDED REFLECTION......Page 4516
PERSONAL CHOICE AND CONTROL......Page 4517
Research Outcomes......Page 4518
Volitional Approach: Implementation Intentions......Page 4520
IMPLEMENTATION INTENTIONS: OUTCOMES......Page 4522
Conclusion......Page 4523
CHAPTER 89: Basic Concepts in Biomechanics and Musculoskeletal Rehabilitation......Page 4529
KINETIC CHAIN THEORY......Page 4530
ADVERSE NEURAL TENSION......Page 4532
Lower Limb......Page 4534
Upper Limb......Page 4535
NEUROMUSCULAR CONTROL......Page 4537
BIOMECHANICAL CONSIDERATIONS IN THE SETTING OF COMMON PHYSICAL EXAMINATION TECHNIQUES......Page 4538
ENDURANCE......Page 4541
Biomechanical Considerations in Common Musculoskeletal Pain Syndromes......Page 4542
CERVICALGIA......Page 4543
PERISCAPULAR AND THORACIC PAIN......Page 4545
LUMBAR PAIN......Page 4549
SACROILIAC AND HIP GIRDLE PAIN......Page 4551
Conclusion......Page 4555
HISTORY OF PAIN REHABILITATION......Page 4560
HISTORY OF FUNCTIONAL RESTORATION AND WORK REHABILITATION......Page 4562
WHAT IS PAIN REHABILITATION?......Page 4563
STAKEHOLDERS IN REHABILITATION......Page 4564
BIOPSYCHOSOCIAL APPROACH VERSUS BIOMEDICAL MODEL FOR PAIN MANAGEMENT......Page 4566
Acute Rehabilitation......Page 4569
More Comprehensive Team Models: A Pain Continuum......Page 4570
Multidisciplinary Treatment......Page 4571
Interdisciplinary Treatment......Page 4572
Outcomes of Multi- and Interdisciplinary Treatment Programs......Page 4573
CASE MANAGEMENT......Page 4574
APPLYING TEAM VALUES......Page 4576
PAIN REHABILITATION PRINCIPLES......Page 4577
Rehabilitation Specialists: Activities and Conceptual Models......Page 4578
THE THERAPIST’S ROLE: BUILDING AN EFFECTIVE THERAPEUTIC RELATIONSHIP......Page 4579
INCORPORATING BEHAVIORAL APPROACHES IN PAIN REHABILITATION......Page 4580
PHYSICAL THERAPY......Page 4581
THERAPEUTIC EXERCISE......Page 4582
EXERCISE PRESCRIPTION......Page 4584
Activities of Daily Living......Page 4585
Pacing......Page 4587
PAIN PSYCHOLOGY......Page 4588
RELAXATION TRAINING......Page 4589
Work Rehabilitation: Work Conditioning and Work Hardening......Page 4591
Measuring Physical Capacity......Page 4595
FUNCTIONAL CAPACITY TESTING......Page 4596
FUNCTIONAL CAPACITY TESTING UTILITY......Page 4598
What Does an “Invalid” Test Mean?......Page 4599
Role of Opioid Management in Pain Rehabilitation......Page 4600
Conclusion......Page 4602
CHAPTER 91: Assessment and Treatment of Substance Use Disorders......Page 4612
Assessment and Treatment of Substance Use Disorders—Addiction Medicine Perspective......Page 4613
History......Page 4614
Laboratory......Page 4615
Self-report Questionnaires......Page 4617
DIAGNOSTIC ASSESSMENT......Page 4618
Co-occurring Psychiatric Disorders......Page 4620
TREATMENT AND/OR REFERRAL......Page 4621
Brief Interventions......Page 4622
Medically Supervised Withdrawal......Page 4623
Opioid Maintenance Treatment......Page 4624
Intensive Outpatient Treatment......Page 4625
Specific Behavioral Treatments......Page 4626
Pharmacotherapies......Page 4629
HISTORY OF OPIOID USE FOR CHRONIC PAIN AS IT RELATES TO IDENTIFYING OPIOID USE DISORDER......Page 4640
IMPLICATIONS FOR THE IDENTIFICATION OF OPIOID USE DISORDER......Page 4646
CLINICAL PREVENTION AND MANAGEMENT OF OPIOID USE DISORDER IN PATIENTS RECEIVING OPIOIDS FOR CHRONIC PAIN......Page 4648
Conclusions: Bridging the Gap between Addiction and Pain Medicine......Page 4649
CHAPTER 92: Biophysical Agents for Pain Management in Physical Therapy......Page 4656
THERMOTHERAPY......Page 4658
CRYOTHERAPY......Page 4661
LASER......Page 4663
MONOCHROMATIC INFRARED ENERGY......Page 4666
Therapeutic Ultrasound......Page 4667
TRANSCUTANEOUS ELECTRICAL NERVE STIMULATION......Page 4672
INTERFERENTIAL CURRENT......Page 4675
IONTOPHORESIS......Page 4677
Somatosensory Desensitization......Page 4680
MANUAL LYMPHATIC DRAINAGE......Page 4683
CUPPING......Page 4684
MIRROR THERAPY AND GRADED MOTOR IMAGERY......Page 4689
Conclusion......Page 4691
CHAPTER 93: Exercise Therapy for Low Back Pain......Page 4705
MUSCULOSKELETAL EXAMINATION FOR LOW BACK PAIN......Page 4708
DESIGNING INDIVIDUALIZED EXERCISE PROGRAMS......Page 4710
Acute Lower Back Pain......Page 4711
PERSISTENT LOWER BACK PAIN STAGE OF MANAGEMENT......Page 4712
Quota Programs for Exercise Dosage......Page 4713
Specific Exercise......Page 4714
Global Exercise......Page 4717
Psychological and Educational Approaches......Page 4719
Efficacy of Spinal Stabilization Exercises......Page 4720
Matching the Exercise Program to the Patient......Page 4722
EVIDENCE FOR GLOBAL EXERCISE APPROACHES......Page 4724
Conclusion......Page 4725
What Is Complementary and Integrative Health?......Page 4732
The Divide......Page 4733
“UNORTHODOX” MEDICINE......Page 4734
COMPLEMENTARY AND ALTERNATIVE MEDICINE......Page 4736
BRIDGING THE DIVIDE: ONE KIND OF MEDICINE......Page 4737
WHAT IS DIFFERENT ABOUT COMPLEMENTARY AND ALTERNATIVE MEDICINE?......Page 4738
WHO USES COMPLEMENTARY AND INTEGRATIVE HEALTH?......Page 4740
CATEGORIZING COMPLEMENTARY AND INTEGRATIVE HEALTH THERAPIES......Page 4741
Why Consider Complementary and Integrative Health Therapies in Pain Management?......Page 4743
CHALLENGES OF EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE THERAPIES......Page 4744
Manipulation......Page 4746
Therapeutic Massage......Page 4748
Body Awareness Therapy......Page 4749
Breath Pattern Retraining......Page 4750
Prolotherapy......Page 4751
The Fascia Model......Page 4752
Trigger Point Manipulation......Page 4753
ENERGY-BASED THERAPIES......Page 4754
Veritable Energy Therapies......Page 4755
Putative Energy Therapies......Page 4757
Biofield Therapies......Page 4761
Conclusion......Page 4764
CHAPTER 95: Stimulation of the Peripheral Nervous System for Pain Relief......Page 4771
Pathophysiology and Mechanisms of Analgesia......Page 4773
Stimulation Technologies......Page 4774
Implantation Techniques......Page 4777
OPEN SURGICAL PLACEMENT......Page 4778
PERCUTANEOUS PLACEMENT WITH FLUOROSCOPIC GUIDANCE......Page 4780
PERCUTANEOUS PLACEMENT WITH ULTRASOUND GUIDANCE......Page 4781
PLACEMENT AT THE NERVE ROOT/DORSAL ROOT GANGLION......Page 4782
Patient Selection and Preoperative Workup......Page 4783
Clinical Indications and Outcomes......Page 4784
Peripheral Nerve Stimulation......Page 4785
Dorsal Root Ganglion Stimulation......Page 4786
Axial Back Pain......Page 4787
Pelvic and Groin Pain......Page 4788
HEADACHE AND FACIAL PAIN......Page 4789
Migraine Headache......Page 4791
Trigeminal Neuralgia and Facial Pain......Page 4793
PERIPHERAL NERVE STIMULATION......Page 4794
DORSAL ROOT GANGLION STIMULATION......Page 4795
Conclusion and Future Directions......Page 4796
History......Page 4803
Basic Science of Conventional Spinal Cord Stimulation......Page 4805
NEUROPHYSIOLOGY AND NEUROCHEMISTRY......Page 4806
HIGH-FREQUENCY SPINAL CORD STIMULATION......Page 4811
BURST SPINAL CORD STIMULATION......Page 4813
MODERATE CHANGES OF CONVENTIONAL SPINAL CORD STIMULATION PARAMETERS......Page 4815
COMPUTER MODELING STUDIES......Page 4816
PERIPHERAL VASCULAR DISEASE......Page 4818
SPINAL CORD STIMULATION FOR ANGINA PECTORIS AND CARDIAC DISEASE......Page 4820
MECHANISMS OF SPINAL CORD STIMULATION IN VISCERAL ABDOMINAL PAIN......Page 4824
NEUROPATHIC PAIN......Page 4826
ISCHEMIC PAIN......Page 4827
CLINICAL GOALS......Page 4828
Prognostic Factors......Page 4829
Patient Selection......Page 4830
SCREENING ELECTRODE CHOICE......Page 4832
PROCEDURAL RISK REDUCTION......Page 4833
Device Options......Page 4834
CHOICE OF ELECTRODE......Page 4835
PROGRAMMING A SPINAL CORD STIMULATION SYSTEM......Page 4837
Patient Management......Page 4838
SPINAL CORD STIMULATION PATIENT PRECAUTIONS......Page 4839
TECHNICAL FAILURE......Page 4840
Cost-effectiveness......Page 4841
Spinal Cord Stimulation Challenges......Page 4842
CHAPTER 97: Deep Brain and Motor Cortex Stimulation......Page 4854
BASIC CONSIDERATIONS......Page 4855
EFFICACY OF DEEP BRAIN STIMULATION......Page 4856
SURGICAL TECHNIQUE......Page 4859
BASIC CONSIDERATIONS......Page 4861
EFFICACY OF MOTOR CORTEX STIMULATION......Page 4863
SURGICAL TECHNIQUE......Page 4865
BASIC CONSIDERATIONS......Page 4868
EFFICACY OF REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION FOR PAIN......Page 4869
Conclusion......Page 4870
CHAPTER 98: Diagnostic and Therapeutic Nerve Blocks......Page 4876
PATIENT......Page 4877
PREPARATION......Page 4878
CONTRAINDICATIONS......Page 4879
Systemic Effects......Page 4880
Damage to Nonneural Structures......Page 4882
Blind Techniques......Page 4883
Fluoroscopy-Guided Techniques......Page 4884
Ultrasound-Guided Techniques......Page 4886
Test Blocks......Page 4888
Prognostic Blocks......Page 4889
SPINAL NERVE BLOCKS......Page 4890
SYMPATHETIC BLOCKS......Page 4892
Controls......Page 4895
Nerve Blocks for Cervical Zygapophysial Joint Pain......Page 4897
Nerve Blocks for Lumbar Zygapophysial Joint Pain......Page 4900
Diagnostic Intra-articular Blocks......Page 4906
Therapeutic Nerve Blocks......Page 4911
Conclusion......Page 4915
Definition......Page 4924
Background......Page 4925
Techniques......Page 4926
CAUDAL INJECTIONS: TECHNIQUE......Page 4927
CAUDAL INJECTIONS: EVIDENCE......Page 4929
INTERLAMINAR INJECTIONS: TECHNIQUE......Page 4931
NONIMAGE-GUIDED INTERLAMINAR TECHNIQUE: EVIDENCE......Page 4934
IMAGE-GUIDED INTERLAMINAR TECHNIQUE: EVIDENCE......Page 4935
TRANSFORAMINAL INJECTIONS......Page 4936
TRANSFORAMINAL INJECTIONS UNDER FLUOROSCOPIC GUIDANCE: EVIDENCE......Page 4941
TRANSFORAMINAL INJECTIONS: DETERMINANTS OF EFFICACY......Page 4946
TRANSFORAMINAL INJECTIONS: ADVERSE EVENTS......Page 4947
TRANSFORAMINAL INJECTIONS UNDER COMPUTED TOMOGRAPHY GUIDANCE: EVIDENCE, ADVERSE EVENTS......Page 4948
TRANSFORAMINAL EPIDURAL STEROID INJECTIONS: THEIR ROLE IN TREATING THE RADICULAR PAIN PATIENT......Page 4949
History of the Development of Intrathecal Drug Delivery Systems......Page 4957
Basic Pharmacology of Intrathecal Drug Administration......Page 4958
Selection of Agents for Intrathecal Drug Delivery......Page 4960
Morphine......Page 4963
Fentanyl and Sufentanil......Page 4964
Opioid-Induced Hyperalgesia and Intrathecal Opioids......Page 4965
LOCAL ANESTHETICS......Page 4966
α2-ADRENERGIC AGONISTS......Page 4967
CALCIUM CHANNEL ANTAGONISTS......Page 4969
N-METHYL-D-ASPARTATE RECEPTOR ANTAGONISTS......Page 4970
GABAPENTIN......Page 4971
SOMATOSTATIN AND SOMATOSTATIN ANALOGUES......Page 4972
TRICYCLIC ANTIDEPRESSANTS......Page 4973
ADENOSINE......Page 4974
PROSTAGLANDIN INHIBITORS......Page 4975
SUBSTANCE P ANTAGONISTS......Page 4976
Patient Selection for Intrathecal Drug Delivery......Page 4977
Trialing Techniques for Intrathecal Drug Delivery......Page 4980
Implantable Pump Technology......Page 4986
SURGICAL TECHNIQUE OF PUMP IMPLANTATION......Page 4988
Complications of Spinal Drug Delivery......Page 4992
Wound Hematoma/Seroma and Epidural Hematoma......Page 4993
Infectious Complications......Page 4994
Cerebrospinal Fluid Leak and Postdural Puncture Headache......Page 4996
Catheter and Pump Problems......Page 4997
Complications Associated with Refill of the Pump Reservoir......Page 4999
Side Effects of Intrathecal Opioids......Page 5001
Opioid Tolerance......Page 5003
Intrathecal Inflammatory Masses (Intrathecal Granuloma)......Page 5005
Drug Withdrawal......Page 5008
CANCER PAIN......Page 5009
INTRATHECAL DRUG DELIVERY FOR CHRONIC NONCANCER PAIN......Page 5010
Conclusion......Page 5012
ACKNOWLEDGMENT......Page 5013
Discogenic Pain......Page 5017
Pathology......Page 5019
Therapies......Page 5026
Intranuclear Radiofrequency......Page 5027
Intradiscal Electrothermal Therapy......Page 5028
Biacuplasty......Page 5029
Intradiscal Steroids......Page 5031
Etanercept......Page 5033
Antibiotics......Page 5034
BIOLOGICS......Page 5035
Stem Cells......Page 5036
Discussion......Page 5037
PRINCIPLES......Page 5046
LIMITATIONS......Page 5047
PHENOL......Page 5049
APPLICATIONS......Page 5050
GLYCEROL......Page 5051
Cryoneurotomy......Page 5052
PHYSICS......Page 5053
PATHOLOGY......Page 5056
Trigeminal Neuralgia......Page 5057
Central Ablative Procedures......Page 5058
Medial Branch Neurotomy......Page 5061
Sacral Lateral Branch Neurotomy......Page 5078
Discussion......Page 5080
CHAPTER 103: Surgery of the Peripheral Nervous System as a Treatment for Pain......Page 5091
Pathophysiology of Neuropathic Pain......Page 5092
Rationale for Neuroma Relocation Surgery......Page 5094
Preoperative Evaluation......Page 5095
Operative Technique......Page 5097
Intercostal and Intercostobrachial Pain......Page 5098
Meralgia Paresthetica......Page 5099
General Results of Neurectomy for Neuropathic Pain......Page 5100
Axial Spine Pain......Page 5102
Cancer Pain......Page 5104
Pathophysiology of Nerve Entrapment Pain......Page 5105
Nerve Entrapment and Systemic Disease......Page 5106
Preoperative Evaluation......Page 5107
Entrapments of the Median Nerve......Page 5112
Entrapments of the Ulnar Nerve......Page 5114
Entrapments of the Radial Nerve......Page 5116
Entrapment of the Suprascapular Nerve......Page 5117
Thoracic Outlet Syndrome......Page 5118
Entrapments of the Lower Extremities......Page 5119
BASIC CONSIDERATIONS......Page 5123
Preoperative Evaluation......Page 5125
INDICATIONS AND OUTCOMES......Page 5127
Occipital Neuralgia......Page 5128
Postsurgical Truncal Pain......Page 5129
Sacral Pain......Page 5130
Extremity Pain......Page 5132
Axial Spine Pain......Page 5133
Sympathetic Efferents......Page 5134
Sympathetically Maintained Pain......Page 5135
Preoperative Evaluation......Page 5137
Operative Techniques......Page 5141
INDICATIONS AND OUTCOMES......Page 5142
POSTOPERATIVE COMPLICATIONS......Page 5143
Conclusion......Page 5144
Patient Presentation......Page 5159
Anatomy......Page 5160
Pathophysiology......Page 5161
Evaluation for Surgery......Page 5162
Microvascular Decompression......Page 5164
OUTCOMES......Page 5167
Percutaneous Rhizotomy......Page 5168
Percutaneous Balloon Compression......Page 5170
Radiosurgery......Page 5171
OUTCOMES......Page 5172
Conclusions......Page 5173
CHAPTER 105: Ablative Neurosurgical Procedures for Chronic Pain......Page 5178
INDICATIONS......Page 5179
TECHNIQUE......Page 5180
OUTCOMES......Page 5181
INDICATIONS......Page 5182
ANATOMY AND PHYSIOLOGY......Page 5183
TECHNIQUE......Page 5185
OUTCOMES......Page 5186
INDICATIONS......Page 5187
ANATOMY AND PHYSIOLOGY......Page 5188
TECHNIQUE......Page 5189
OUTCOMES......Page 5190
INDICATIONS......Page 5191
ANATOMY AND PHYSIOLOGY......Page 5192
TECHNIQUES......Page 5193
OUTCOMES......Page 5195
Ablative Procedures of the Brainstem......Page 5196
ANATOMY AND PHYSIOLOGY......Page 5197
TECHNIQUES......Page 5199
OUTCOMES......Page 5200
Conclusion......Page 5201
History of Interdisciplinary Chronic Pain Management......Page 5207
EMPIRICAL SUPPORT FOR INTERDISCIPLINARY CHRONIC PAIN MANAGEMENT......Page 5209
THEORETICAL BASIS OF THE INTERDISCIPLINARY APPROACH......Page 5213
COMPOSITION OF THE INTERDISCIPLINARY TEAM AND ROLES OF MEMBERS......Page 5214
The Process of Interdisciplinary Chronic Pain Management......Page 5220
Interdisciplinary Chronic Pain Management in Veterans Healthcare Administration: Overview of a Model System......Page 5223
Future Considerations for Interdisciplinary Chronic Pain Management......Page 5227
Conclusion......Page 5228
CHAPTER 107: Spine Clinics......Page 5232
Treatment Components......Page 5235
PAIN MANAGEMENT......Page 5236
PHYSICAL THERAPY......Page 5237
OCCUPATIONAL THERAPY......Page 5238
SPINE SURGERY......Page 5239
CHRONIC PAIN MANAGEMENT PROGRAM......Page 5240
POTENTIAL BENEFITS OF A SPINE SPECIALTY CLINIC......Page 5241
RESEARCH AND EDUCATION......Page 5243
Conclusion......Page 5245
ECONOMIC IMPLICATIONS OF CHRONIC PAIN......Page 5248
CHRONIC PAIN MANAGEMENT: THE STATUS QUO......Page 5249
A New Approach to Chronic Pain Management......Page 5250
WHO TREATS CHRONIC ILLNESS?......Page 5251
WHY PRIMARY CARE IS INVOLVED?......Page 5252
Training in Pain......Page 5253
Disagreement among Experts—To Treat and Not to Treat......Page 5254
Barriers to Treating Pain......Page 5255
MYTHS AND BIASES......Page 5259
PATIENT RESISTANCE......Page 5260
Pain Practitioner: A Primary Care Model......Page 5261
NEW FOCUS......Page 5262
ASSESSMENT AND EVALUATION DURING SHORT VISITS......Page 5263
Validating the Patient......Page 5264
Assessment Tools......Page 5265
Goal Setting and Plan of Action......Page 5266
PHARMACOLOGIC TREATMENT......Page 5267
MOTIVATING BEHAVIOR CHANGE IN PATIENTS WITH CHRONIC PAIN......Page 5269
Conclusion......Page 5275
Introduction......Page 5279
PALLIATIVE CARE......Page 5280
HOSPICE......Page 5281
Pain Syndromes Common at the End of Life......Page 5282
NONCANCER DIAGNOSES......Page 5283
CHALLENGES IN PAIN ASSESSMENT......Page 5284
PAIN ASSESSMENT IN THE COGNITIVELY IMPAIRED......Page 5285
PAIN ASSESSMENT IN THOSE UNABLE TO COMMUNICATE......Page 5286
Oral, Sublingual, Transmucosal, and Buccal Routes......Page 5287
Transmucosal Immediate-Release Fentanyl Products......Page 5288
Enteral and Rectal......Page 5289
Parenteral......Page 5290
Topical......Page 5291
INTRACTABLE PAIN OR UNMANAGEABLE ADVERSE EFFECTS OF TREATMENT......Page 5292
Myoclonus......Page 5293
Intractable Pain at End of Life......Page 5295
Fears of Hastening Death......Page 5298
Suffering and Existential Distress......Page 5299
NONPHARMACOLOGIC TECHNIQUES......Page 5301
Palliative Sedation......Page 5302
Conclusion......Page 5305
Background......Page 5315
TRUST......Page 5316
MORALS AND ETHICS......Page 5318
Background and First Attempt at Change of Treatment Plan to Opioid Cessation......Page 5320
Modification in Engagement with Patient and Treatment Plan following the Consultation and Reflection......Page 5322
Analysis......Page 5323
Analysis......Page 5325
Background......Page 5327
Analysis......Page 5329
DIALOGUE......Page 5330
EMPATHY......Page 5331
NARRATIVE MEDICINE......Page 5332
Conclusion......Page 5333
The Evolution of Pain Medicine as a Subspecialty......Page 5336
Pain Medicine as a Primary Medical Specialty......Page 5343
Training in Pain Medicine in Europe......Page 5346
Training and Credentialing in Interventional Pain Medicine......Page 5348
Conclusion......Page 5351
ACKNOWLEDGMENTS......Page 5353
The American Society of Anesthesiologists Closed Claims Project......Page 5356
Bleeding Complications......Page 5359
Infectious Complications......Page 5363
Local Anesthetic Systemic Toxicity......Page 5368
UNINTENDED DESTINATIONS FOLLOWING LOCAL ANESTHETIC ADMINISTRATION......Page 5370
VASOVAGAL REACTIONS......Page 5371
Complications Associated with Intrathecal Drug Delivery......Page 5372
OPIOID WITHDRAWAL......Page 5374
Anaphylactic and Anaphylactoid Reactions......Page 5375
CATASTROPHIC NEURAL INJURIES AND THE ADMINISTRATION OF PARTICULATE STEROIDS......Page 5377
Conclusion......Page 5382
CHAPTER 113: Pain Management in the Emergency Department......Page 5387
The Prevalence of Pain in the Emergency Department......Page 5388
The Assessment of Pain in the Emergency Department......Page 5391
Oligoanalgesia in the Emergency Department......Page 5393
Pain and Opioid Abuse in the Emergency Department......Page 5394
Definitions......Page 5395
Pain and “Drug-Seeking Behavior” in the Emergency Department......Page 5398
Pain and Substance Abuse in the Emergency Department: A Balanced Perspective......Page 5400
The Example of Sickle Cell Disease......Page 5402
Pain Treatment and Procedural Sedation in the Emergency Department......Page 5403
Specific Treatment Modalities......Page 5404
NONOPIOIDS......Page 5405
OPIOIDS......Page 5406
PROCEDURAL SEDATION AND ANALGESIA......Page 5408
Evolving Emergency Department Pain Management Practice......Page 5415
Conclusion......Page 5416
Pain, Analgesia, and Critical Illness......Page 5422
Evaluation and Monitoring of Pain in the Intensive Care Unit......Page 5426
Managing Pain and Analgesia in the Intensive Care Unit......Page 5430
PHARMACOLOGIC TREATMENT OF PAIN IN THE INTENSIVE CARE UNIT: PARENTERAL OPIOIDS......Page 5431
Fentanyl......Page 5433
Hydromorphone......Page 5434
Morphine......Page 5435
Remifentanil......Page 5436
Ketamine......Page 5437
Methadone......Page 5438
Other Analgesics and Adjuvant Agents......Page 5439
NONPHARMACOLOGIC MANAGEMENT OF PAIN IN THE INTENSIVE CARE UNIT......Page 5440
REGIONAL ANESTHETIC APPROACHES TO PAIN IN THE INTENSIVE CARE UNIT......Page 5441
ANALGOSEDATION IN THE INTENSIVE CARE UNIT......Page 5442
ANALGESIA AS A COMPONENT OF COMPREHENSIVE BUNDLED INTENSIVE CARE UNIT CARE......Page 5445
Pain and Analgesia at the End of Life in the Intensive Care Unit......Page 5446
ACKNOWLEDGMENTS......Page 5448
CHAPTER 115: The Future of Pain Medicine: An Epilogue......Page 5457
Index......Page 5464

Citation preview

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Acquisitions Editor: Keith Donnellan Product Development Editor: Rebeca Barroso/Elizabeth Schaeffer Editorial Coordinator: Jeremiah Kiely Editorial Assistant: Levi Bentley Marketing Manager: Rachel Mante-Leung Production Project Manager: Marian Bellus Design Coordinator: Elaine Kasmer Manufacturing Coordinator: Beth Welsh Prepress Vendor: Absolute Service, Inc. 5th edition Copyright © 2019 Wolters Kluwer Copyright © 2010 Lippincott Williams & Wilkins, a Wolters Kluwer business. All rights reserved. This book is protected by copyright. No part of this book may be reproduced or transmitted in any form or by any means, including as photocopies or scanned-in or other electronic copies, or utilized by any information storage and retrieval system without written permission from the copyright owner, except for brief quotations embodied in critical articles and reviews. Materials appearing in this book prepared by individuals as part of their official duties as U.S. government employees are not covered by the above-mentioned copyright. To request permission, please contact Wolters Kluwer at Two Commerce Square, 2001 Market Street, Philadelphia, PA 19103, via email at [email protected], or via our website at shop.lww.com (products and services). Cover Figure Credits: Top: fMRI of cognitive modulation of pain, Sean Mackey, MD, PhD, Stanford University Left: Cupola of the Etherdome at Massachusetts General Hospital (inside), James P. Rathmell Left Center: Laocoön and his sons in the Vatican. Marble, copy after an Hellenistic original from ca. 200 BC. Found in the Baths of Trajan, 1506, [Public domain], via Wikimedia Commons 4

Right Center: Papaver orientale, ornamental relative of Papaver somniferum, the opium poppy, James P. Rathmell Right: Capsicum chinese var. Habenero, Les Ferme Lufa, Montréal, Québec Cover Design: James P. Rathmell 987654321 Printed in China Library of Congress Cataloging-in-Publication Data Names: Ballantyne, Jane, 1948- editor. | Fishman, Scott, 1959- editor. | Rathmell, James P., editor. Title: Bonica’s management of pain / editors, Jane C. Ballantyne, Scott M. Fishman, James P. Rathmell. Description: Fifth edition. | Philadelphia : Wolters Kluwer Health, [2019] | Includes bibliographical references and index. Identifiers: LCCN 2018038021 | ISBN 9781496349033 (hardback) Subjects: | MESH: Pain Management Classification: LCC RB127 | NLM WL 704.6 | DDC 616/.0472—dc23 LC record available at https://lccn.loc.gov/2018038021 This work is provided “as is,” and the publisher disclaims any and all warranties, express or implied, including any warranties as to accuracy, comprehensiveness, or currency of the content of this work. This work is no substitute for individual patient assessment based upon healthcare professionals’ examination of each patient and consideration of, among other things, age, weight, gender, current or prior medical conditions, medication history, laboratory data, and other factors unique to the patient. The publisher does not provide medical advice or guidance and this work is merely a reference tool. Healthcare professionals, and not the publisher, are solely responsible for the use of this work including all medical judgments and for any resulting diagnosis and treatments.

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Given continuous, rapid advances in medical science and health information, independent professional verification of medical diagnoses, indications, appropriate pharmaceutical selections and dosages, and treatment options should be made and healthcare professionals should consult a variety of sources. When prescribing medication, healthcare professionals are advised to consult the product information sheet (the manufacturer’s package insert) accompanying each drug to verify, among other things, conditions of use, warnings, and side effects and identify any changes in dosage schedule or contraindications, particularly if the medication to be administered is new, infrequently used, or has a narrow therapeutic range. To the maximum extent permitted under applicable law, no responsibility is assumed by the publisher for any injury and/or damage to persons or property, as a matter of products liability, negligence law or otherwise, or from any reference to or use by any person of this work. shop.lww.com

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TO THE LASTING MEMORY OF JOHN BONICA AND HIS ENDURING QUEST TO END NEEDLESS PAIN.

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John and Emma L. Bonica

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Section Editors Jane C. Ballantyne, MD, FRCA Professor of Anesthesiology and Pain Medicine University of Washington Seattle, Washington Nikolai Bogduk, BSc(Med), MB, BS, MD, PhD, DSc, MMed, FAFRM, FFPM(ANZCA) Emeritus Professor of Pain Medicine The University of Newcastle Newcastle, New South Wales, Australia David J. Copenhaver, MD, MPH Associate Professor Department of Anesthesiology and Pain Medicine Department of Neurological Surgery Associate Director, Center for Advancing Pain Relief Director, Cancer Pain Management University of California at Davis Sacramento, California Emad N. Eskandar, MD Professor Department of Neurosurgery Harvard Medical School Boston, Massachusetts

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Scott M. Fishman, MD Fullerton Endowed Chair of Pain Medicine Chief, Division of Pain Medicine and Professor of Anesthesiology Director, Center for Advancing Pain Relief Department of Anesthesiology and Pain Medicine University of California, Davis School of Medicine Sacramento, California Rollin M. Gallagher, MD, MPH Clinical Professor Psychiatry and Anesthesiology Perelman School of Medicine, University of Pennsylvania Philadelphia, Pennsylvania G.F. Gebhart, PhD (Retired) Professor (emeritus) Department of Pharmacology Carver College of Medicine University of Iowa Iowa City, Iowa Arthur G. Lipman†, PharmD Professor Emeritus Pharmacotherapy University of Utah School of Medicine Adjunct Professor of Anesthesiology and Director of Clinical Pharmacology Pain Management University of Utah Salt Lake City, Utah Timothy J. Ness, MD, PhD Simon Gelman Endowed Professor of Anesthesiology Department of Anesthesiology and Perioperative Medicine University of Alabama at Birmingham Birmingham, Alabama 10

James P. Rathmell, MD Chair, Department of Anesthesiology, Perioperative and Pain Medicine Brigham and Women’s Hospital Leroy D. Vandam Professor of Anaesthesia, Harvard Medical School Boston, Massachusetts Steven H. Richeimer, MD Professor of Anesthesiology and Psychiatry Chief, Division of Pain Medicine Department of Anesthesiology Keck School of Medicine University of Southern California Los Angeles, California Virtaj Singh, MD Clinical Assistant Professor Department of Rehabilitation University of Washington Medical Director Seattle Spine and Sports Medicine Seattle, Washington Mark S. Wallace, MD Professor of Clinical Anesthesiology Chair, Division of Pain Medicine Department of Anesthesiology University of California San Diego La Jolla, California Christopher L. Wu, MD Clinical Professor of Anesthesiology Department of Anesthesiology The Hospital for Special Surgery, Weill Cornell Medical College New York, New York †Deceased.

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Contributing Authors Alaa Abd-ElSayed, MD Assistant Professor/Medical Director University of Wisconsin-Madison Madison, Wisconsin Roger J. Allen, PhD, PT Distinguished Professor School of Physical Therapy Neuroscience Program University of Puget Sound Tacoma, Washington Kevin N. Alschuler, PhD Associate Professor Department of Rehabilitation Medicine University of Washington School of Medicine Rehabilitation Psychologist UW Medicine Multiple Sclerosis Center University of Washington Medical Center Seattle, Washington David Arcella, MD Private Practice Trident Pain Center Charleston, South Carolina

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Charles E. Argoff, MD Professor of Neurology Albany Medical College Director, Comprehensive Pain Center and Pain Management Fellowship Albany Medical Center Albany, New York Paul M. Arnstein, PhD, RN, FAAN Adjunct Associate Professor Nursing MGH Institute for Health Professions Clinical Nurse Specialist for Pain Relief Institute for Patient Care Massachusetts General Hospital Boston, Massachusetts Desiree Azizoddin, PsyD Pain Psychology Fellow Department of Anesthesiology, Perioperative and Pain Medicine Stanford University Palo Alto, California Miroslav Backonja, MD Clinical Professor Neurology University of Washington Seattle, Washington Emeritus Professor Department of Neurology University of Wisconsin Madison, Wisconsin Matthew J. Bair, MD, MS Associate Professor of Medicine Medicine Indiana University School of Medicine 13

Core Investigator Center for Health Information and Communication Rondebush VA Medical Center Indianapolis, Indiana Zahid H. Bajwa, MD, FAHS Director, Boston Headache Institute Director, Clinical Research, Boston PainCare Center Waltham, Massachusetts Tufts University School of Medicine Boston, Massachusetts Samir K. Ballas, MD, FACP, FASCP, DABPM, FAAPM Emeritus Professor of Medicine and Pediatrics Department of Medicine, Cardeza Foundation for Hematologic Research Thomas Jefferson University Honorary Staff Member Medicine, Division of Hematology Sidney Kimmel Medical College Philadelphia, Pennsylvania Andrew Baranowski, BScHons, MBBS, FRCA, MD, FFPMRCA Honorary Senior Lecturer Department of Pain Medicine University College London Consultant Pain Medicine University College London Hospitals London, United Kingdom Andrei Barasch, DMD, MDSc Associate Professor Medicine Weill Cornell Medical College Attending Medicine 14

New York Presbyterian Hospital New York, New York David Barnard, PhD, JD Retired Miles J. Edwards Chair in Professionalism and Comfort Care Center for Ethics in Health Care Oregon Health & Science University Portland, Oregon Kelly Barth, DO Associate Professor Department of Psychiatry and Behavioral Sciences Medical University of South Carolina Charleston, South Carolina William C. Becker, MD Associate Professor Department of Internal Medicine Yale School of Medicine New Haven, Connecticut Sharona Ben-Haim, MD Assistant Professor Department of Neurosurgery University of California, San Diego San Diego, California Charles Berde, MD, PhD Professor Anesthesia Harvard Medical School Sara Page Mayo Chair and Chief, Division of Pain Medicine Anesthesiology, Critical Care and Pain Medicine Boston Children’s Hospital Boston, Massachusetts Sarah K. Bick, MD 15

Resident Department of Neurosurgery Massachusetts General Hospital Boston, Massachusetts Klaus Bielefeldt, MD, PhD Professor of Medicine Medicine University of Utah Section Chief, Gastroenterology Medicine George E. Wahlen VAMC Salt Lake City, Utah Nikolai Bogduk, BSc(Med), MB, BS, MD, PhD, DSc, MMed, FAFRM, FFPM(ANZCA) Emeritus Professor of Pain Medicine The University of Newcastle Newcastle, New South Wales, Australia Christina Elise Bokat, MD Assistant Professor Anesthesiology University of Utah Salt Lake City, Utah Michael M. Bottros, MD Associate Professor Department of Anesthesiology, Division of Pain Medicine Washington University School of Medicine St. Louis, Missouri Gary J. Brenner, MD, PhD Associate Professor Department of Anesthesia, Critical Care and Pain Medicine Harvard Medical School

16

Director, Massachusetts General Hospital Pain Medicine Fellowship Department of Anesthesia, Critical Care and Pain Medicine Massachusetts General Hospital Boston, Massachusetts Shane E. Brogan, MB, BCH Director of Pain Medicine Anesthesiology Huntsman Cancer Hospital Salt Lake City, Utah Chad Brummett, MD Associate Professor of Anesthesiology Director, Clinical Anesthesia Research University of Michigan Ann Arbor, Michigan Kelly A. Bruno, MD Pain Medicine Fellow Department of Anesthesiology and Pain Medicine University of California, San Diego San Diego, California Thomas N. Bryce, MD Professor Rehabilitation Medicine Icahn School of Medicine Attending Physician Rehabilitation Medicine Mount Sinai Hospital New York, New York Asokumar Buvanendran, MD Professor, Department of Anesthesiology William Gottschalk, Endowed Chair of Anesthesiology Vice Chair Research and Director of Orthopedic Anesthesia

17

Rush University Medical Center Chicago, Illinois Jacqueline Casillas, MD, MSHS Professor Pediatrics Division of Hematology-Oncology University of California, Los Angeles Los Angeles, California Medical Director Pediatric Hematology-Oncology Miller Children’s Hospital Long Beach, California Ausim Chaghtai, MD Neurology Resident Albany Medical Center Albany, New York Wilson J. Chang, MD, MPH Pain Specialist Pain Services Swedish Medical Center Seattle, Washington C. Richard Chapman, PhD Professor Emeritus Pain Research Center Department of Anesthesiology University of Utah Salt Lake City, Utah Martin D. Cheatle, PhD Associate Professor Department of Psychiatry Perelman School of Medicine, University of Pennsylvania Philadelphia, Pennsylvania

18

Srinivas Chiravuri, MD Clinical Associate Professor Department of Anesthesiology University of Michigan Medical School Ann Arbor, Michigan Roger Chou, MD Professor Department of Medical Informatics and Clinical Epidemiology, Department of Medicine Oregon Health & Science University Portland, Oregon Thomas Tai Chung, MD Clinical Assistant Professor Physical Medicine and Rehabilitation University of Washington School of Medicine Staff Physical Medicine and Rehabilitation Swedish Medical Center Seattle, Washington Michael R. Clark, MD, MPH, MBA Chair, Department of Psychiatry and Behavioral Health Inova Health System Falls Church, Virginia Daniel J. Clauw, MD Professor Department of Anesthesiology, Medicine (Rheumatology), and Psychiatry University of Michigan Director Chronic Pain and Fatigue Research Center, Department of Anesthesiology Michigan Medicine Ann Arbor, Michigan

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James F. Cleary, MD, FRACP, FAChPM Professor Medicine University of Wisconsin School of Medicine and Public Health Madison, Wisconsin Richard F. Cody Jr., MD Neuroradiology Fellow Department of Radiology University of Washington School of Medicine/Harborview Medical Center Seattle, Washington Peggy Compton, RN, PhD, FAAN Associate Professor School of Nursing University of Pennsylvania Philadelphia, Pennsylvania David S. Craig, PharmD Pharmacist Lead, Supportive Care Medicine and Acute Pain Department of Pharmacy Moffitt Cancer Center and Research Institute Tampa, Florida Lara Wiley Crock, MD, PhD Research and Clinical Fellow Department of Anesthesiology Washington University School of Medicine St. Louis, Missouri Taylor Crouch, PhD Instructor Department of Psychiatry and Behavioral Sciences Medical University of South Carolina Charleston, South Carolina Michele Curatolo, MD, PhD 20

Professor of Anesthesiology and Pain Medicine Endowed Professor in Medical Education and Research Department of Anesthesiology & Pain Medicine University of Washington Seattle, Washington Melissa A. Day, PhD NHMRC Early Career Fellow School of Psychology The University of Queensland Brisbane, Australia Jennifer J. DeBerry, PhD Assistant Professor Anesthesiology − Perioperative Medicine University of Alabama at Birmingham Birmingham, Alabama Richard A. Deyo, MD, MPH Professor Family Medicine and Internal Medicine Oregon Health & Science University Portland, Oregon Jan Dommerholt, PT, DPT, DAIPM Associate Professor Fisioterapia Universidad CEU Cardenal Herrera Valencia, Spain President/Chief Executive Officer Bethesda Physiocare Inc Bethesda, Maryland Robert H. Dworkin, PhD Professor of Anesthesiology, Neurology, and Psychiatry Department of Anesthesiology

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University of Rochester School of Medicine and Dentistry Rochester, New York Robert Edwards, PhD, MSPH Associate Professor Anesthesiology Harvard School of Medicine Psychologist Anesthesiology Brigham and Women’s Hospital Boston, Massachusetts Elon Eisenberg, MD Professor of Neurology and Pain Medicine Rappaport Faculty of Medicine Technion—Israel Institute of Technology Head, Pain Research Unit Institute of Pain Medicine Rambam Health Care Campus Haifa, Israel Andrew J. Engel, MD Affordable Pain Management Chicago, Illinois Joyce M. Engel, PhD, OT Professor Occupational Science and Technology College of Health Sciences University of Wisconsin-Milwaukee Milwaukee, Wisconsin Joel Brian Epstein, DMD, MSD Professor Department of Surgery Cedars-Sinai Health System

22

Los Angeles, California Medical Director, Dentistry Department of Surgery City of Hope National Medical Center Duarte, California Emad N. Eskandar, MD Professor Department of Neurosurgery Massachusetts General Hospital Harvard Medical School Boston, Massachusetts Svetlana Faktorovich, MD Clinical Neurophysiology Fellow Department of Neurology Icahn School of Medicine at Mount Sinai New York, New York Ronnie Fass, MD Professor of Medicine Medicine Case Western Reserve University Medical Director, Digestive Health Center Medicine MetroHealth Medical Center Cleveland, Ohio Roger B. Fillingim, PhD Distinguished Professor Pain Research and Intervention Center of Excellence University of Florida Gainesville, Florida Ezekiel Fink, MD Triple Board Certified in Neurology, Pain Management, and Brain Injury

23

Medicine Medical Director of Pain Management Houston Methodist Hospital Houston, Texas Assistant Clinical Professor David Geffen School of Medicine at UCLA Los Angeles, California Nanna Brix Finnerup, MD, Phd Professor Department of Clinical Medicine, Danish Pain Research Center Aarhus University Aarhus, Denmark Scott M. Fishman, MD Fullerton Endowed Chair of Pain Medicine Chief, Division of Pain Medicine and Professor of Anesthesiology Director, Center for Advancing Pain Relief Department of Anesthesiology and Pain Medicine University of California, Davis School of Medicine Sacramento, California Dermot Fitzgibbon, MB, BCh Professor Department of Anesthesiology and Pain Medicine University of Washington School of Medicine Medical Director, Pain and Anesthesia Services Seattle Cancer Care Alliance Seattle, Washington Gregory C. Gardner, MD, FACP Gilliland-Henderson Professor of Medicine Division of Rheumatology Adjunct Professor of Orthopedics and Rehabilitation Medicine University of Washington Seattle, Washington 24

Robert J. Gatchel, PhD, ABPP Distinguished Professor and Director, Center of Excellence for the Study of Health and Chronic Illnesses, Nancy P. and John G. Penson Endowed Professor of Clinical Health Psychology Department of Psychology, College of Science University of Texas at Arlington Arlington, Texas G.F. Gebhart, PhD (Retired) Professor (emeritus) Department of Pharmacology Carver College of Medicine University of Iowa Iowa City, Iowa Youssef Ghabrial, MB, ChB, MOrth, DS, FRCS, FRACS Professor of Orthopedic Surgery School of Medicine and Public Health Faculty of Health and Medicine The University of Newcastle Staff Specialist Department of Orthopedic Surgery John Hunter Hospital Newcastle, New South Wales, Australia Kimberly Varney Gill, PharmD, BCPS, BCCCP Clinical Pharmacy Specialist, Critical Care, Medical Respiratory ICU, VCU Medical Center Associate Clinical Professor of Pharmacy, VCU School of Pharmacy Assistant Clinical Professor of Medicine, VCU Department of Internal Medicine Richmond, Virginia Christopher Gilligan, MD, MBA Assistant Professor Anesthesia 25

Harvard Medical School Chief, Division of Pain Medicine Department of Anesthesiology, Perioperative and Pain Medicine Brigham and Women’s Hospital Boston, Massachusetts Aaron M. Gilson, MS, MSSW, PhD Research Program Manager/Senior Scientist Carbone Cancer Center University of Wisconsin School of Medicine and Public Health Madison, Wisconsin Lee Glass, MD, JD Associate Medical Director Department of Labor and Industries Olympia, Washington Peter J. Goadsby, MD, PhD, DSc, FRACP, FRCP, FMedSci Professor of Neurology Institute of Psychiatry, Psychology and Neuroscience King’s College London London, United Kingdom Layne A. Goble, PhD Clinical Psychologist Anesthesia Charleston VA Medical Center Associate Professor Anesthesia and Perioperative Medicine Medical University of South Carolina Charleston, South Carolina Michael S. Gold, PhD Professor of Neurobiology Department of Neurobiology University of Pittsburgh School of Medicine

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Pittsburgh, Pennsylvania Douglas L. Gourlay, MD, MSc, FRCP(C), DFASAM Educational Consultant Ontario, Canada Benjamin L. Grannan, MD Resident Physician Department of Neurosurgery Massachusetts General Hospital Boston, Massachusetts Robert Griffin, MD, PhD Clinical Assistant Professor Anesthesiology Weill Cornell Medical College Assistant Attending Anesthesiologist Anesthesiology, Critical Care, and Pain Management Hospital for Special Surgery New York, New York Narasimha R. Gundamraj, MD Assistant Professor College of Human Medicine Michigan State University Physician Pain Management Center Sparrow Hospital East Lansing, Michigan Muhamed Hadzipasic, MD, PhD Resident Physician Department of Neurosurgery Massachusetts General Hospital Boston, Massachusetts Neil A. Hagen, MD, FRCPC 27

Professor Emeritus Departments of Oncology, Clinical Neurosciences and Medicine Cumming School of Medicine, University of Calgary Calgary, Canada Emily Hagn, MD Assistant Professor Department of Anesthesiology University of Utah Salt Lake City, Utah Marie N. Hanna, MD, MEHP Associate Professor, Chief Division of Regional Anesthesia and Acute Pain Management Deparment Anesthesia and Critical Care Medicine Johns Hopkins University Baltimore, Maryland Robert Norman Harden, MD Professor Rehabilitation Institute of Chicago Northwestern University Chicago, Illinois Simon Haroutounian, PhD, MSc Pharm Assistant Professor Department of Anesthesiology Washington University School of Medicine St. Louis, Missouri Michael Hauck, MD, PhD Research Fellow Institute of Pathophysiology and Neurophysiology University Medical Center Hamburg-Eppendorf Attending Physician Department of Neurology

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University Medical Center Hamburg-Eppendorf Hamburg, Germany Howard A. Heit, MD, FACP, FASAM Educational Consultant Reston, Virginia Jeanne Hernandez, PhD, MSPH Director of Behavioral Medicine, Assistant Professor (Retired) Department of Anesthesiology School of Medicine, University of North Carolina Chapel Hill Chapel Hill, North Carolina Keela Herr, PhD, RN, AGSF, FGSA, FAAN Professor and Associate Dean for Faculty College of Nursing University of Iowa Iowa City, Iowa Anita H. Hickey, MD Pain Management Physician Naval Medical Center San Diego San Diego, California Joseph Gregory Hobelmann, MD, MPH Adjunct Faculty Department of Psychiatry and Behavioral Sciences Johns Hopkins University Baltimore, Maryland Chief Medical Officer Ashley Addiction Treatment Havre de Grace, Maryland Pamela J. Hughes, DDS Associate Professor and Department Chair Oral and Maxillofacial Surgery Oregon Health and Science University 29

Portland, Oregon Robert W. Hurley, MD, PhD Professor Section Chief of Pain Medicine Anesthesiology and Public Health Sciences Wake Forest University Executive Director Pain Service Line Wake Forest Baptist Health Winston-Salem, North Carolina S. Asra Husain, JD, MA Legal and Policy Analyst UW Carbone Cancer Center Pain & Policy Studies Group University of Wisconsin Madison, Wisconsin Charles E. Inturrisi, PhD Professor Department of Pharmacology Weill Cornell Medicine New York, New York Gordon Irving, MB, BS, MSc (Med), MMED, FFA(SA) Attending Swedish Pain Services Swedish Medical Center Seattle, Washington Robert N. Jamison, PhD Professor Departments of Anesthesia and Psychiatry Harvard Medical School Boston, Massachusetts

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Pain Management Center Brigham and Women’s Hospital Chestnut Hill, Massachusetts Nora Janjan, MD, MPSA, MBA Senior Fellow National Center for Policy Analysis Dallas, Texas Mark P. Jensen, PhD Professor and Vice Chair for Research Rehabilitation Medicine University of Washington Seattle, Washington Kaj Johansen, MD, PhD Clinical Professor of Surgery Department of Surgery University of Washington School of Medicine Staff Vascular Surgeon Department of Surgery Swedish Medical Center Seattle, Washington Anand B. Joshi, MD, MHA Assistant Professor Orthopedic Surgery Duke University School of Medicine Assistant Professor Orthopedic Surgery Duke Health Durham, North Carolina James D. Kang, MD Chairman Orthopedic Surgery

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Harvard Medical School Brigham and Women’s Hospital Boston, Massachusetts Roy L. Kao, MD Assistant Clinical Professor Pediatrics David Geffen School of Medicine at UCLA Los Angeles, California Pediatric Hematologist/Oncologist Miller Children’s and Women’s Hospital Long Beach, California Michael L. Kent, MD Assistant Professor Department of Anesthesiology Uniformed Services University Staff Anesthesiologist Department of Anesthesiology Walter Reed National Military Medical Center Bethesda, Maryland Wade King, MB, BS, MMedSc, MMed (Pain Mgt.), GDMuscMed, FAFMM Pain Physician Mayo Multidisciplinary Pain Clinic Mayo Private Hospital Taree, New South Wales, Australia Nancy D. Kishino, OTR/L, CVE Director West Coast Spine Restoration Center Riverside, California Claudia Kohner, PhD Licensed Clinical Psychologist

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Private Practice Encino, California Kristen Lynn Labovsky, MD Assistant Professor Department of Anesthesiology Medical College of Wisconsin/Children’s Hospital of Wisconsin Milwaukee, Wisconsin Irfan Lalani, MD Assistant Professor Department of Anesthesiology and Pain Medicine University of Texas M.D. Anderson Cancer Center Houston, Texas Hai V. Le, MD Resident Physician Orthopedic Surgery Harvard Medical School Brigham and Women’s Hospital Boston, Massachusetts David Justin Levinthal, MD, PhD Assistant Professor Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition University of Pittsburgh School of Medicine Director, Neurogastroenterology and Motility Center Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition University of Pittsburgh Medical Center Pittsburgh, Pennsylvania Bengt Linderoth, MD, PhD Professor Emeritus Department of Clinical Neuroscience

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Karolinska Institutet Retired Professor of Functional Neurosurgery Department of Neurosurgery Karolinska University Hospital Stockholm, Sweden Arthur G. Lipman†, PharmD Professor Emeritus Pharmacotherapy University of Utah School of Medicine Adjunct Professor of Anesthesiology and Director of Clinical Pharmacology Pain Management University of Utah Salt Lake City, Utah Dave Loomba, MD Assistant Professor Director of Resident Education Department of Anesthesiology and Pain Medicine University of California UC Davis Health System Sacramento, California Jürgen Lorenz, MD, PhD Professor Faculty of Life Sciences Hamburg University of Applied Sciences University Clinic Hamburg-Eppendorf Institute of Neurophysiology and Pathophysiology University of Hamburg Hamburg, Germany John MacVicar, MB, ChB, MPainMed Medical Director Southern Rehab 34

Christchurch, New Zealand Gagan Mahajan, MD Professor Anesthesiology and Pain Medicine University of California, Davis Sacramento, California Muhammad Hassan Majeed, MD Research Scholar Pain Management Boston PainCare Waltham, Massachusetts Attending Psychiatrist Psychiatry Natchaug Hospital Mansfield Center, Connecticut Athar N. Malik, MD, PhD Resident Physician Department of Neurosurgery Massachusetts General Hospital Harvard Medical School Boston, Massachusetts Georgios Manousakis, MD Assistant Professor Department of Neurology University of Minnesota Minneapolis, Minnesota Kenneth R. Maravilla, MD Professor Radiology and Neurological Surgery Radiology University of Washington Attending Neuroradiologist

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Radiology University of Washington Medical Center Seattle, Washington Michael T. Massey, DO University of Washington Seattle, Washington Martha A. Maurer, PhD, MPH, MSSW Associate Scientist UW Carbone Cancer Center Pain & Policy Studies Group University of Wisconsin—Madison Madison, Wisconsin Timothy Philip Maus, MD Professor Department of Radiology Mayo Clinic College of Medicine Rochester, Minnesota Lance M. McCracken, PhD Professor of Behavioral Medicine King’s College London Health Psychology Section Psychology Department Institute of Psychiatry, Psychology and Neuroscience (IoPPN) London, United Kingdom Ellen McGough, PT, PhD Associate Professor Department of Rehabilitation Medicine University of Washington Seattle, Washington Matthew K. Mian, MD Chief Resident 36

Department of Neurosurgery Massachusetts General Hospital Harvard Medical School Boston, Massachusetts Kristin Miller, MD, MS Assistant Professor Division of Pulmonary Disease and Critical Care Medicine Virginia Commonwealth University Health System, Medical College of Virginia Associate Medical Director Medical Respiratory Intensive Care Unit Department of Internal Medicine Virginia Commonwealth University Health System Richmond, Virginia James R. Miner, MD, FACEP Professor Department of Emergency Medicine University of Minnesota Chief Department of Emergency Medicine Hennepin County Medical Center Minneapolis, Minnesota Asako Miyakoshi, MD Radiologist Radiology Southern California Permanente Medical Group/Kaiser Permanente San Diego, California Jane Moore, MBBS, MRCOG Consultant Gynecologist Nuffield Department of Women’s and Reproductive Health University of Oxford Oxford, United Kingdom 37

David B. Morris, PhD University Professor (Retired) University of Virginia Richmond, Virginia James Michael Mossner, BS Medical Student University of Michigan Medical School Ann Arbor, Michigan Jennifer L. Murphy, PhD Clinical Assistant Professor Department of Neurology University of South Florida College of Medicine Supervisory Psychologist, Pain Section Mental Health and Behavioral Sciences James A. Haley Veterans’ Hospital Tampa, Florida Timothy J. Ness, MD, PhD Simon Gelman Endowed Professor of Anesthesiology Department of Anesthesiology and Perioperative Medicine University of Alabama at Birmingham Birmingham, Alabama Maureen Young Shin Noh, MD Adjunct Professor Orthopedics Duke University Staff Physician Physical Medicine and Rehabilitation Services VA Medical Center Durham, North Carolina Richard B. North, MD Professor of Neurosurgery (Retired)

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Anesthesiology and Critical Care Medicine Johns Hopkins University School of Medicine President The Neuromodulation Foundation Inc Baltimore, Maryland Kenneth C. Nwosu, MD Spine Fellow Orthopedic Surgery Harvard Medical School Brigham and Women’s Hospital Boston, Massachusetts Akiko Okifuji, PhD Professor Anesthesiology, Pain Research and Management Center University of Utah Salt Lake City, Utah John E. Olerud, MD Professor Emeritus University of Washington Division of Dermatology Seattle, Washington Jean-Pierre P. Ouanes, DO Assistant Professor Anesthesiology and Critical Care Medicine The Johns Hopkins University School of Medicine Clinical Faculty Anesthesiology and Critical Care Medicine The Johns Hopkins Hospital Baltimore, Maryland Judith A. Paice, PhD, RN Research Professor of Medicine Feinberg School of Medicine

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Northwestern University Director, Cancer Pain Program Division of Hematology-Oncology Northwestern Medicine Chicago, Illinois Tonya M. Palermo, PhD Professor Anesthesiology and Pain Medicine University of Washington School of Medicine Associate Director Center for Child Health, Behavior and Development Seattle Children’s Research Institute Seattle, Washington Parag G. Patil, MD, PhD Associate Professor and Associate Chair Departments of Neurosurgery, Neurology, Anesthesiology and Biomedical Engineering University of Michigan Medical School Ann Arbor, Michigan David M. Peterson, PharmD Adjunct Associate Professor Department of Pharmacotherapy University of Utah College of Pharmacy Drug Information Specialist Department of Pharmacy Services University of Utah Hospital Salt Lake City, Utah Stacy J. Peterson, MD Assistant Professor Anesthesiology, MCW Pain Management Center Medical College of Wisconsin Milwaukee, Wisconsin 40

Ravi Prasad, PhD Clinical Associate Professor Department of Anesthesiology, Perioperative and Pain Medicine Stanford University Stanford, California Amir Ramezani, PhD Psychologist Surgery University of California, Davis Sacramento, California Alan Randich, PhD Professor Emeritus Anesthesiology University of Alabama at Birmingham Birmingham, Alabama Ahmed M.T. Raslan, MD Associate Professor of Neurological Surgery School of Medicine Neuroscience Quality Director Oregon Health & Science University Portland, Oregon James P. Rathmell, MD Chair, Department of Anesthesiology, Perioperative and Pain Medicine Brigham and Women’s Hospital Leroy D. Vandam Professor of Anesthesia, Harvard Medical School Boston, Massachusetts Maria Regina Reyes, MD Associate Professor Department of Rehabilitation Medicine University of Washington Staff Physician

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Spinal Cord Injury Service Department of Veterans Affair VA Puget Sound Health Care System Seattle, Washington Ben A. Rich, JD, PhD Emeritus Chair and Professor of Bioethics Internal Medicine and Anesthesiology and Pain Medicine UC Davis School of Medicine Sacramento, California Steven H. Richeimer, MD Professor of Anesthesiology and Psychiatry Chief, Division of Pain Medicine Department of Anesthesiology Keck School of Medicine University of Southern California Los Angeles, California Bobbie L. Riley, MD, FAAP Instructor Anesthesia Harvard Medical School Staff Anesthesiology, Critical Care and Pain Medicine Boston Children’s Hospital Boston, Massachusetts James P. Robinson, MD, PhD Clinical Professor Department of Rehabilitation Medicine University of Washington Seattle, Washington Edgar Ross, MD Associate Professor Anesthesia

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Harvard Medical School Brigham and Women’s Hospital Boston, Massachusetts Nathan J. Rudin, MD, MA Professor Department of Orthopedics and Rehabilitation University of Wisconsin School of Medicine and Public Health Madison, Wisconsin Ramsey Saba, MD Resident PGY4 Anesthesia Harvard Medical School Department of Anesthesiology, Perioperative and Pain Medicine Brigham and Women’s Hospital Boston, Massachusetts Friedhelm Sandbrink, MD Clinical Associate Professor Department of Neurology Uniformed Services University Bethesda, Maryland Director Pain Management Program Department of Neurology Washington DC VA Medical Center Washington, DC Andrew J. Saxon, MD Professor Department of Psychiatry and Behavioral Sciences University of Washington Director, Center of Excellence in Substance Abuse Treatment and Education Mental Health VA Puget Sound Health Care System 43

Seattle, Washington Michael E. Schatman, PhD Adjunct Clinical Assistant Professor Department of Public Health and Community Medicine Tufts University School of Medicine Boston, Massachusetts Director Research and Network Development Boston Pain Care Waltham, Massachusetts Neil L. Schechter, MD Associate Professor Anesthesiology Harvard Medical School Director, Chronic Pain Clinic Anesthesiology, Critical Care, Pain Medicine Boston Children’s Hospital Boston, Massachusetts Jerome Schofferman, MD Founder and Current Member Section on Rehabilitation, Interventions and Medical Spine Immediate Past Chair, Committee on Ethics and Professionalism North American Spine Society Private Practice (Retired) Sausalito, California Curtis N. Sessler, MD, FCCP, FCCM Orhan Muren Distinguished Professor of Medicine Department of Internal Medicine Virginia Commonwealth University Director, Center for Adult Critical Care Medical Director, Critical Care Medical Director, Medical Respiratory ICU 44

Virginia Commonwealth University Health System Richmond, Virginia Jay P. Shah, MD Affiliate Professor Bioengineering Department George Mason University Fairfax, Virginia Senior Staff Physiatrist and Clinical Investigator Rehabilitation Medicine Department, Clinical Center National Institutes of Health Bethesda, Maryland Sam R. Sharar, MD Professor, Vice Chair for Faculty Affairs and Development Anesthesiology and Pain Medicine University of Washington School of Medicine Attending Anesthesiologist Anesthesiology Harborview Medical Center Seattle, Washington Charles A. Simpson, DC, DABCO Senior Clinical Advisor Clinical Services The CHP Group Beaverton, Oregon David M. Simpson, MD, FAAN Professor of Neurology Director, Clinical Neurophysiology Laboratories Director, Neuromuscular Division Director, Neuro-AIDS Program Icahn School of Medicine at Mount Sinai New York, New York

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Jill Sindt, MD Assistant Professor Department of Anesthesiology University of Utah Associate Director Pain Medicine Huntsman Cancer Hospital Salt Lake City, Utah Christopher D. Sletten, PhD, ABPP Clinical Director, MCPRC Assistant Professor of Psychology Department of Pain Medicine Mayo Medical School Mayo Clinic Florida Jacksonville, Florida Howard S. Smith†, MD Associate Professor & Academic Director of Pain Management Department of Anesthesiology Albany Medical College Albany, New York Benjamin C. Soydan, PT, DPT, OCS, CSCS Physical Therapist Physical Medicine and Rehabilitation Services VA Medical Center Durham, North Carolina Pamela Squire, MD Associate Clinical Professor Department of Medicine University of British Columbia Vancouver, Canada Steven P. Stanos, DO Physiatrist 46

Pain Medicine, Physical Medicine and Rehabilitation Swedish Pain Services—First Hill Seattle, Washington Milan P. Stojanovic, MD Anesthesiology Critical Care and Pain Medicine Service VA Boston Healthcare System Harvard Medical School Boston, Massachusetts Edith Nourse Rogers Memorial Veterans Hospital Bedford, Massachusetts Mark D. Sullivan, MD, PhD Professor Department of Psychiatry and Behavioral Sciences University of Washington Attending Physician Psychiatry University of Washington Medical Center Seattle, Washington Lalitha Sundararaman, MBBS, MD Clinical Instructor Department of Anesthesiology Brigham and Women’s Hospital Clinical Instructor Anesthesiology Brigham and Women’s Hospital, Harvard Medical School Boston, Massachusetts Kimberly Shawn Swanson, PhD Psychologist Behavioral Health St. Charles Medical Center Bend, Oregon 47

Pratik A. Talati, MD, PhD Resident Department of Neurosurgery Harvard Medical School Massachusetts General Hospital Boston, Massachusetts Rajbala Thakur, MBBS Professor of Anesthesiology and Physical Medicine and Rehabilitation Department of Anesthesiology University of Rochester Rochester, New York Siddarth Thakur, MD Instructor, Research Faculty Pain Medicine The University of Texas MD Anderson Cancer Center Houston, Texas Brian R. Theodore, PhD Research Scientist II Kaiser Permanente Kaiser Foundation Rehabilitation Center Vallejo, California George I. Thomas, MD Emeritus Clinical Professor Surgery University of Washington School of Medicine Seattle, Washington Beverly E. Thorn, PhD Professor Emerita Department of Psychology The University of Alabama Tuscaloosa, Alabama

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Vicente Garcia Tomas, MD Assistant Professor Director, Acute Pain Service at Bayview Medical Center Division of Regional Anesthesia and Acute Pain Medicine Johns Hopkins University Baltimore, Maryland Dennis C. Turk, PhD John and Emma Bonica Endowed Chair and Professor of Anesthesiology and Pain Research Department of Anesthesiology and Pain Medicine University of Washington Seattle, Washington Jan Van Zundert, MD, PhD, FIPP Associate Professor Anesthesiology and Pain Management Ziekenhuis Oost-Limburg Genk, Belgium Maastricht University Medical Center Maastricht, The Netherlands Mary Alice Vijjeswarapu, MD Assistant Program Director, Pain Medicine Anesthesia Fellowship Program Department of Anesthesiology Cedars-Sinai Medical Center Los Angeles, California Katy Vincent, MRCOG, DPhil Senior Pain Fellow Nuffield Department of Women’s and Reproductive Health University of Oxford Consultant Gynecologist Department of Obstetrics and Gynecology John Radcliffe Hospital, Oxford University Foundation Trust Oxford, United Kingdom 49

Ashwin Viswanathan, MD Associate Professor Department of Neurosurgery Baylor College of Medicine Houston, Texas Yakov Vorobeychik, MD, PhD Professor Department of Anesthesiology and Perioperative Medicine Penn State Milton S. Hershey Medical Center Hershey, Pennsylvania Simon Vulfsons, MD Director, Institute for Pain Medicine Rambam Health Care Campus Technion—Israel Institute of Technology Haifa, Israel Gary A. Walco, PhD Professor Anesthesiology and Pain Medicine University of Washington Director Pain Medicine Seattle Children’s Hospital Seattle, Washington David Walk, MD Associate Professor Department of Neurology University of Minnesota Minneapolis, Minnesota Ajay D. Wasan, MD, MSc Vice Chair for Pain Medicine Department of Anesthesiology

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Professor of Anesthesiology and Psychiatry University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania Faye M. Weinstein, PhD Associate Professor Anesthesiology and Psychiatry University of Southern California Los Angeles, California Steven J. Weisman, MD Jane B. Pettit Chair in Pain Management Children’s Hospital of Wisconsin Professor of Anesthesiology and Pediatrics Medical College of Wisconsin Milwaukee, Wisconsin Shelley A. Wiechman, PhD, ABPP (Rp) Associate Professor Rehabilitation Medicine University of Washington Attending Psychologist University of Washington Burn Center Harborview Medical Center Seattle, Washington Matthew S. Willsey, MD Resident in Neurosurgery University of Michigan Medical School Ann Arbor, Michigan Hilary D. Wilson, PhD Research Scientist Outcomes Research Evidera Seattle, Washington

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Cynthia A. Wong, MD Professor, Chair and Department Executive Officer Department of Anesthesia University of Iowa Carver College of Medicine Iowa City, Iowa R. Joshua Wootton, MDiv, PhD Assistant Professor Anesthesia Harvard Medical School Boston, Massachusetts Director of Pain Psychology Department of Anesthesia, Critical Care and Pain Medicine Beth Israel Deaconess Medical Center Brookline, Massachusetts Christopher L. Wu, MD Clinical Professor of Anesthesiology Department of Anesthesiology The Hospital for Special Surgery, Weill Cornell Medical College New York, New York Takahisa Yamasaki, MD, PhD Research Fellow Division Gastroenterology and Hepatology MetroHealth Medical Center Visiting Scholar Case Western Reserve University Cleveland, Ohio Jimmy Chen Yang, MD Clinical Fellow Department of Neurosurgery Harvard University Resident Physician Department of Neurosurgery 52

Massachusetts General Hospital Boston, Massachusetts Lynda J. Yang, MD, PhD Clinical Professor Department of Neurosurgery University of Michigan Medical School Ann Arbor, Michigan Shelley Yang, MD Dermatology Chief Resident University of Washington Division of Dermatology Seattle, Washington Adam C. Young, MD Assistant Professor, Department of Anesthesiology Director of Acute Pain Management Rush University Medical Center Chicago, Illinois Lin Yu, PhD Researcher Pain Management Centre Guy’s and St. Thomas NHS Foundation Trust London, United Kingdom Fadel Zeidan, PhD Assistant Professor Department of Neurobiology and Anatomy Associate Director of Neuroscience Center for Integrative Medicine Wake Forest School of Medicine Winston Salem, North Carolina Lonnie Zeltzer, MD Distinguished Professor Pediatrics, Anesthesiology, Psychiatry and Behavioral Sciences 53

David Geffen School of Medicine at UCLA Director Pediatric Pain & Palliative Care Program Pediatrics UCLA Center for Health Sciences UCLA Mattel Children’s Hospital Los Angeles, California

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Foreword This, the fifth edition of Bonica’s Management of Pain, continues the tradition that John J. Bonica, MD, started with the publication of the first edition in 1953. That was a herculean endeavor and a monumental achievement, as no one had ever attempted to comprehensively describe all that was known about pain and how to diagnose and treat it. The first edition was almost exclusively the work of Dr. Bonica; only minor sections were contributed by his colleagues. It took him 30 years to bring out the second edition, which was the product of not only Bonica but also of a long list of contributors who in fact wrote more than half of the pages. This edition was characterized by extensive consideration of the anatomy and physiology underlying pain and by the discussion of multidisciplinary pain management and pain clinics. The field of pain medicine, launched by Bonica’s own practice and teaching and by his founding of the International Association for the Study of Pain, had flourished by the time of the second edition, as pain medicine and research were developing rapidly. Bonica knew that another edition of the Bonica’s Management of Pain would have to be written to keep his textbook current. Unfortunately, his health limited his ability to undertake this task. Shortly before he died, I promised him that there would be a third edition that I would edit with the help of colleagues at the University of Washington. This was published in 2000, firmly based on the format of the prior editions but expanding the content to keep up with developments in both basic science and clinical pain management. Another decade passed; the sciences basic to pain and clinical practice continued to rapidly expand. The fourth edition of this great book was 55

produced by new editors who assembled an all-star group of contributors to continue what Bonica began over 60 years ago. Now, it is time for the fifth edition to be created to set the pace for the coming decade of pain research, teaching, and patient care. Whereas everyone active in pain research or patient care knew John Bonica in the last 30 years of the 20th century, we now have spawned a generation or two of workers in this field who know him only through his publications or the occasional prophetic story. Although this is an understandable reality, it is unfortunate. John Bonica was a truly great man whose efforts almost single-handedly caused pain to be put on the road maps of both basic science and health care. As I wrote in his obituary published in Pain1: “He cared about his patients for whom he tirelessly worked. He cared about the research that scientists undertook to understand the mechanisms of pain. He cared about those who suffered in far-away places; he wanted their doctors to learn about pain management. He cared about how governments impacted the delivery of pain management services. He cared about his students, trainees, and colleagues. He really cared about those who attempted to continue what he had started. He cared about his children and his wife, although his career took time away from them.”(p2) More than an inscription on his gravestone, the continued life of Bonica’s Management of Pain tells us of his accomplishments. It was a privilege to have known him and his family. Working for and with him and carrying on the traditions that he launched has been an honor. JJB, as he was known to all who worked alongside him, would have been thrilled to see the advances that he inspired. His greatness will live on through the publication of this fifth edition. JOHN D. LOESER, M.D. June 2018 1Loeser JD. Obituary: John J Bonica, M.D. and Emma B. Bonica. Pain 1994;59:1–3.

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Preface to the Fifth Edition (2019) This book was first introduced 66 years ago, at a time that many believe marks the beginning of the multidisciplinary field of pain management. The idea for a clinical textbook devoted to the management of pain came from John Bonica, and in its first edition, he wrote that the book offers a synthesis of information from disparate disciplines to form a complete discussion on pain and its management. Such a book, he believed, would strengthen the field of medicine by assimilating new insights and growing knowledge from many interested disciplines. Since the first edition in 1953, the purpose of the book has remained the same despite extraordinary growth in the science and practice of pain management and the emergence of pain medicine as its own discipline. The book has remained a key reference for clinicians largely because of the high quality of the original book and its ability to attract world-class experts to engage in his project, even years after Dr. Bonica’s death in 1994. It was with trepidation and pride that we, the three chief editors, first accepted the task of shepherding the fourth edition of this essential book to publication. We quickly realized that we were no match for Bonica, who formulated and wrote large parts of the original book himself, and from the start, we solicited help from expert subeditors. As an editorial group, we made several key decisions: that we would keep the book near its original manageable size, that understanding anew the key role played by central mechanisms in pain, that we would shift the book’s emphasis from its focus on peripheral (anatomically based) mechanisms to one with a greater focus on neural (global) mechanisms, and that we would include new or updated chapters on issues that impact clinical pain management such as pain training, 57

regulatory and political issues, and conducting clinical trials. In his first edition, John Bonica tells us that he was called to write his book out of the “. . . deep feeling for those who are afflicted with intractable pain, and by an intense desire to contribute something toward the alleviation of their suffering.” This commitment originated from his experiences in treating wounded soldiers with intractable pain during the Second World War. It is sad and ironic that this fourth edition was published in 2009 at a time when inadequate treatment of pain had come to be more widely recognized than ever and, in part, informed by wounded soldiers returning from the wars in Iraq and Afghanistan. In the year just prior to publishing the fourth edition, the US Congress passed, and the President of the United States signed into law, two bills that aimed to improve pain care for active military personnel and veterans, respectively. More than 50 years after Bonica began to raise awareness about the plight of those in pain, our society was coming to increasingly value safe and effective control of pain, and the trend echoed Bonica’s vision of a world free of suffering from treatable pain. Over the past 9 years, since the publication of the fourth edition of the textbook, there has been widespread recognition of a devastating crisis in opioid abuse and deaths as well as excessive prescribing of opioids. Much controversy has arisen regarding the use of opioids, particularly opioids for chronic pain. This controversy plays out in the pages of this the fifth edition, and you will find opposing and at times mutually exclusive opinions expressed. We, the editors, did not try to align the opinions of all of the experts expressed in the text. We allow readers to consider the disparate opinions on their own while we await the science we need to point us toward the best practices. The fourth edition of the textbook remained faithful to Bonica’s original intent that his book should provide a comprehensive reference for practicing clinicians across all disciplines. In 1953, Bonica was one of few experts in a nascent new field that would become pain medicine, and he almost single-handedly undertook the task of producing the first clinical textbook. Now, there are many experts with a remarkable depth of knowledge. It is a testament to Bonica that the many leading authorities contributing to the fourth and now this fifth edition as authors and section editors feel sincerely indebted to him, and they have willingly given of 58

their time to maintain his legacy. Through its second and third editions, the book maintained a structure and organization similar to the first edition. In the fourth edition, every chapter was revised, substantially rewritten, or represented a completely new chapter and or topic. With a text of such broad scope, some degree of overlap was inevitable; indeed, we have often allowed significant overlap, so that each chapter would stand on its own during independent perusal or study. Like the fourth edition, this fifth edition of the book is divided into six parts: (1) Basic Considerations; (2) Economic, Political, Legal, and Ethical Considerations; (3) Evaluation of the Pain Patient; (4) Pain Conditions; (5) Methods for Symptomatic Control; and (6) Provision of Pain Treatment. Basic Considerations offers an orientation to the history of pain management and the concepts and paradigms fundamental to this field, including taxonomy, basic science, anatomy, physiology, psychology, and social science. Economic, Political, Legal, and Ethical Considerations represents new content for this textbook, reflecting the emerging social impact of pain and pain management. Evaluation of the Pain Patient covers physical and psychological assessment and use of imaging and other technology-based testing as well as special assessment for function, disability, addiction, and multidisciplinary care. Pain Conditions is the largest single part of the text, comprising 9 sections and 53 chapters. These sections include neuropathic pain syndromes; psychological contributions to pain; vascular, cutaneous, and musculoskeletal pains; pain due to cancer; acute pain; pain in special populations; visceral pain; regional pain; and neck and low back pain. The section on pain in special populations addresses populations such as children, older persons, and those with pain and addiction. The regional pain section is a holdover from past editions and covers pain disorders that are associated with discrete parts of the body such as facial pain, cranial neuralgias, and pain syndromes associated with upper or lower extremities. Methods of Symptomatic Control is another large part of the text which is partitioned into the following six sections: pharmacologic therapies, psychological techniques, physical and other noninterventional therapeutic modalities, implanted electrical stimulators, interventional pain management, and surgical approaches. Provision of Pain Treatment is the final part of this text, addressing 59

systems for delivery of care and means for training pain specialists. Special areas of medicine in which pain has a prominent role are addressed, including primary care, end-of-life care, intensive care, and emergency care. The text concludes with a brief view toward the future of pain management. This book would not be possible without the extensive contributions of the section editors and particularly the efforts of the chapter authors; the success of this work is directly attributable to these individuals. The editors are indebted to Brian Brown and Keith Donnellan of Wolters Kluwer who served critical roles in shepherding this project into existence and managed its development with skill and diplomacy. As the field of pain medicine has evolved, so has this text. Despite much that is new or revised, the text remains incomplete, a reflection of an emerging field that awaits profound discoveries and development. Through the many chapters and pages of this new fifth edition of his classic text, we hope that John Bonica’s passion for an integrated, coherent, and compassionate field will live on. Like Bonica, our central purpose is to assist students and practitioners across all medical disciplines, advance their knowledge of pain medicine, and relieve suffering.

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Preface to the First Edition (1953) The purpose of this book is to present within one volume a concise but complete discussion of the fundamental aspects of pain, the various diseases and disorders in which pain constitutes a major problem, and the methods employed in its management, with special emphasis on the use of analgesic block as an aid in the diagnosis, prognosis, and therapy. Although several books dealing with certain phases of this problem are available, none is complete from the standpoint of the practitioner; for it is necessary for him to consult several texts in order to obtain information regarding the cause, characteristics, mechanisms, effects, diagnosis, and therapy of pain and management of its intractable variety with analgesic block and certain adjuvant methods. The present volume is the product of the author’s desire to facilitate the task of the busy practitioner and to supply him easily accessible information with the conviction that this will induce more clinicians to employ these methods of diagnosis and therapy. One need not elaborate on the reasons for writing on the management of pain, for reflection emphasized that this age-old problem is still one of the most difficult and often vexing phases of medical practice—a fact well appreciated by most physicians. This fact, as well as other reasons, are presented in the introduction and are emphasized throughout the book, particularly in Chapter 5. I have been motivated to write this volume by a deep feeling for those who are afflicted with intractable pain, and by an intense desire to contribute something toward the alleviation of their suffering. The plan for its writing was germinated almost a decade ago during the Second World War, while I was Chief of the Anesthesia Section of a large Army hospital, 61

where I was afforded the opportunity to observe and manage an unusually large number of patients with severe intractable pain. The gratifying results obtained with analgesic block in some instances impressed me with the efficacy of this method in selected cases. In addition, the fact that these procedures effected relief which frequently was not only dramatic, but outlasted by hours and days the transient physiochemical interruption of nerve impulses, fascinated me and aroused my interest. Perusal of the literature revealed a paucity of material on this subject—a situation which has not changed much since then and which clearly indicated an obvious need for a practical source of information about this perplexing phenomenon and the application of analgesic block to its management. This book is composed of three parts. The first part includes a discussion of the fundamental aspects of pain. While some of the material, on superficial thought, might be considered too detailed or entirely unnecessary, it has been included because of my conviction that in order to manage pain properly its anatomical, physiological and psychological bases must be understood. As is true in all fields of endeavor, a thorough knowledge of fundamental principles is an essential prerequisite without which optimal results are precluded. In order to diagnose and treat it properly, the physician must know the course of pain from its place of origin to the apperception centers in the brain and must be well versed in all the essentials and components of which pain consists; he must know its causes, mechanisms, characteristics, varieties, its localizations and significance, and the mental and physical effects it produces. The second part deals with methods and techniques of managing pain. It was originally planned to include only the method which is the central theme of the book—analgesic block. However, it was soon realized that while this important phase is, to be sure, here treated in a comprehensive manner, it does not present the complete story of the management of pain; because frequently other adjuvant methods are employed in conjunction with nerve blocking. To illustrate the point, trigeminal neuralgia is frequently treated with neurolytic blocks, but sometimes this does not afford sufficiently long relief, and neurotomy is resorted to. The pain associated with malignancy is managed with alcohol nerve block, but roentgen therapy is frequently employed as an adjuvant. Moreover 62

physical and/or psychiatric therapy constitute integral phases of the management of pain without which optimal results cannot be hoped for. After careful consideration, it was decided to include another section in Part II in which are presented methods that are frequently employed in conjunction with analgesic block. It is hoped that such inclusion will give the book a wider scope and greater usefulness. In the third part are presented various diseases or disorders with painful syndromes which have been and can be managed with analgesic block with or without the aid of other methods. The arrangement of this part is explained in detail on page 671. It is suggested that the reader refer to that page before proceeding further to read any on the pain syndromes. Though the material in this part mainly represents my observations, clinical impressions, and opinions, obtained or developed from experience with, and statistical analysis of, many thousands of cases, it also includes unpublished data of several outstanding authorities who have kindly placed them at my disposal. Moreover, it includes the published views and clinical experiences of others, with credit given where it is due. In writing this comprehensive treatise, which has involved no small amount of time and effort, the one principle which has always been kept in mind and adhered to has been to present the fundamental considerations and principles of the problem before the practical aspects are discussed. I have endeavored to make this book as complete as possible, and to this end have thoroughly searched the literature, both English and foreign, and have taken from it all that I thought might be valuable to the reader. In order to comply with the aim of completeness and still keep the book concise and within reasonable size, the material has been selected with care and discretion. In a field so vast and complex as pain, it is unavoidable that what might be thought sufficiently important to deserve detailed discussion is presented in an abbreviated manner or entirely omitted. In other instances, mere mention or omission represents a reluctant compliance with the requirements dictated by the size of the volume. Nonetheless, I believe thoroughness and important detail have not been sacrificed. The bibliography represents the most important references, and many excellent articles on each subject were also reluctantly omitted for that reason. 63

The book is intended for practitioners of every field of medicine, because pain is universal and provides the main reason why patients seek the aid of the doctor. It is hoped that it will prove useful, not only to the anesthesiologist, neurologist, neurosurgeon, orthopedist, and physiatrist to whom especially is relegated the task of caring for patients with intractable pain, but also to the general practitioner, surgeon, internist, psychiatrist, and any other physician who may be confronted with this problem. It is especially intended for general practitioners, particularly those practicing in smaller communities where the services of a specialist in analgesic blocking are not available. With this aim in mind the techniques of analgesic block are presented in such a manner that most of them may be effectively accomplished by any physician, even though he may be a novice with regional analgesia. In order to facilitate the task of the busy reader, less relevant facts—material which has been included because of its academic importance, for the sake of completeness, or for consumption by students and those who wish to delve deeper into the problem—are presented in small type. These can be omitted without losing continuity of thought. In this manner, while completeness, detail, and thoroughness are not sacrificed, emphasis is laid on the practical aspects of the problem at hand. The unusually large number of illustrations, many of which are original and composed from dissected material or clinical cases, have been included with the conviction that these frequently tell the story much better than words. A book of this nature is made possible only by the contribution of many individuals. The information set forth in the first part of the volume represents the fruition of the joint effort of anatomists, physiologists, pharmacologists, neurologists, neurosurgeons, anesthesiologists, psychiatrists, and many other laboratory and clinical investigators who have spent untold time, labor, and effort to discover the mystery of pain. I am grateful for their elucidating knowledge. To clinicians who have reported their experiences, and to others who have placed at my disposal unpublished data, observations, and opinions, my sincere thanks. I am particularly obliged to General Maxwell Keeler, and Col. Clinton S. Lyter, of Madigan Army Hospital for their continuous cooperation in obtaining 64

much of the clinical data embraced in this volume. I want to express my gratitude to Mr. Harold Woodworth for his friendship, sympathetic understanding and devotion to the cause of medicine. I also want to thank the other members of the Board of Trustees of Tacoma General Hospital, but particularly Mr. Alex Babbit, and Mr. Walter Heath and John Dobyns, Directors of the hospital. Their continuous cooperation has facilitated the activities of the Department of Anesthesia, Nerve Block Clinic, and Pain Clinic. I am very grateful to Dr. Robert Johnson, Associate Professor of Anatomy of the University of Washington School of Medicine, for his encouragement and criticism of some parts of the manuscript; to Doctor Frederick Haugen for his assistance, criticism and suggestion. My collaborators, Professor Robert Ripley, Doctors Wendell Peterson, Frank Rigos, John T. Robson, Col. Clark Williams, M.C., and Lieut. Col. Walter Lumpkin, M.D., have my heartfelt thanks for their contributions and cooperation. My appreciation is extended to Miss Joy Polis, Miss Virginia Coleman, and other artists for the illustrations and to Mr. Kenneth Ollar for the photography; to Mrs. Louise Cameron for her cooperation in obtaining the roentgenograms; to Mrs. Katherine Rogers Miller, Miss Eleanor Ekberg and the late Mrs. Blanch DeWitt of Tacoma, Miss Bertha Hallam, Portland, and Mr. Alderson Fry, Seattle—all librarians whose cooperation has facilitated a difficult task, and to Mr. John Morrison for editorial work. This preface would be incomplete if I did not acknowledge my indebtedness to my secretaries, Miss Katherine Stryker and Mrs. Dorothy Richmond, for the inestimable aid they have given me in the preparation of the manuscript. My appreciation is extended to my publishers for their courtesy, cooperation, and considerateness throughout the preparation of this volume. JOHN J. BONICA Tacoma, Washington

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Acknowledgments Jane C. Ballantyne and James P. Rathmell thank Dr. Warren Zapol, immediate past Chair of the Department of Anesthesiology and Critical Care at Massachusetts General Hospital, for his encouragement and support. Scott M. Fishman thanks the exceptional faculty of the Division of Pain Medicine and Dr. Richard Applegate, Chair of the Department of Anesthesiology and Pain Medicine at the University of California, Davis, for encouragement and support.

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Contents PA R T O N E Basic Considerations CHAPTER 1 Intellectual Milestones in Our Understanding and Treatment of Pain G.F. GEBHART

Pain Understood as Part of a Larger Philosophy or Worldview Mechanistic Views of Pain 19TH CENTURY—PAIN AS A SPECIFIC SENSE AFFERENT SIGNALING GATE CONTROL THEORY Treatments for Pain Cognitive Treatment for Pain Pharmacologic Treatment of Pain Anatomically Specific Treatments for Pain The Specialty of Pain Medicine ACKNOWLEDGMENTS CHAPTER 2 Pain Terms and Taxonomies of Pain DENNIS C. TURK AND AKIKO OKIFUJI

Definition of Commonly Used Pain Terms Taxonomies EXPERT-BASED CLASSIFICATIONS OF PAIN CLASSIFICATION BASED ON ANATOMY CLASSIFICATION BASED ON DURATION CLASSIFICATION BASED ON THE ETIOLOGY OF PAIN 67

CLASSIFICATION BASED ON BODY SYSTEM CLASSIFICATION BASED ON SEVERITY CLASSIFICATION BASED ON FUNCTIONING CLASSIFICATION BASED ON INTENSITY AND FUNCTIONING CLASSIFICATION BASED ON PROGNOSIS MECHANISM-BASED CLASSIFICATION OF PAIN Multiaxial Classifications Empirically Based Classification of the Psychological Components of Pain COMPREHENSIVE, MULTIDIMENSIONAL CLASSIFICATION OF PAIN: INTERNATIONAL ASSOCIATION FOR THE STUDY OF PAIN TAXONOMY COMPREHENSIVE, MULTIDIMENSIONAL CLASSIFICATION OF PAIN: ACTTION-AMERICAN PAIN SOCIETY AND ACTTION-AMERICAN PAIN SOCIETYAMERICAN ACADEMY OF PAIN MEDICINE INDUCTIVE EMPIRICALLY BASED CLASSIFICATIONS OF PAIN PSYCHOMETRIC CONSIDERATIONS Conclusion CHAPTER 3 Peripheral Pain Mechanisms and Nociceptor Sensitization MICHAEL S. GOLD

Functional Characterization of Nociceptors Identification of Putative Nociceptors Nociceptor Characteristics ANATOMY OF THE NOCICEPTOR STIMULUS TRANSDUCTION PASSIVE ELECTROPHYSIOLOGIC PROPERTIES AND THE SPREAD OF THE GENERATOR POTENTIAL ACTION POTENTIAL GENERATION ACTION POTENTIAL PROPAGATION TRANSMITTER RELEASE Nociceptor Sensitization 68

Clinical Implications of Nociceptor Function CHAPTER 4 Substrates of Spinal Cord Nociceptive Processing JENNIFER J. DEBERRY, ALAN RANDICH, AND TIMOTHY J. NESS

Defining Nociceptive Systems MODELS OF PAIN PROCESSING METHODS OF NEURONAL CHARACTERIZATION DEFINING NOCICEPTIVE SECOND-ORDER NEURONS DEVELOPMENT OF SENSORY SYSTEMS Targets of Primary Afferent Input GROSS ANATOMY OF THE SPINAL CORD SPINAL LAMINAE FUNCTIONAL CHARACTERIZATION OF NOCICEPTIVE NEURONS CLASSIFICATION ACCORDING TO SITE OF PROJECTION Targets of Axonal Projections INTRASPINAL PATHWAYS SPINOTHALAMIC TRACT Ventrolateral (Anterolateral) Axonal Pathways Neospinothalamic versus Paleospinothalamic Laminar Distribution of Spinothalamic Tract Neurons Functional Characterization of Spinothalamic Tract Neurons Dorsolateral and Ventromedial Axonal Pathways SPINORETICULAR AND SPINOMESENCEPHALIC TRACTS Ventrolateral (Anterolateral) Axonal Pathways Features of Spinoreticular Neurons Features of Spinomesencephalic Neurons POSTSYNAPTIC DORSAL COLUMN NEURONS OTHER ASCENDING PATHWAYS Neurochemistry of Second-order Neurons NEUROTRANSMITTERS FROM PRIMARY AFFERENTS Excitatory Amino Acids: Ionotropic Receptor/Channels Metabotropic Glutamate Receptors Substance P Calcitonin Gene-Related Peptide 69

Cholecystokinin Other Neuropeptides Adenosine Triphosphate Colocalization of Neurotransmitters NEUROTRANSMITTERS FROM INTERNEURONS Inhibitory Amino Acids Opioids Acetylcholine Other Neurotransmitters within Interneurons NEUROTRANSMITTERS FROM SUPRASPINAL SOURCES Serotonin (5-Hydroxytryptamine) Noradrenaline Other Neurotransmitters in Descending Systems NEUROTRANSMITTERS FROM GLIA OR UNKNOWN SOURCES OTHER IMPORTANT RECEPTORS/CHANNELS What Is Important to the Clinician ACKNOWLEDGMENTS CHAPTER 5 Modulation of Spinal Nociceptive Processing TIMOTHY J. NESS, ALAN RANDICH, AND JENNIFER J. DEBERRY

Spinal Cord–Based Modulatory Mechanisms ACUTE SEGMENTAL MODULATORY EFFECTS HETEROSEGMENTAL MODULATORY SYSTEMS C-FIBER WIND-UP AND CENTRAL SENSITIZATION Supraspinal Modulatory Systems TONIC DESCENDING INFLUENCES SUPRASPINAL SUBSTRATES MEDIATING THE DESCENDING MODULATION OF PAIN Periaqueductal Grey of the Mesencephalon and the Rostral Ventral Medulla Other Deep Brain Sites Cortical Structures SUMMARY OF SUPRASPINAL INFLUENCES ON, OFF, AND NEUTRAL CELLS 70

Triggers of Clinical Hypersensitivity ALLODYNIA AND HYPERALGESIA INFLAMMATION-INDUCED HYPERSENSITIVITY AND INHIBITORY SYSTEMS STRESS-INDUCED ANALGESIA AND HYPERALGESIA NEUROPATHIC PAIN OPIOID-INDUCED HYPERALGESIA Conclusion CHAPTER 6 Supraspinal Mechanisms of Pain and Nociception MICHAEL HAUCK AND JÜRGEN LORENZ

Functional Imaging of Pain in Humans METHODOLOGIES OF NONINVASIVE AND INVASIVE FUNCTIONAL BRAIN IMAGING IN PAIN Brainstem PERIAQUEDUCTAL GRAY MATTER—A KEY STRUCTURE OF ENDOGENOUS ANALGESIA MESOLIMBIC DOPAMINE SYSTEM Hypothalamus Thalamus THE LATERAL PAIN SYSTEM—THE SENSORYDISCRIMINATIVE PATHWAY SPINAL CONNECTIONS TO BRAINSTEM AND MEDIAL THALAMUS—THE AFFECTIVE PATHWAY Cortex SENSORY AREAS Primary Somatosensory Cortex Secondary Somatosensory Cortex LIMBIC AREAS Insular Cortex Cingulate Cortex Prefrontal Cortex Amygdala Hippocampus Vigilance, Arousal, and Attention in Pain Processing 71

Pain Plasticity Summary and Conclusion CHAPTER 7 Psychological Aspects of Pain DENNIS C. TURK, KIMBERLY SHAWN SWANSON, AND HILARY D. WILSON

Cognitive Factors: Predispositions, Appraisals, Beliefs, Perceived Control, and Self-efficacy PREDISPOSITIONS APPRAISAL AND BELIEFS CATASTROPHIZING AND FEAR-AVOIDANCE BELIEFS PERCEIVED CONTROL AND SELF-EFFICACY COPING Stress and Autonomic Responses: Hypothalamic-Pituitary-Adrenal Axis Dysregulation Emotion ANXIETY DEPRESSION ANGER AND HOSTILITY Psychogenic Conceptualizations of Chronic Pain PSYCHOGENIC VIEW Behavioral Formulations CLASSICAL CONDITIONING OPERANT CONDITIONING SOCIAL (OBSERVATIONAL) LEARNING GATE CONTROL THEORY Cognitive-Behavioral Perspective TREATMENTS BASED ON THE COGNITIVE-BEHAVIORAL PERSPECTIVE Biopsychosocial, Contextual Model Families and Family Systems Perspective Conclusion CHAPTER 8 Individual Differences in Pain: The Roles of Gender, Ethnicity, and Genetics ROGER B. FILLINGIM

Sex and Gender Differences in Pain 72

CLINICAL PAIN EXPERIMENTAL PAIN RESPONSES TO PAIN TREATMENT BIOPSYCHOSOCIAL MECHANISMS Ethnic Group Differences in Pain CLINICAL PAIN EXPERIMENTAL PAIN RESPONSES TO PAIN TREATMENT BIOPSYCHOSOCIAL MECHANISMS Genetic Contributions to Pain CLINICAL PAIN EXPERIMENTAL PAIN Interactions among Individual Difference Factors Conclusion ACKNOWLEDGMENTS CHAPTER 9 Functional Neuroanatomy of the Nociceptive System ROBERT GRIFFIN, EZEKIEL FINK, AND GARY J. BRENNER

Organization of the Peripheral Nociceptive System Peripheral Nervous System Structures of Pain Sensation Functional Anatomy of the Central Nervous System DORSAL HORN SPINOTHALAMIC TRACT THALAMUS SENSORY CORTEX DESCENDING PATHWAYS OF THE CENTRAL NERVOUS SYSTEM CENTRAL PAIN CENTRAL PAIN AFTER SPINAL CORD INJURY Autonomic Nervous System PERIPHERAL AUTONOMIC NERVOUS SYSTEM PARASYMPATHETIC DIVISION CRANIAL PARASYMPATHETICS SACRAL PARASYMPATHETICS SYMPATHETIC (THORACOLUMBAR) DIVISION 73

Sympathetic Preganglionic Neurons Sympathetic Postganglionic Neurons SENSATION IN VISCERAL ORGANS AUTONOMIC CENTERS IN THE CENTRAL NERVOUS SYSTEM TRANSMISSION IN THE PERIPHERAL AUTONOMIC NERVOUS SYSTEM PHYSIOLOGY OF THE AUTONOMIC NERVOUS SYSTEM ENTERIC NERVOUS SYSTEM Conclusion CHAPTER 10 Clinical Trials ROGER CHOU AND RICHARD A. DEYO

Uncontrolled Studies Paradigm CONTROL GROUPS: AN IMPROVEMENT OVER THE CASE SERIES Randomized Allocation of Treatment and Control Groups Other Methods for Reducing Bias in Clinical Trials BASELINE SIMILARITY OF STUDY GROUPS BLINDING WERE GROUPS TREATED EQUALLY EXCEPT FOR THE EXPERIMENTAL TREATMENT? LOW LOSS TO FOLLOW-UP AND INTENTION-TO-TREAT ANALYSIS Other Issues in Clinical Trials MEASUREMENT OF OUTCOMES REPORTING THE RESULTS STATISTICAL POWER GENERALIZABILITY OF RESULTS AND EFFICACY VERSUS EFFECTIVENESS SUBGROUP ANALYSES EFFECTS OF FUNDING SOURCE ASSESSMENT OF HARMS TRIAL-BASED COST-EFFECTIVENESS ANALYSIS Alternative Study Designs 74

CLUSTER TRIALS CROSSOVER TRIALS FACTORIAL DESIGN New Directions in Clinical Trials PRAGMATIC TRIALS ENRICHED ENROLLMENT RANDOMIZED WITHDRAWAL TRIALS EXPERTISE-BASED TRIALS COMPARATIVE EFFECTIVENESS EQUIVALENCE AND NONINFERIORITY TRIALS STEPPED WEDGE DESIGN BAYESIAN STATISTICAL INFERENCE AND ADAPTIVE DESIGNS Systematic Reviews Conclusion PA R T T W O Economic, Political, Legal, and Ethical Considerations C H A P T E R 11 Transdermal Pain: A Sociocultural Perspective DAVID B. MORRIS

What Is Transdermal Pain? Ethnicity, Race, Sex, Gender, Age: Whose Pain? Across Cultures: Beliefs, Attitudes, Perceptions, Behaviors Pain and Narrative: Culture, Meaning, Ethics Beyond the Gate: Consciousness and the Limits of a Molecular Gaze Pain and Globalization: Power, Money, Systems Conclusion: Summary and Synthesis ACKNOWLEDGMENT CHAPTER 12 Ethical Issues in Pain Management BEN A. RICH

Pain, Suffering, and the Core Values of Health Care THE DUTY TO RELIEVE PAIN AND SUFFERING CURATIVE VERSUS PALLIATIVE PARADIGMS OF PATIENT CARE 75

The Phenomenon of Undertreated Pain IDENTIFYING THE BARRIERS TO PAIN RELIEF Professional Barriers Patient Barriers Societal Barriers Ethical Implications of the Barriers Embracing a New Ethic of Pain Relief Conclusion CHAPTER 13 Ethical Issues in the Care of Dying Patients DAVID BARNARD

Introduction THE QUEST FOR MORAL ORDER AMID EXISTENTIAL DISORDER THE CONTRIBUTIONS AND LIMITATIONS OF ETHICAL ANALYSIS IN END-OF-LIFE CARE The Transition from Curative to Palliative and End-of-Life Care NEGOTIATING TREATMENT PREFERENCES: THE IDEAL DECISION-MAKING PROCESS DEPARTURES FROM THE IDEAL Prognosis and Clinical Judgment Patients’ Attitudes and Values Physicians’ Attitudes and Values COMMUNICATION WITH PATIENTS ABOUT TREATMENT PREFERENCES NEAR THE END OF LIFE Surrogate Decision Making ASSESSING DECISIONAL CAPACITY RULING OUT OR ELIMINATING REVERSIBLE CAUSES OF INCAPACITY IDENTIFYING A SURROGATE THE SURROGATE’S ROLES AND RESPONSIBILITIES A REALISTIC PROCESS OF ADVANCE CARE PLANNING Three Basic Problems A Realistic Approach Responding to Demands for Nonbeneficial Treatment 76

THE ETHICAL BASIS OF THE CONFLICT THE CLINICAL CONTEXT OF THE CONFLICT DIFFERENTIAL DIAGNOSIS OF THE CONFLICT Physician-Assisted Death TERMINOLOGY ETHICAL CONSIDERATIONS ALONG THE CLINICAL SPECTRUM TWO LEVELS OF RESPONSE: SOCIAL POLICY AND CLINICAL CARE Social Policy Clinical Care Conclusion: Beyond the Patient–Physician Dyad CHAPTER 14 Laws and Policies Affecting Pain Management in the United States AARON M. GILSON AND JAMES F. CLEARY

Introduction PREVALENCE OF UNRELIEVED PAIN IS A PUBLIC HEALTH PROBLEM BARRIERS TO THE SAFE AND EFFECTIVE USE OF OPIOID ANALGESICS FOR PAIN MANAGEMENT POLICIES GOVERNING THE USE OF OPIOID ANALGESICS FOR PAIN MANAGEMENT International Treaties: Establishing Balance between Drug Control and Medical Use US Federal Law: Preserving Balance between Drug Control and Medical Use THE FEDERAL FOOD, DRUG, AND COSMETIC ACT US FEDERAL CONTROLLED SUBSTANCES LAW The Controlled Substances Act Ensures Availability of Controlled Substances for Medical Purposes The Controlled Substances Act Does Not Regulate Medical Practice The Controlled Substances Act Distinguishes Treatment of Addiction from Treatment of Pain, but Legal Definitions Create Confusion 77

The Controlled Substances Act and Regulations Do Not Limit Prescription Amount or Duration Regulations Implementing the Controlled Substances Act Now Authorize a Greater Variety of Secure Disposal Opportunities for Controlled Substances US State Laws: Striving for Balance between Drug Control and Medical Use STATE PAIN POLICY DEVELOPMENT: AN EMERGING TREND EVALUATING THE QUALITY OF STATE PAIN POLICY Policy Evaluation Findings A PROGRESS REPORT CARD TO MEASURE CHANGES IN THE QUALITY OF STATE PAIN POLICIES Progress Report Card Findings THE IMPORTANCE OF IMPROVING STATE PAIN POLICY The Need to Implement and Communicate Policy Considering Additional US Policies Taking Diversion into Account Conclusions CHAPTER 15 Litigation Involving Pain Management BEN A. RICH

Administrative Proceedings IN THE MATTER OF DILEO HOOVER V AGENCY FOR HEALTH CARE ADMINISTRATION OREGON BOARD OF MEDICAL EXAMINERS V BILDER ACCUSATION OF EUGENE WHITNEY, MD Civil Litigation ESTATE OF HENRY JAMES V HILLHAVEN CORPORATION BERGMAN V CHIN, MD, AND EDEN MEDICAL CENTER TOMLINSON V BAYBERRY CARE CENTER, ET AL. Criminal Litigation STATE V NARAMORE 78

Federal Criminal Prosecutions UNITED STATES V ROSEN (1978) UNITED STATES V HURWITZ UNITED STATES V MCIVER Constitutional Cases Lessons from the Litigation CHAPTER 16 International Access to Therapeutic Opioids JAMES F. CLEARY, MARTHA A. MAURER, AND S. ASRA HUSAIN

Pain Relief Is Part of Cancer and HIV/AIDS Control PAIN AND PALLIATIVE CARE Opioids Are Essential Medicines and Controlled Substances GOVERNMENTS MUST ENSURE ADEQUATE OPIOID AVAILABILITY Disparities in Opioid Consumption MORPHINE EQUIVALENCE METRIC GLOBAL OPIOID CONSUMPTION TRENDS DISPARITIES IN CONSUMPTION BY INCOME LEVEL Regional Opioid Consumption Trends WORLD HEALTH ORGANIZATION REGION FOR AFRICA (AFRO) WORLD HEALTH ORGANIZATION REGION FOR THE AMERICAS (AMRO) WORLD HEALTH ORGANIZATION REGION FOR THE EASTERN MEDITERRANEAN (EMRO) WORLD HEALTH ORGANIZATION REGION FOR EUROPE (EURO) WORLD HEALTH ORGANIZATION REGION FOR SOUTHEAST ASIA (SEARO) WORLD HEALTH ORGANIZATION REGIONS FOR THE WESTERN PACIFIC (WPRO) Barriers to Opioid Availability and Accessibility KNOWLEDGE AND ATTITUDES ABOUT PAIN, OPIOIDS, AND DEPENDENCE SYNDROME Inadequate Education of Health Care Professionals 79

Concerns about Dependence Syndrome (Addiction) Concerns about Potential Side Effects Health Care Professionals’ Fear of Prosecution or Sanction EXCESSIVELY STRICT LAWS OR REGULATORY POLICIES MEDICATION DISTRIBUTION SYSTEM BARRIERS ECONOMIC FACTORS INCLUDING AFFORDABILITY United Nations’ Recommendations Efforts to Address Barriers and Improve Opioid Availability and Accessibility Conclusion PA R T T H R E E Evaluation of the Pain Patient

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CHAPTER 17 Evaluation of the Chronic Pain Patient GORDON IRVING AND PAMELA SQUIRE

Introduction GENERAL GUIDELINES FOR ASSESSMENT OF PERSISTENT PAIN Outline of a Multidimensional Assessment Questionnaire for Persistent Pain History SUMMARY OF SOME NONPROPRIETARY QUESTIONNAIRES OTHER POTENTIALLY USEFUL QUESTIONS TO CONSIDER FOR GAUGING EFFECTIVENESS OF THERAPY SUMMARY OF PROPRIETARY QUESTIONNAIRES TO CONSIDER The Pain History O: ONSET OF PAIN P: PROVOCATIVE/PALLIATIVE Q: QUALITY OR CHARACTER R: REGION/RADIATION S: SEVERITY/INTENSITY OF PAIN T: TIMING OF PAIN ALTERED PERCEPTION Past Medical and Surgical History MOOD ASSESSMENT PSYCHOSOCIAL FACTORS COPING STRATEGIES SLEEP DISORDERS COGNITIVE IMPAIRMENT VOCATIONAL HISTORY AND CURRENT VOCATIONAL DISABILITY HABITS Risk of Opioid Misuse, Abuse, or Dependence Assessment of Function Current and Past Treatments CURRENT AND PAST MEDICATIONS INCLUDING OVER81

THE-COUNTER MEDICATIONS ALLERGIES INVESTIGATIONS AND CONSULTATIONS Goals Physical Examination GENERAL EXAM: OBSERVE, IDENTIFY AND DOCUMENT SITE OF PAIN Observe Palpate Test NEUROLOGIC EXAM Observe or Ask About Palpate Test BEDSIDE METHOD FOR QUANTITATIVE SENSORY TESTING Light Touch Vibration Punctate/Pinprick Warm and Noxious Heat Cool and Noxious Cold Grading the Tests CAVEATS TO QUANTITATIVE SENSORY TESTING INTERPRETATION FURTHER INVESTIGATIONS OR CONSULTS Follow-up Visits Conclusion GOALS Considering the Right Goal for You Setting SMART Goals Appendix 17.1: Initial Visit Questionnaire Appendix 17.2: Pain Diagram Appendix 17.3: Goal Setting Appendix 17.4: Follow-up Questionnaire CHAPTER 18 82

Electrodiagnosis in Pain Medicine NATHAN J. RUDIN

The Electrodiagnostic Laboratory Electrodiagnostic Tests NERVE CONDUCTION STUDIES NEEDLE ELECTROMYOGRAPHY Application in Selected Conditions Conclusion CHAPTER 19 Diagnostic Imaging of Pain RICHARD F. CODY Jr, ASAKO MIYAKOSHI, AND KENNETH R. MARAVILLA

Headache ACUTE HEADACHE Computed Tomography Angiography and Magnetic Resonance Angiography CHRONIC HEADACHE INTRACRANIAL HYPOTENSION INTRACRANIAL HYPERTENSION (PSEUDOTUMOR CEREBRI) Facial Pain Spinal Pain OVERVIEW COMPRESSION FRACTURES BENIGN VERSUS MALIGNANT; INFECTION/INFLAMMATION DISCOGENIC PAIN Limb Pain and Magnetic Resonance Neurography MAGNETIC RESONANCE NEUROGRAPHY THORACIC OUTLET SYNDROME PIRIFORMIS SYNDROME PERIPHERAL NERVE ENTRAPMENT SYNDROMES Imaging Guided Injection Future Application of Pain Imaging Conclusion CHAPTER 20 Measurement of Pain 83

MARK P. JENSEN

Introduction VALIDITY, RELIABILITY, AND UTILITY IN THE CONTEXT OF PAIN ASSESSMENT Validity Reliability Utility HOW MANY PAIN PROBLEMS SHOULD BE ASSESSED? WHICH PAIN DOMAIN(S) SHOULD BE ASSESSED? RECALL RATINGS VERSUS SUMMARY SCORES FROM MULTIPLE RATINGS USING DIARIES Measuring Pain’s Domains MEASURING PAIN INTENSITY Recommendations for Assessing Pain Intensity MEASURING PAIN AFFECT Recommendations for Assessing Pain Affect MEASURING PAIN QUALITY Using Pain Quality Measures as Diagnostic Aides Strengths and Weaknesses of Pain Quality Measures as Diagnostic Aids Pain Quality Scales as Descriptive and Outcome Measures Strengths and Weakness of Descriptive and Outcome Measures of Pain Quality MEASURING PAIN’S SPATIAL CHARACTERISTICS Recommendations for Assessing Pain Site MEASURING PAIN’S TEMPORAL CHARACTERISTICS Recommendations for Assessing Pain’s Temporal Characteristics MEASURING PAIN INTERFERENCE Brief Pain Inventory Pain Interference Scale Patient-Reported Outcomes Measurement Information System Pain Interference Item Bank and Short Forms Recommendations for Assessing Pain Interference Measuring Pain in Special Populations SIMPLIFIED MEASURES OF PAIN Simple Pain Measures to Consider 84

Selecting the Best Measure for a Patient or Population BEHAVIOR OBSERVATION MEASURES Measuring Pain in Busy Clinical Settings Summary and Conclusions CHAPTER 21 Pain Psychology Evaluation RAVI PRASAD, DESIREE AZIZODDIN, AND AMIR RAMEZANI

Psychosocial History EARLY LIFE EXPERIENCES VOCATIONAL HISTORY EDUCATIONAL HISTORY Current Functioning BELIEF STRUCTURES SOCIAL SUPPORT CULTURAL FACTORS Substance Use NICOTINE ALCOHOL PRESCRIBED AND NONPRESCRIBED DRUG USE Psychiatric Functioning BEHAVIORAL OBSERVATIONS DEPRESSION ANXIETY POSTTRAUMATIC STRESS DISORDER SOMATIZATION Psychological Screening for Advanced Interventional Procedures Conclusion CHAPTER 22 Disability Evaluation of Patients with Chronic Pain JAMES P. ROBINSON AND LEE GLASS

Basic Concepts Conceptual and Empirical Issues IMPAIRMENT AND DISABILITY Impairment Disability ASSOCIATIONS BETWEEN IMPAIRMENT AND 85

DISABILITY THE “EMBEDDEDNESS” PROBLEM PRACTICAL PROBLEMS IN IDENTIFYING THE ROLE OF PAIN IN DISABILITY DETERMINATIONS Methods for Evaluating Chronic Pain in Applicants for Disability Benefits EVALUATION METHODS IN THE SOCIAL SECURITY ADMINISTRATION OUTCOMES OF SOCIAL SECURITY ADMINISTRATION EVALUATIONS DISABILITY EVALUATION AND DISABILITY MANAGEMENT IN THE WASHINGTON STATE DEPARTMENT OF LABOR AND INDUSTRIES WASHINGTON STATE DEPARTMENT OF LABOR AND INDUSTRIES PROGRAMS TO REDUCE DISABILITY METHODS USED BY WASHINGTON STATE DEPARTMENT OF LABOR AND INDUSTRIES TO EVALUATE INJURED WORKERS FOR PERMANENT DISABILITY BENEFITS OUTCOMES OF WASHINGTON STATE DEPARTMENT OF LABOR AND INDUSTRIES EVALUATIONS Conclusion CHAPTER 23 Multidisciplinary Assessment of Patients with Chronic Pain DENNIS C. TURK AND JAMES P. ROBINSON

Conceptual Issues CONUNDRUMS IN THE ASSESSMENT OF PAIN A CONCEPTUAL MODEL FOR ASSESSING PAIN Pain Behavior Classes of Variables Underlying Pain Behavior Assessment of Medical Factors ARE THERE RED FLAGS? ARE THERE RISK FACTORS FOR DELAYED RECOVERY? SPECIFIC EVALUATION PROCEDURES History 86

Physical Examination Ancillary Studies CONCLUSION Assessment of Central Nervous System Sensitization Assessment of Psychosocial Factors PSYCHOLOGICAL FACTORS AS CAUSES VERSUS CONSEQUENCES OF CHRONIC PAIN Psychological Factors as Causal Agents in Development of Chronic Pain Psychological Consequences of Chronic Pain ELEMENTS OF THE PSYCHOLOGICAL EVALUATION Interviews Self-report Inventories PROBLEM AREAS TO ASSESS Assessment of Pain Assessment of Overt Expressions of Pain Assessment of Emotional Distress Assessment of Fear Assessment of Beliefs, Coping, and Psychosocial Adaptation to Pain Assessing Functional Impact SELF-REPORT MEASURES OF FUNCTION Assessment of Physical Capacity Assessment of Social Factors Organization of Multidisciplinary Evaluations Conclusion PA R T F O U R Pain Conditions

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NEUROPATHIC PAIN CONDITIONS CHAPTER 24 Painful Neuropathies GEORGIOS MANOUSAKIS, MIROSLAV BACKONJA, AND DAVID WALK

Pain as a Symptom of Neuropathy The Evaluation and Diagnosis of Neuropathy NEUROPATHY CLASSIFICATION HISTORY, EXAMINATION, AND DIAGNOSTIC STUDIES Painful Neuropathies DISTAL SYMMETRIC POLYNEUROPATHIES Metabolic Causes Infectious Causes Toxic Neuropathies Nutritional Neuropathies Hereditary Neuropathies OTHER WIDESPREAD BUT NONLENGTH-DEPENDENT NEUROPATHIES Neuropathy with Paraproteinemia Autoimmune Demyelinating Neuropathies PAINFUL MONONEUROPATHY MULTIPLEX AND FOCAL NEUROPATHIC SYNDROMES Vasculitic Neuropathy Neuralgic Amyotrophy Diabetic Amyotrophy Other Diabetic Mononeuropathies SENSORY NEURONOPATHIES Postherpetic Neuralgia Sjögren’s Syndrome Paraneoplastic Sensory Neuronopathy Toxic Neuronopathy Treatment of Painful Neuropathies GENERAL PRINCIPLES OF THERAPY ANALGESIA THERAPY: GUIDELINES FOR PHARMACOTHERAPY Tricyclic Agents 88

α2δ Ligands Serotonin and Norepinephrine Reuptake Inhibitors Opioids Tramadol and Tapentadol Other Pharmacologic Agents Cannabinoids Topical Agents Principles of Pharmacotherapy for Pain from Neuropathy Unresolved Questions CHAPTER 25 Complex Regional Pain Syndrome MICHAEL T. MASSEY AND ROBERT NORMAN HARDEN

Epidemiology Pathophysiology ANIMAL MODELS HUMAN MODELS INFLAMMATION IMMUNOLOGIC FACTORS Afferent Dysfunction CENTRAL DYSFUNCTION SYMPATHETIC DYSFUNCTION TROPHIC, DYSTROPHIC, AND NUTRITIONAL ABNORMALITIES MOTOR AND MOVEMENT DISORDERS IMMOBILIZATION AND DISUSE Genetics A Convergent Pathophysiologic Theory Diagnosis THE INTERNATIONAL ASSOCIATION FOR THE STUDY OF PAIN CRITERIA THE BUDAPEST CRITERIA SEQUENTIAL STAGES AND SUBSETS OF COMPLEX REGIONAL PAIN SYNDROME PSYCHOLOGICAL FACTORS IN COMPLEX REGIONAL PAIN SYNDROME 89

Treatment THE RATIONALE FOR FUNCTIONAL RESTORATION REHABILITATION-BASED TREATMENT MODALITIES PHARMACOTHERAPY PSYCHOLOGICAL INTERVENTIONS INTERVENTIONAL THERAPIES OTHER THERAPEUTIC MODALITIES CHAPTER 26 Phantom Pain KELLY A. BRUNO, HOWARD S. SMITH, IRFAN LALANI, AND CHARLES E. ARGOFF

Epidemiology Modulation of Phantom Pain Pathophysiology of Phantom Pain Prevention of Phantom Pain Treatment of Phantom Pain Pharmacologic Interventions ANTIDEPRESSANTS ANTIEPILEPTIC DRUGS OPIOIDS NMDA RECEPTOR ANTAGONISTS CALCITONIN TRANSIENT RECEPTOR POTENTIAL CATION CHANNEL SUBFAMILY V MEMBER 1 (TRPV1) MODULATORS INTERVENTIONAL THERAPY NEUROMODULATION SURGICAL INTERVENTIONS BEHAVIORAL MEDICINE INTERVENTIONS MISCELLANEOUS TREATMENTS FOR RESIDUAL LIMB PAIN Summary CHAPTER 27 Herpes Zoster and Postherpetic Neuralgia SIDDARTH THAKUR, ROBERT H. DWORKIN, AND RAJBALA THAKUR

Clinical Picture and Natural History of Herpes Zoster PRODROME RASH 90

PAIN DISTRIBUTION OF HERPES ZOSTER CLINICAL VARIANTS Herpes Zoster Ophthalmicus Herpes Zoster Oticus (Ramsay-Hunt Syndrome) Zoster Sine Herpete Diagnosis of Herpes Zoster LABORATORY TESTING Viral Culture Direct Immunofluorescence Assay Viral DNA Testing Biopsy Testing for Underlying Disorders Epidemiology of Herpes Zoster Pathophysiology of Herpes Zoster and Mechanisms of Acute Pain Complications Associated with Herpes Zoster OPHTHALMIC COMPLICATIONS MOTOR NEUROPATHY RARE NEUROLOGIC COMPLICATIONS VISCERAL COMPLICATIONS DECREASED QUALITY OF LIFE Treatment of Herpes Zoster PATIENT EDUCATION ANTIVIRAL THERAPY ANALGESIC TREATMENT CORTICOSTEROIDS Lidocaine Patch NEURAL BLOCKADE COMPLEMENTARY AND ALTERNATIVE MEDICINE SPINAL CORD STIMULATION Prevention of Herpes Zoster CHILDHOOD VACCINATION VARICELLA-ZOSTER IMMUNOGLOBULIN HERPES ZOSTER VACCINATION FOR ADULTS Clinical Picture of Postherpetic Neuralgia 91

DIAGNOSIS AND ASSESSMENT OF POSTHERPETIC NEURALGIA Laboratory Diagnosis Epidemiology and Natural History of Postherpetic Neuralgia RISK FACTORS FOR POSTHERPETIC NEURALGIA Pathophysiology of Postherpetic Neuralgia Treatment of Postherpetic Neuralgia ANTICONVULSANTS: GABAPENTIN AND PREGABALIN ANTIDEPRESSANT MEDICATIONS Tricyclic Antidepressants Selective Serotonin and Norepinephrine Reuptake Inhibitors (Dual Reuptake Inhibitors) OPIOID ANALGESICS TRAMADOL TAPENTADOL TOPICAL THERAPIES Topical Lidocaine Topical Capsaicin Other Topical Treatments COMBINATION THERAPY N-METHYL-D-ASPARTIC ACID ANTAGONISTS OTHER PHARMACOLOGIC THERAPIES INVASIVE TREATMENTS FOR POSTHERPETIC NEURALGIA Botulinum Toxin Dorsal Root Ganglion Blocks Peripheral Nerve Blocks Neuroaugmentive Techniques Sympathetic Nerve Blocks Neuraxial Blocks PSYCHOLOGICAL INTERVENTIONS ELECTROANALGESIA Transcutaneous Electrical Nerve Stimulation Scrambler Therapy Surgical Approaches 92

Prevention of Postherpetic Neuralgia Conclusions CHAPTER 28 Central Pain States NANNA BRIX FINNERUP AND SHARONA BEN-HAIM

Diagnosis Clinical Characteristics Clinical Assessment Specific Central Pain Conditions CENTRAL POSTSTROKE PAIN CENTRAL PAIN IN MULTIPLE SCLEROSIS CENTRAL PAIN IN SPINAL CORD INJURY OTHER CENTRAL PAIN CONDITIONS Preclinical Models Mechanisms Treatment of Central Pain PHARMACOLOGIC TREATMENT First-line Pharmacologic Treatments Second- and Third-Line Pharmacologic Treatments Other Drugs, Combination Therapy, and Intrathecal Drug Administration PSYCHOLOGICAL AND PHYSIOTHERAPY TREATMENT NEUROSURGICAL MANAGEMENT Targeted Drug Delivery Neuroablation Neuromodulation PSYCHOLOGICAL CONTRIBUTIONS TO PAIN CHAPTER 29 The Psychophysiology of Pain C. RICHARD CHAPMAN AND FADEL ZEIDAN

Historical Perspective: Mind–Body Issues Emotions: Definition and Mechanisms WHAT ARE EMOTIONS? EMOTION IN A SOCIOBIOLOGIC PERSPECTIVE ADAPTIVE FUNCTIONS OF EMOTION 93

EMOTIONS AND BEHAVIOR THE CENTRAL NEUROANATOMY OF EMOTION: LIMBIC STRUCTURES PERIPHERAL NEUROANATOMY OF EMOTION: THE AUTONOMIC NERVOUS SYSTEM Autonomic Arousal and Subjective Experience The Role of Feedback Relationship of Central and Peripheral Mechanisms NOXIOUS SIGNALING AND CENTRAL LIMBIC PROCESSING Central Neurotransmitter Systems LOCUS COERULEUS AND THE DORSAL NORADRENERGIC BUNDLE THE VENTRAL NORADRENERGIC BUNDLE AND THE HYPOTHALAMO-PITUITARY-ADRENOCORTICAL AXIS PRIMARY AND SECONDARY FEATURES OF THE AFFECTIVE DIMENSION OF PAIN SUMMARY OF THE CONSTRUCTION AND MODULATION OF PAIN Emotion and Cognition The Sense of Self COGNITIVE PERSPECTIVE MULTIPLE PERSPECTIVES ON THE SELF Stress, Sickness, and Pain BASIC DEFINITIONS: STRESS, HOMEOSTASIS, AND ALLOSTASIS PHYSIOLOGIC MECHANISMS OF STRESS Neural Substrates Immune Mechanisms The Sickness Response The Sickness Response and Depression SUMMARY OF THE PHYSIOLOGIC MECHANISMS OF STRESS STRESS AND CHRONIC PAIN Future Directions 94

CHAPTER 30 Pain and Learning ROBERT J. GATCHEL, BRIAN R. THEODORE, AND NANCY D. KISHINO

Overview of the Three Major Principles of Learning CLASSICAL CONDITIONING OPERANT CONDITIONING OBSERVATIONAL LEARNING Operant Conditioning and Pain THE HALLMARK WORK OF WILBERT FORDYCE OPERANT CONDITIONING AND CHRONIC PAIN: THE BASICS Classical Conditioning and Pain AVERSIVE CLASSICAL CONDITIONING AND PAIN CLASSICALLY CONDITIONED FEAR/AVOIDANCE AND PAIN Observational Learning and Pain Integrating Learning Principles in the Treatment of Pain COGNITIVE-BEHAVIORAL THERAPY AND PAIN COGNITIVE-BEHAVIORAL THERAPY AS AN ESSENTIAL COMPONENT OF A COMPREHENSIVE INTERDISCIPLINARY APPROACH TO PAIN MANAGEMENT Conclusion CHAPTER 31 Psychiatric Illness, Depression, Anxiety, and Somatic Symptom Disorder JOSEPH GREGORY HOBELMANN, MARK D. SULLIVAN, MICHAEL R. CLARK, AND AJAY D. WASAN

Psychiatric Nosology and Diagnostic and Treatment Approaches Framework for Describing Psychiatric Symptoms Depression SUICIDAL IDEATION AND BEHAVIOR WHICH CAME FIRST, DEPRESSION OR PAIN? DIFFERENTIAL DIAGNOSIS BIOLOGIC TESTS FOR DEPRESSION DYSTHYMIC DISORDER 95

EPIDEMIOLOGY OF DEPRESSION PAIN AND DEPRESSION: MECHANISMS OF ASSOCIATION Biologic Theories Psychological Theories Anthropologic Theories DEPRESSION TREATMENT Pharmacologic Agents PSYCHOTHERAPY Psychodynamic Psychotherapy Behavioral Model Cognitive Model Cognitive-Behavioral Model Anxiety Disorders GENERALIZED ANXIETY DISORDER PANIC DISORDER EPIDEMIOLOGY TREATMENT Posttraumatic Stress Disorder DIAGNOSIS EPIDEMIOLOGY OF POSTTRAUMATIC STRESS DISORDER IN CHRONIC PAIN PATIENTS POSTTRAUMATIC STRESS DISORDER AND ASSOCIATIONS WITH PAIN TREATMENT Personality Disorders EPIDEMIOLOGY OVERVIEW OF PERSONALITY DISORDERS PERSONALITY AND PAIN TREATMENT OUTCOME Somatic Symptom Disorders, Illness Behavior, and Sick Role DEFINITIONS OVERVIEW OF SOMATOFORM DISORDERS AND SOMATIC SYMPTOM DISORDERS Somatic Symptom Disorder Conversion Disorder (Functional Neurologic Symptom Disorder) 96

ILLNESS ANXIETY DISORDER Conclusion: Pain and Suffering and Psychiatry CHAPTER 32 Treatment of Pain in Patients with Addiction PEGGY COMPTON, FRIEDHELM SANDBRINK, AND MARTIN D. CHEATLE

Substance Use Disorder Clinical Implications of Substance Use Disorders on Pain NEUROBIOLOGIC OVERLAP BETWEEN PAIN AND ADDICTION SYSTEMS Tolerance Dependence Analgesic Effects of Drugs of Abuse EFFECTS OF SUBSTANCE USE DISORDER ON PAIN EFFECTS OF OPIOID USE DISORDER ON PAIN Genetics of Pain and Opioid Use Disorder Tolerance Physical Dependence Opioid-Induced Hyperalgesia Pain Management in Persons with Substance Use Disorder PREVALENCE OF SUBSTANCE USE DISORDERS IN PATIENTS WITH PAIN PRINCIPLES OF PAIN TREATMENT IN PATIENTS WITH SUBSTANCE USE DISORDERS Provide Effective Pain Relief Reinforce or Introduce Substance Use Disorder Treatment Document Pain Treatment Plan and Involve Patient and Family in the Plan of Care Pain, Substance Use Disorder, and Suicide Conclusions CHAPTER 33 The Doctor–Patient Relationship in Pain Management: Dealing with Difficult Clinician–Patient Interactions ROBERT N. JAMISON

Difficult Patients and Difficult Doctor–Patient Relationships PSYCHIATRIC AND PERSONALITY ISSUES OPIOID THERAPY 97

DIFFICULT “NORMAL” PATIENTS COMORBID MEDICAL CONDITIONS SUBSTANCE USE DISORDERS Physician Factors Health Care System Factors Patient Interaction Strategies PATIENT-FOCUSED CARE Communication Framework: WIPS and E’s Clinical Scenarios SCENARIO 1 SCENARIO 2 SCENARIO 3 SCENARIO 4 SCENARIO 5 SCENARIO 6 SCENARIO 7 Summary and Conclusions ACKNOWLEDGMENT VASCULAR, CUTANEOUS, AND MUSCULOSKELETAL PAINS CHAPTER 34 Arthritis GREGORY C. GARDNER

Basic Considerations PROBLEM IN PERSPECTIVE JOINT ANATOMY Nerve and Blood Supply Clinical Approach to Joint Pain HISTORY Number of Joints Affected Pattern Recognition Systemic Features of Arthritis PHYSICAL EXAMINATION EXAMINATION OF SYNOVIAL FLUID Clinical Considerations OSTEOARTHRITIS 98

Epidemiology and Pathophysiology Symptoms and Signs SECONDARY OSTEOARTHRITIS Laboratory Findings Treatment RHEUMATOID ARTHRITIS Etiology and Pathophysiology Symptoms and Signs Laboratory Findings Treatment Philosophy Current Management of Rheumatoid Arthritis Important Complications of Rheumatoid Arthritis Presenting with Pain THE SPONDYLOARTHROPATHIES Ankylosing Spondylitis Spondylodiskitis REACTIVE ARTHRITIS Symptoms and Signs Laboratory Findings Treatment Complications of Reactive Arthritis Associated with Chronic Pain PSORIATIC ARTHRITIS Symptoms and Signs Laboratory Findings Treatment ARTHRITIS ASSOCIATED WITH INFLAMMATORY BOWEL DISEASE Treatment ARTHRITIS CAUSED BY CRYSTALS Calcium Pyrophosphate Deposition Disease Pathophysiology Symptoms and Signs Treatment URATE GOUT 99

Etiology and Pathophysiology Pathophysiology of Acute Gouty Arthritis Signs and Symptoms Laboratory Findings Treatment INFECTIOUS ARTHRITIS Nongonococcal Bacterial Arthritis Gonococcal Arthritis POLYMYALGIA RHEUMATICA CHAPTER 35 Myofascial Pain Syndrome JAN DOMMERHOLT AND JAY P. SHAH

Brief Historical Overview Basic Myofascial Pain Concepts Muscle Physiology The Motor Endplate Sensitization and Activation of Muscle Nociceptors Central Sensitization The Biochemical Milieu of Myofascial Trigger Points pH and Muscle Pain Neuropeptides, Inflammatory Mediators, and Tissue Injury and Pain Catecholamines and the Autonomic Nervous System Cytokines and Pain Clinical Management TRIGGER POINT DIAGNOSIS PHYSICAL EXAMINATION AND DIAGNOSIS TREATMENT OPTIONS Patient Education Physical Therapy Needling Therapies NONINVASIVE TREATMENT OPTIONS Summary CHAPTER 36 Fibromyalgia: A Discrete Disease or the End of the Continuum DANIEL J. CLAUW AND CHAD BRUMMETT

Historical Perspective 100

Epidemiology CHRONIC WIDESPREAD PAIN FIBROMYALGIA SIGNIFICANCE OF TENDER POINTS OTHER FEATURES OF FIBROMYALGIA GLEANED FROM EPIDEMIOLOGIC OR OBSERVATIONAL STUDIES Etiology ANIMAL MODELS OF FIBROMYALGIA GENETIC FACTORS EVIDENCE OF CENTRAL NERVOUS SYSTEM DISTURBANCES IN PAIN AND SENSORY PROCESSING EVIDENCE OF A GLOBAL INCREASE IN SENSORY PROCESSING OF NONPAINFUL STIMULI BRAIN IMAGING STUDIES THE ROLE OF NEUROENDOCRINE OR AUTONOMIC ABNORMALITIES THE ROLE OF PERIPHERAL FACTORS IN FIBROMYALGIA EVIDENCE OF ABNORMAL CYTOKINES OR OF IMMUNE DYSFUNCTION IN FIBROMYALGIA THE ROLE OF “SMALL FIBER NEUROPATHY” IN FIBROMYALGIA Diagnosis DIAGNOSIS OF FIBROMYALGIA Treatment GENERAL APPROACH PHARMACOLOGIC THERAPY Tricyclic Agents Serotonin and Norepinephrine Reuptake Inhibitors Anticonvulsants Combination Drug Therapy Other Central Nervous System–Acting Drugs Classic Analgesics NEUROSTIMULATORY THERAPIES NONPHARMACOLOGIC THERAPIES Prognosis 101

Conclusion Key Points CHAPTER 37 Pain of Dermatologic Disorders SHELLEY YANG AND JOHN E. OLERUD

Basic Considerations: Anatomy and Physiology of the Skin Clinical Disorders LEUKOCYTOCLASTIC VASCULITIS Etiology Pathogenesis Treatment POLYARTERITIS NODOSA Symptoms and Signs Treatment ANTINEUTROPHILIC CYTOPLASMIC ANTIBODIESASSOCIATED VASCULITIDES: GRANULOMATOSIS WITH POLYANGIITIS (FORMERLY KNOWN AS WEGENER’S GRANULOMATOSIS) Symptoms and Signs Treatment MICROSCOPIC POLYANGIITIS Treatment EOSINOPHILIC GRANULOMATOSIS WITH POLYANGIITIS (FORMERLY KNOWN AS CHURG-STRAUSS SYNDROME) Symptoms and Signs Treatment RHEUMATOID VASCULITIS Treatment LIVEDOID VASCULOPATHY Treatment Other Vascular Disorders ANTIPHOSPHOLIPID SYNDROME Symptoms and Signs Treatment WARFARIN (COUMADIN) SKIN NECROSIS 102

Pathophysiology Symptoms and Signs Treatment COCAINE LEVAMISOLE TOXICITY CALCINOSIS CUTIS CALCIPHYLAXIS Treatment Ulcers ISCHEMIC ULCERS Treatment VENOUS ULCERS Treatment PYODERMA GANGRENOSUM Painful Infections NECROTIZING SOFT TISSUE INFECTION/NECROTIZING FASCIITIS HERPES ZOSTER HERPES SIMPLEX Symptoms and Signs Diagnosis Treatment ERYSIPELAS AND CELLULITIS Treatment FURUNCULOSIS AND CARBUNCLE Treatment ERYSIPELOID Inflammations PANNICULITIS Erythema Nodosum Treatment DERCUM DISEASE (ADIPOSA DOLOROSA) Treatment HIDRADENITIS SUPPURATIVA Etiology Symptoms and Signs 103

Diagnosis Treatment INFLAMED EPIDERMAL CYST BULLOUS DERMATOSES WITH EROSIONS Stevens-Johnson/Toxic Epidermal Necrolysis Syndrome Pemphigus Vulgaris Paraneoplastic Pemphigus Bullous Pemphigoid Epidermolysis Bullosa Disorders of Connective Tissue Structure (Cartilage Disorders) RELAPSING POLYCHONDRITIS Treatment CHONDRODERMATITIS NODULARIS HELICIS Neurovascular Cutaneous Disease SENSORY MONONEUROPATHIES Treatment ERYTHROMELALGIA FABRY’S DISEASE Symptoms and Signs Treatment Other Painful Dermatologic Disorders CUTANEOUS ENDOMETRIOSIS PAINFUL NEOPLASMS ACKNOWLEDGMENTS CHAPTER 38 Pain Due to Vascular Causes KAJ JOHANSEN

Basic Neuroanatomic and Neurophysiologic Considerations Vascular Pain Syndromes INTERMITTENT CLAUDICATION AORTIC AND OTHER LARGE ARTERY PAIN REST PAIN, ULCERS, AND GANGRENE PAIN SYNDROMES FOLLOWING STROKE PAIN ASSOCIATED WITH DISEASES INVOLVING SMALL ARTERIES 104

PAIN ASSOCIATED WITH VENOUS DISORDERS PAIN ASSOCIATED WITH LYMPHATIC DISEASES PAIN ASSOCIATED WITH AMPUTATION Differentiating Vascular from Nonvascular Pain The Relief of Vascular Pain Conclusion CHAPTER 39 Pain Due to Thoracic Outlet Syndrome KAJ JOHANSEN, THOMAS TAI CHUNG, AND GEORGE I. THOMAS

Anatomy and Pathophysiology Clinical Presentation: Symptoms and Signs Diagnostic Tests Differential Diagnosis Management Outcomes CHAPTER 40 Pain Following Spinal Cord Injury KEVIN N. ALSCHULER, MARIA REGINA REYES, AND THOMAS N. BRYCE

Extent and Impact of the Problem Assessment and Classification of Pain Following Spinal Cord Injury MUSCULOSKELETAL PAIN Shoulder Pain Elbow and Wrist Pain Back Pain Muscle Pain Related to Spasticity VISCERAL PAIN OTHER NOCICEPTIVE PAIN AT- AND BELOW-LEVEL SPINAL CORD INJURY PAIN OTHER NEUROPATHIC PAIN PSYCHOSOCIAL ASPECTS OF PAIN AFTER SPINAL CORD INJURY Psychological Factors Social and Environmental Factors Management of Pain in People with Spinal Cord Injury NOCICEPTIVE PAIN Musculoskeletal Pain 105

Management of Spasticity-Related Pain VISCERAL PAIN OTHER NOCICEPTIVE PAIN OTHER NEUROPATHIC PAIN AND OTHER PAIN AT- AND BELOW-LEVEL NEUROPATHIC PAIN Anticonvulsants Antidepressants Local Anesthetics N-Methyl-D-Aspartate Receptor Antagonists Opioids Cannabinoids Drug Combinations Spinal Drug Administration PSYCHOLOGICAL AND ENVIRONMENTAL MANAGEMENT OTHER NONPHARMACOLOGIC MANAGEMENT OF PAIN IN PEOPLE WITH SPINAL CORD INJURY Neurostimulation Massage Acupuncture Physical Therapy and Exercise SURGICAL INTERVENTIONS Conclusion PAIN DUE TO CANCER CHAPTER 41 Epidemiology, Prevalence, and Cancer Pain Syndromes NEIL A. HAGEN

Epidemiology of Cancer Pain PAIN RELATED TO EXTENT OF DISEASE: THE CANCER DISEASE TRAJECTORY SPECIAL NEEDS OF PARTICULAR AGE GROUPS: PEDIATRIC, YOUNG ADULT, ADULT, GERIATRIC SPECIAL NEEDS OF PARTICULAR ETHNIC GROUPS: COMMUNICATION STYLES, COMMON PREFERENCES, AND MANAGING TABOOS 106

COMORBIDITIES ASSOCIATED WITH SPECIFIC CANCERS: LUNG DISEASE, LIVER DISEASE, RENAL DISEASE, AND NEUROLOGIC DISEASE CANCER PAIN AND SUBSTANCE ABUSE CANCER PAIN IN INMATES Components of the Comprehensive Medical Evaluation of a Patient with Chronic Cancer Pain Pain History DEFINITION OF PAIN DEFINITION OF SUFFERING VALIDATED ASSESSMENT TOOLS TYPES OF PAIN PRESENTING COMPLAINT Pain Onset Pain Progression Focality Symptoms That Accompany Pain Formulating the Presenting Complaint DETAILS OF THE PAIN HISTORY Physical Examination GENERAL PHYSICAL EXAMINATION THE REGIONAL PAIN PHYSICAL EXAMINATION BEDSIDE PROVOCATIVE MANEUVERS SPECIFIC BEDSIDE PROVOCATIVE MANEUVERS AND THEIR ROLE IN PAIN DIAGNOSIS Spurling’s Test Dermatomal Pain Sclerotomal Pain Myotomal Pain Myofascial Pain: How Hard Should You Press? Back Pain Retroperitoneal Pain Stretch Maneuver Abdominal Wall Pain Formulating a Cancer Pain Diagnosis SYNDROME DIAGNOSIS 107

PATHOPHYSIOLOGIC DIAGNOSIS Complementary Clinical Perspectives in the Care of Cancer Patients THE MEDICAL MODEL: PAIN IS A MANIFESTATION OF DISEASE PALLIATIVE MODEL: PAIN IS BOTH USELESS AND HARMFUL REHABILITATIVE (“CHRONIC NONMALIGNANT PAIN”) MODEL: FOCUS ON DYSFUNCTIONAL PAIN BEHAVIOR AND PAIN-RELATED DECONDITIONING ANESTHETIC MODEL: DIAGNOSTIC AND THERAPEUTIC BLOCKS Management of Pain in Specific Clinical Presentations BONE PAIN PAIN AND DELIRIUM PAIN AND NAUSEA PAIN AND ANOREXIA/CACHEXIA/ASTHENIA PAIN AND BOWEL DISEASE MANAGING CANCER PAIN IN THE ADDICT SAFE PRESCRIBING PRACTICES: UNIVERSAL PRECAUTIONS SYMPTOM CLUSTERS PAIN AT THE END OF LIFE CANCER PAIN EMERGENCIES OPIOID DIVERSION AT THE END OF LIFE Conclusion CHAPTER 42 Assessment and Diagnosis of the Cancer Patient with Pain DERMOT FITZGIBBON

Issues in Assessment and Diagnosis of Cancer Pain Pain and the Cancer Patient MOLECULAR MECHANISM OF TUMOR PAIN SOMATIC PAIN VISCERAL PAIN NEUROPATHIC PAIN AFFECTIVE PROCESSING AND SUFFERING 108

PSYCHOLOGICAL FACTORS AND THE COMPLEXITIES OF CANCER PAIN Depression in Cancer Patients DETECTING AND ASSESSING DEPRESSION IN THE CANCER PATIENT Cancer-Related Fatigue Sleep Disturbance in Cancer Sources of Pain in the Cancer Patient Classification of Cancer Pain by Feature CHRONICITY INTENSITY/SEVERITY PATHOPHYSIOLOGY/MECHANISMS Tumor Involvement of Encapsulated Organs Tumor Infiltration of Peripheral Nerves Tumor Infiltration of Soft Tissues Tumor Infiltration of Bone Tumor Infiltration of Abdominal Hollow Organs Tumor Infiltration and Inflammation of Serous Mucosa TUMOR TYPE AND STAGE OF DISEASE Pancreatic Cancer Ovarian Cancer Cervical Cancer Prostate Cancer Breast Cancer Lung Cancer Renal Cell Cancers Colorectal Cancer Leukemias and Lymphomas Multiple Myeloma Tumor Markers PATTERNS OF CANCER PAIN CANCER PAIN SYNDROMES Bone Metastases CHARACTERISTICS OF METASTATIC BONE PAIN PROGNOSIS 109

SACRAL INSUFFICIENCY FRACTURES GRANULOCYTE COLONY-STIMULATING FACTORS– ASSOCIATED BONE PAIN Visceral Pain MECHANISM VISCERAL PAIN DESCRIPTIONS BY SITE Neuropathic Pain NEUROPATHIC PAIN SECONDARY TO CANCERRELATED PATHOLOGY IN CRANIAL NERVES Cervical Plexopathy Tumor-Related Mononeuropathy Radicular Pain/Radiculopathy Leptomeningeal Metastases Myelopathies in Cancer Brachial Plexopathy Lumbosacral Plexopathy Tumor Infiltration of the Sacrum and Sacral Nerves Spinal and Radicular Pain Central Pain Syndromes Caused by Cancer Paraneoplastic Peripheral Neuropathy NEUROPATHIC PAIN SECONDARY TO THERAPEUTIC INTERVENTIONS Postsurgical Neuropathic Pain Radiation Myelopathy, Plexopathy, and Neuropathy Chemotherapy-Induced Peripheral Neuropathy ORAL MUCOSITIS GRAFT-VERSUS-HOST DISEASE Metastatic Epidural Spinal Cord Compression MECHANISM PATTERN OF PAIN PRESENTATION AND PHYSICAL FINDINGS INVESTIGATIONS PROGNOSIS Stepwise Approach to Pain Assessment FEATURES OF PAIN HISTORY 110

Onset Location Intensity Quality Timing Exacerbating/Relieving Factors Responses to Previous Analgesic and Disease-Modifying Therapies Impact of Pain Effects of Pain on Activities of Daily Living Psychological State Familial, Vocational, Social Function QUALITY OF LIFE ASSESSMENT GENERAL ASSESSMENT ASSOCIATED SYMPTOMS LABORATORY AND IMAGING DATA PHYSICAL EXAMINATION DIAGNOSIS Summary CHAPTER 43 Cancer Pain: Principles of Management and Pharmacotherapy DERMOT FITZGIBBON

Cancer Pain Management Overview PRIMARY ANTICANCER TREATMENT Surgery Stenting, Drainage Procedures, and Antibiotics Symptomatic Cancer Pain Management WORLD HEALTH ORGANIZATION ANALGESIC LADDER By Mouth By the Clock By the Ladder For the Individual With Attention to Detail Nonsteroidal Anti-Inflammatory Drugs EFFICACY IN CANCER PAIN 111

Acetaminophen Opioid-Induced Bowel Dysfunction Antiemetics Adjuvant Analgesics GENERAL PURPOSE ADJUVANTS MUSCULOSKELETAL PAIN ADJUVANTS NEUROPATHIC PAIN ADJUVANTS BONE PAIN ADJUVANTS VISCERAL PAIN ADJUVANTS Psychotropic Drugs Cannabinoids Opioid Analgesics SELECTION OF OPIOID THERAPY IN CANCER PAIN MANAGEMENT TOLERANCE AND HYPERALGESIA MORPHINE OXYCODONE OXYMORPHONE HYDROMORPHONE METHADONE LEVORPHANOL FENTANYL Transdermal Fentanyl Oral Transmucosal/Intranasal/Sublingual Fentanyl Fentanyl-Associated Deaths BUPRENORPHINE HYDROCODONE CODEINE TRAMADOL TAPENTADOL OPIOIDS NOT RECOMMENDED FOR ROUTINE USE IN CANCER PAIN CONTROL OPIOID-RELATED SIDE EFFECTS Prevention or Minimizing Opioid-Related Side Effects OPIOID EFFECTS ON COGNITION, MOTOR SKILLS, AND 112

DRIVING ABILITY OPIOID ROTATION IN CANCER PAIN PARENTERAL OPIOID THERAPY INTRACEREBROVENTRICULAR OPIOIDS Substance Abuse in Oncology Home Infusion Therapy Integrative Oncology Summary CHAPTER 44 Interventional Pain Therapies SHANE E. BROGAN, JILL SINDT, AND ASHWIN VISWANATHAN

Intrathecal Drug Therapy INDICATIONS INTRATHECAL DRUG DELIVERY SYSTEMS Simple Percutaneous Intrathecal Catheter Tunneled Intrathecal Catheter Implantable Drug Delivery Systems INTRATHECAL VERSUS EPIDURAL DRUG DELIVERY IMPLANTABLE OR EXTERIORIZED INTRATHECAL DRUG DELIVERY: COST ANALYSIS OUTCOME STUDIES PATIENT-CONTROLLED INTRATHECAL ANALGESIA PHARMACOLOGY Opioids Ziconotide Local Anesthetics Clonidine Other Drugs CONTRAINDICATIONS AND RISK MANAGEMENT COMPLICATIONS AND SIDE EFFECTS INTRATHECAL THERAPY AND ONGOING ONCOLOGIC CARE Spinal Chemoneurolysis SPINAL CHEMONEUROLYSIS TECHNIQUE Lumbosacral Neurolysis 113

Cervical and Thoracic Neurolysis ADVERSE EFFECTS CONTRAINDICATIONS Celiac Plexus Block INDICATIONS ANATOMY OF THE CELIAC PLEXUS GENERAL CONSIDERATIONS ADVERSE EFFECTS CELIAC PLEXUS BLOCK TECHNIQUES Posterior Approach to the Splanchnic Nerves and Celiac Plexus Anterior Approaches OUTCOME STUDIES Superior Hypogastric Plexus Block INDICATIONS ANATOMY OF THE SUPERIOR HYPOGASTRIC PLEXUS GENERAL CONSIDERATIONS ADVERSE EFFECTS TECHNIQUES OUTCOME STUDIES Ganglion of Impar Block INDICATIONS ANATOMY OF THE GANGLION OF IMPAR GENERAL CONSIDERATIONS ADVERSE EFFECTS TECHNIQUE Intercostal Nerve Block INDICATIONS ANATOMY OF THE INTERCOSTAL NERVES GENERAL CONSIDERATIONS ADVERSE EFFECTS TECHNIQUE OUTCOME STUDIES Blocks of the Head and Neck Nerve Blocks of the Trigeminal Nerve and Its Branches INDICATIONS 114

ANATOMY OF THE TRIGEMINAL NERVE AND ITS BRANCHES GENERAL CONSIDERATIONS ADVERSE EFFECTS TECHNIQUES OUTCOME STUDIES OTHER HEAD AND NECK INTERVENTIONAL TARGETS Spinal Cord Stimulation Vertebral Augmentation INDICATIONS CONTRAINDICATIONS OUTCOMES Spinal Cord Ablation Cordotomy INDICATIONS SURGICAL TECHNIQUES OUTCOMES COMPLICATIONS Myelotomy INDICATIONS SURGICAL TECHNIQUE PERCUTANEOUS RADIOFREQUENCY LESIONING OPEN LIMITED MYELOTOMY OUTCOMES COMPLICATIONS Dorsal Root Entry Zone Lesioning IMAGE-GUIDED ABLATION OF PAINFUL BONE METASTASES Summary CHAPTER 45 Pain Caused by Cancer of the Head and Neck and Oral and Oropharynx ANDREI BARASCH AND JOEL BRIAN EPSTEIN

Pain Mechanisms Due to Local and Regional Cancer of the Head and Neck TUMOR-INDUCED ALGESIA 115

Pain Mechanisms Due to Chemotherapy and/or Radiotherapy Pain Due to Surgery Pain Due to Mucositis EPIDEMIOLOGY PATHOGENESIS HEMATOPOIETIC CELL TRANSPLANTATION HEAD AND NECK RADIATION THERAPY COMBINED RADIATION THERAPY, SURGERY, AND/OR CHEMOTHERAPY Pain Assessment Management of Oral Mucositis Pain Management BASIC ORAL CARE BLAND ORAL RINSES TOPICAL ANESTHETICS AND ANALGESICS TOPICAL ANTIMICROBIALS SYSTEMIC ANALGESICS ANTI-INFECTIVE APPROACHES Hyposalivation BIOLOGIC RESPONSE MODIFIERS AND CYTOKINES COGNITIVE AND BEHAVIORAL INTERVENTIONS Conclusion CHAPTER 46 Cancer-Related Bone Pain EDGAR ROSS, LALITHA SUNDARARAMAN, AND MARY ALICE VIJJESWARAPU

Epidemiology Review PATHOPHYSIOLOGY EVALUATION OF THE PATIENT WITH BONE CANCER Radiography Bone Scan Computed Tomography 18F-FDG-PET-CT Magnetic Resonance Imaging TREATMENT CYCLOOXYGENASE-2-SPECIFIC INHIBITORS 116

CORTICOSTEROIDS BISPHOSPHONATES CALCITONIN OPIOIDS/OPIATE ANTAGONISTS ADJUVANT ANALGESICS N-METHYL-D-ASPARTATE ANTAGONISM AND α2 AGONISTS HORMONAL THERAPY RADIONUCLEOTIDES PROCEDURAL INTERVENTIONS Intralesional Injection Percutaneous Vertebroplasty/Kyphoplasty Rhizotomy ASSOCIATED PROCESSES Avascular Necrosis GRANULOCYTE COLONY-STIMULATING FACTOR RELATED PAIN Conclusion CHAPTER 47 Cancer-Related Visceral Pain MARY ALICE VIJJESWARAPU, LALITHA SUNDARARAMAN, AND EDGAR ROSS

Epidemiology Review Characteristics of Visceral Pain ANATOMY AND PHYSIOLOGY SENSITIZATION LOCALIZATION VISCERAL AFFERENTATION ASCENDING PATHWAYS Visceral Pain Syndromes ORAL MUCOSA Paraneoplastic Pemphigus Oropharyngeal Mucositis and Stomatitis MEDIASTINUM 5-Fluorouracil-Induced Anginal Chest Pain Pleura 117

Pancoast Syndrome PANCREAS Midline Retroperitoneal Syndrome Pancreatic Cancer LIVER PAIN Hepatic Distension Syndrome INTESTINAL PAIN Chronic Intestinal Obstruction Peritoneal Carcinomatosis Radiation Enteritis Intraperitoneal Chemotherapy Pain PELVIC PAIN Malignant Perineal Pain Ureteral Obstruction Ovarian Cancer Pain Tumor-Related Gynecomastia Intravesical Chemotherapy or Immunotherapy Corticosteroid-Induced Perineal Discomfort ADRENAL PAIN SYNDROME Vascular Obstruction Venous Thrombosis Superior Vena Cava Obstruction Acute Mesenteric Vein Thrombosis PAIN SYNDROMES RELATED TO INTRAVENOUS CHEMOTHERAPEUTIC AGENTS Hepatic Artery Infusion Pain COMPLEX VISCERAL PAIN SYNDROMES POSTRADIATION VISCERAL PAIN Radiation Enteritis and Proctitis Burning Perineum Syndrome Radiation Cystitis POSTCHEMOTHERAPY VISCERAL PAIN Treatment N-METHYL-D-ASPARTATE RECEPTOR ANTAGONISTS CORTICOSTEROIDS 118

GABAPENTIN SHORT INTERFERING RNA THERAPEUTICS T-TYPE CALCIUM CHANNEL ANTAGONISTS AMPA/KAINATE ANTAGONISTS P38 KINASE INHIBITORS CHEMOKINE RECEPTOR TYPE 2 ANTAGONISTS P2X PURINOCEPTOR 3 ANTAGONISTS NEWER OPIOID DERIVATIVES FOR THE TREATMENT OF CHRONIC PAIN Cebranopadol PROCEDURAL INTERVENTIONS Ganglion Impar Block Thoracic Sympathetic Ganglion Block Interpleural Catheters Surgery Dorsal Myelotomy for Treatment of Intractable Visceral Cancer Pain Hypophysectomy and Cancer Pain Conclusion CHAPTER 48 Radiotherapy and Chemotherapy in Cancer Pain Management NORA JANJAN

Introduction BONE DISEASE CLINICAL APPLICATIONS OF RADIATION THERAPY Response of Tumors to Radiotherapy TRACHEA, BRONCHI, AND LUNGS PANCREATIC CANCER PELVIS SKIN AND SUBCUTANEOUS TISSUES BRAIN METASTASES Bone Metastases Single-Fraction Radiation Stereotactic Radiation for Nonspine Bone Metastases Reirradiation 119

Pathologic Fracture Spinal Cord Compression RADIATION TOLERANCE OF THE SPINAL CORD CLINICAL MANAGEMENT Treatment of Diffuse Bone Metastases WIDE-FIELD RADIOTHERAPY RADIOPHARMACEUTICALS Role of Palliative Chemotherapy CLINICAL APPLICATIONS PALLIATIVE CHEMOTHERAPY LYMPHOMA BREAST CANCER HEAD AND NECK CANCER OVARIAN CANCER LUNG CANCER GASTROINTESTINAL CANCERS PROSTATE CANCER DECISION MAKING ABOUT CHEMOTHERAPY SIDE EFFECTS AND COMPLICATIONS Endocrine Therapy ENDOCRINE THERAPY FOR RELIEF OF CANCER PAIN Bisphosphonates Summary CHAPTER 49 Cancer Pain in Children ROY L. KAO, LONNIE ZELTZER, AND JACQUELINE CASILLAS

Overview of Childhood Cancer EPIDEMIOLOGY TREATMENT SURVIVORSHIP Pain in Children: How Does This Differ from That in Adults? INFANTS–PRESCHOOL SCHOOL AGE–ADOLESCENCE Pediatric Cancer Pain EPIDEMIOLOGY OF PEDIATRIC CANCER PAIN 120

UNDERTREATMENT AND IMPACT OF PEDIATRIC CANCER PAIN Evaluation of Pediatric Cancer Pain HISTORY AND PHYSICAL EXAM SENSORY EXPERIENCE—SELF-REPORT SENSORY EXPERIENCE—OBSERVATION EMOTIONAL AND COGNITIVE EXPERIENCE FUNCTIONAL AND QUALITY OF LIFE ASSESSMENT PAST PAIN-DIRECTED THERAPIES CANCER HISTORY—DIAGNOSIS CANCER HISTORY—TREATMENTS PAST MEDICAL, PSYCHIATRIC, SOCIAL, AND SPIRITUAL HISTORY PROXY REPORTS INTEGRATING DATA IN EVALUATION OF THE WHOLE CHILD INCORPORATING TECHNOLOGY INTO ASSESSMENT Etiologies of Cancer Pain DISEASE-RELATED PAIN Bone Marrow Infiltration Brain and Spinal Tumors Visceral Pain Bone Tumors PROCEDURE-RELATED PAIN Postlumbar Puncture Headache Postoperative Pain Phantom Limb Pain TREATMENT-RELATED PAIN Bone Marrow Expansion Mucositis Neuropathic Pain PAIN FROM OTHER ETIOLOGIES Infection Graft-versus-host Disease Bone Complications of Therapy 121

PAIN IN SURVIVORSHIP Management of Pain Pharmacologic Management of Cancer-Related Pain in Children Overview of Opioid Analgesia in Children ADVERSE EFFECTS DEPENDENCE AND ADDICTION TOLERANCE TO OPIOIDS “WEAK” OPIOID ADJUVANT THERAPIES FOR NEUROPATHIC PAIN Physical and Psychological Therapies for Pain in the Pediatric Cancer Patient ACUPUNCTURE BEHAVIORAL INTERVENTIONS HYPNOTHERAPY EXPRESSIVE ARTS THERAPIES MASSAGE BIOFEEDBACK BOTANICALS CANNABIS MAGNETS SPIRITUALITY/RELIGIOSITY THERAPEUTIC YOGA Palliative Care for Children with Cancer Summary ACUTE PAIN CHAPTER 50 Acute Pain Management in Children STACY J. PETERSON, KRISTEN LYNN LABOVSKY, AND STEVEN J. WEISMAN

Pain Assessment in Infants and Children Analgesic Pharmacology in Infants and Children Nonopioid Analgesics ONTOGENY OF PROSTANOID BIOSYNTHESIS AND CYCLO-OXYGENASES ASPIRIN AND OTHER SALICYLATES ACETAMINOPHEN 122

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS KETAMINE ANTICONVULSANTS Opioids ONTOGENY OF OPIOID ACTIONS CODEINE TRAMADOL OXYCODONE MORPHINE HYDROMORPHONE METHADONE FENTANYL MEPERIDINE Opioid Administration in Infants and Children INTERMITTENT INTRAVENOUS BOLUS DOSING CONTINUOUS OPIOID INFUSIONS PATIENT-, NURSE-, AND PARENT-CONTROLLED ANALGESIA TREATMENT OF OPIOID SIDE EFFECTS LOCAL ANESTHETICS AND REGIONAL ANESTHESIA IN INFANTS AND CHILDREN CUTANEOUS ANALGESIA WOUND INFILTRATION Epidural Analgesia in Infants and Children DRUGS AND DRUG DOSING USED FOR EPIDURAL ANALGESIA Peripheral Nerve Blocks in Children SUPRACLAVICULAR INFRACLAVICULAR SCIATIC NERVE BLOCK Sciatic-Subgluteal Approach Popliteal Approach FEMORAL BLOCK TRANSVERSUS ABDOMINIS PLANE BLOCK Painful Conditions in Pediatric Hospital Care 123

CANCER PAIN PAIN ASSOCIATED WITH SICKLE CELL VASOOCCLUSIVE EPISODES CHILDREN WITH TRAUMA CHILDREN WITH DEVELOPMENTAL DISABILITIES Conclusions CHAPTER 51 Acute Pain in Adults ROBERT W. HURLEY, MICHAEL L. KENT, AND CHRISTOPHER L. WU

Acute and Chronic Effects of Acute Pain Neurobiology of Acute Pain PRIMARY AFFERENTS AND PERIPHERAL NERVE NEUROTRANSMITTERS SPINAL CORD AND SUPRASPINAL STRUCTURES Prevention PREVENTIVE ANALGESIA Treatment Methods SYSTEMIC ANALGESIC TECHNIQUES Opioids Nonsteroidal Anti-inflammatory Agents Excitatory Amino Acids Anticonvulsants α-Adrenergic Medications Steroids Serotoninergic Medications NONSELECTIVE NORADRENERGIC AND SEROTONINERGIC MEDICATIONS INTRAVENOUS PATIENT-CONTROLLED ANALGESIA

124

REGIONAL ANALGESIC TECHNIQUES Single-Dose Neuraxial Opioids Continuous Epidural Analgesia PERIPHERAL REGIONAL ANALGESIA Intra-articular Analgesia ENHANCED RECOVERY AFTER SURGERY PATHWAYS Analgesia in Special Populations WAR TRAUMA AMBULATORY SURGICAL PATIENTS ELDERLY PATIENTS OPIOID-TOLERANT PATIENTS OBESITY, OBSTRUCTIVE SLEEP APNEA, AND SLEEP Gender or Sex Differences in Analgesia Inpatient Pain Services Long-term Impact of Acute Pain CHAPTER 52 Regional Anesthesia Techniques for Acute Pain Management MARIE N. HANNA, JEAN-PIERRE P. OUANES, AND VICENTE GARCIA TOMAS

Continuous Epidural Analgesia THORACIC EPIDURAL ANALGESIA BLOCK TECHNIQUE: EPIDURAL Subarachnoid/Intrathecal Analgesia TECHNIQUE CLINICAL SUBARACHNOID ANALGESIA Opioids Clonidine Combined Spinal and Epidural TECHNIQUE OF COMBINED SPINAL EPIDURAL Needle through Needle Technique Separate Needles Techniques COMPLICATIONS AND CHALLENGES WITH COMBINED SPINAL EPIDURAL Contraindications of Neuraxial Techniques SEPSIS, FEVER, AND VIRAL INFECTIONS COAGULOPATHY, THROMBOCYTOPENIA, AND 125

BLEEDING DISORDERS CENTRAL NERVOUS SYSTEM DISORDERS Analgesic Adjuvants for Central and Peripheral Analgesia INTRODUCTION NEURAXIAL OPIOIDS PERINEURAL OPIOIDS PERINEURAL CLONIDINE AND DEXMEDETOMIDINE PERINEURAL DEXAMETHASONE Transversus Abdominis Plane Block, Ilioinguinal Iliohypogastric Block, Rectus Sheath Block TRANSVERSUS ABDOMINIS PLANE BLOCK Landmark Technique Ultrasound-Guided Transversus Abdominis Plane ILIOHYPOGASTRIC AND ILIOINGUINAL BLOCK RECTUS SHEATH BLOCK Peripheral Nerve Blocks and Catheters Interscalene Block INDICATIONS LANDMARKS TECHNIQUES Nerve Stimulation Ultrasound Guidance CLINICAL EFFECTS Supraclavicular Block INDICATIONS LANDMARKS ULTRASOUND TECHNIQUE CLINICAL EFFECTS Infraclavicular Block INDICATIONS LANDMARKS TECHNIQUE CLINICAL EFFECTS Axillary Block INDICATIONS 126

LANDMARKS TECHNIQUES Nerve Stimulation Transarterial Technique Ultrasound Guidance CLINICAL EFFECTS Suprascapular and Axillary Nerve Block INDICATIONS LANDMARKS ULTRASOUND TECHNIQUE Axillary Nerve Block CLINICAL EFFECTS Brachial Plexus Terminal Branch Blocks at the Elbow and Below INDICATIONS TECHNIQUES Nerve Stimulation Ultrasound Guidance CLINICAL EFFECTS Paravertebral Nerve Block INDICATIONS AND LANDMARKS TECHNIQUES Landmark Technique Ultrasound Technique CONTRAINDICATIONS CLINICAL EFFECTS Nerve Blocks of the Lumbar Plexus INDICATIONS AND LANDMARKS TECHNIQUES Landmark Technique Ultrasound Guidance COMPLICATIONS CLINICAL EFFECTS Femoral Block INDICATIONS LANDMARKS 127

TECHNIQUES Nerve Stimulator-Guided Femoral Block Ultrasound Technique COMPLICATIONS CLINICAL EFFECTS Adductor Canal Block INDICATIONS CLINICAL EFFECTS TECHNIQUE Ultrasound Guidance Landmark Approach COMPLICATIONS Fascia Iliaca Block INDICATIONS TECHNIQUES Landmark Approach Ultrasound Guidance CLINICAL EFFECTS COMPLICATIONS Lateral Femoral Cutaneous Nerve Block INDICATIONS AND LANDMARKS TECHNIQUES Landmark Technique Ultrasound Guidance CLINICAL EFFECTS COMPLICATIONS Obturator Nerve INDICATIONS AND LANDMARKS TECHNIQUES Landmark Technique Ultrasound Guidance COMPLICATIONS Sacral Plexus-Sciatic Nerve Block INDICATIONS LANDMARKS 128

TECHNIQUES Landmark Technique Ultrasound Technique CLINICAL EFFECTS COMPLICATIONS Ankle Block INDICATIONS TECHNIQUES Landmark Technique Classic Ultrasound Technique CLINICAL EFFECTS COMPLICATIONS Quadratus Lumborum Block INDICATIONS ULTRASOUND TECHNIQUE Quadratus Lumborum 1 CLINICAL EFFECTS COMPLICATIONS PECS/Serratus Anterior Plane Block INDICATIONS ULTRASOUND TECHNIQUE PECS I and PECS II Serratus Anterior Plane Block CLINICAL EFFECTS COMPLICATIONS Complications of Peripheral Nerve Blocks NEUROLOGIC COMPLICATIONS POSTSURGICAL INFLAMMATORY NEUROPATHY NONNEUROLOGIC COMPLICATIONS SUMMARY OF TREATMENT OF LOCAL ANESTHETIC SYSTEMIC TOXICITY Summary CHAPTER 53 Burn Pain SHELLEY A. WIECHMAN AND SAM R. SHARAR

129

The Nature of Burn Pain Psychological Factors Generalized Treatment Paradigm for Burn Pain Pharmacologic Approaches OPIOIDS NONOPIOIDS ANXIOLYTICS ANESTHETICS PHARMACOLOGIC OPTIONS FOR BACKGROUND PAIN MANAGEMENT PHARMACOLOGIC OPTIONS FOR PROCEDURAL PAIN MANAGEMENT PHARMACOLOGIC OPTIONS FOR POSTOPERATIVE PAIN MANAGEMENT Nonpharmacologic Approaches COGNITIVE INTERVENTIONS AND COPING STYLES PREPARATORY INFORMATION BEHAVIORAL INTERVENTIONS HYPNOSIS VIRTUAL REALITY Conclusion ACKNOWLEDGMENT PAIN IN SPECIAL POPULATIONS CHAPTER 54 Persistent Pain in Children BOBBIE L. RILEY, TONYA M. PALERMO, GARY A. WALCO, CHARLES BERDE, AND NEIL L. SCHECHTER

Epidemiology of Chronic Pain in Children MUSCULOSKELETAL PAIN Arthritis Nonrheumatologic Musculoskeletal Pain Fibromyalgia Syndrome Complex Regional Pain Syndrome Back Pain Temporomandibular Disorders 130

HEADACHE CHRONIC ABDOMINAL PAIN DISEASE- OR TREATMENT-RELATED PAIN Sickle Cell Disease Cystic Fibrosis Phantom Limb ADDITIONAL CONSIDERATIONS Impact of Persistent Pain on Children and Families Clinical Evaluation of the Child with Chronic Pain BACKGROUND HISTORY MEASUREMENT OF PAIN AND FUNCTIONING PHYSICAL EVALUATION CLINICAL FORMULATION FEEDBACK WITH THE FAMILY Treatment GENERAL PRINCIPLES OF TREATMENT SPECIFIC INTERVENTIONS FOR CHRONIC/PERSISTENT PAIN Pharmacologic Interventions Psychological Interventions School and Social Reintegration Sleep Intensive Rehabilitation Therapy Specific Entities MUSCULOSKELETAL PAIN COMPLEX REGIONAL PAIN SYNDROMES BACK PAIN HEADACHE FUNCTIONAL GASTROINTESTINAL PAIN Barriers to Care Conclusion CHAPTER 55 Pain in the Older Person PAUL M. ARNSTEIN AND KEELA HERR

131

Overview THE PREVALENCE OF PAIN IN OLDER ADULTS Pain in the Older Person IMPACT OF PAIN ON FUNCTIONING AND QUALITY OF LIFE UNDERTREATMENT OF PAIN IN OLDER PERSONS CHANGE IN PAIN PROCESSING AND MODULATION Assessment of Pain in the Older Person CLINICAL EVALUATION OF PAIN NONVERBAL, COGNITIVELY IMPAIRED OLDER ADULTS Pharmacologic Treatment of Pain in Older Persons PHARMACOKINETICS AND PHARMACODYNAMICS ASSOCIATED WITH AGING SAFE, EFFECTIVE USE OF NONOPIOIDS IN THE OLDER PERSON Acetaminophen Nonsteroidal Anti-inflammatory Drugs Safe Nonsteroidal Anti-inflammatory Drug Product Selection and Monitoring Use SAFE, EFFECTIVE USE OF OPIOIDS IN THE OLDER PERSON POTENTIAL RISKS OF OPIOID ANALGESICS Potential Safety Concerns with Opioids Prudent Product Selection and Use SAFE, EFFECTIVE USE OF ADJUVANTS IN THE OLDER PERSON Additional Treatments for Pain of Older Person INTERVENTIONAL APPROACHES PHYSICAL MODALITIES PSYCHOSOCIAL MODALITIES COMPLEMENTARY AND INTEGRATIVE HEALTH MULTIDISCIPLINARY PAIN TREATMENTS Summary CHAPTER 56 Obstetric Pain CYNTHIA A. WONG

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Historical Notes Pain of Childbirth CHILDBIRTH PAIN MECHANISMS AND PATHWAYS FACTORS THAT AFFECT THE PAIN OF CHILDBIRTH EFFECTS OF PAIN ON THE MOTHER AND FETUS Physiologic Changes of Pregnancy RESPIRATORY CHANGES CARDIOVASCULAR CHANGES Aortocaval Compression Implications for Labor Analgesia CENTRAL NERVOUS SYSTEM CHANGES Anatomy of the Spinal Column and Analgesic Implications Neurohormonal Changes and Analgesic Implications PHARMACOKINETIC CHANGES UTEROPLACENTAL UNIT Transfer of Drugs across the Placenta Nonpharmacologic Methods of Labor Analgesia ANTENATAL CHILDBIRTH EDUCATION LABOR SUPPORT HYDROTHERAPY INTRADERMAL WATER INJECTIONS HYPNOSIS TRANSCUTANEOUS ELECTRICAL STIMULATION ACUPUNCTURE AND ACUPRESSURE Systemic Analgesia INHALATIONAL ANALGESIA PARENTERAL OPIOID ANALGESIA Patient-Controlled Intravenous Analgesia Neuraxial Analgesia EPIDURAL ANALGESIA Drugs for Initiation of Epidural Analgesia COMBINED SPINAL-EPIDURAL ANALGESIA Drugs for Initiation of Combined Spinal-Epidural Analgesia MAINTENANCE OF EPIDURAL ANALGESIA OTHER CENTRAL NEURAXIAL TECHNIQUES 133

Single-Shot and Continuous Spinal Analgesia Dural Puncture Epidural Analgesia Caudal Analgesia SIDE EFFECTS OF NEURAXIAL ANALGESIA Hypotension Pruritus Fetal Bradycardia Maternal Hyperthermia COMPLICATIONS OF NEURAXIAL ANALGESIA Unintentional Dural Puncture Respiratory Depression Other Regional Analgesic Techniques PARACERVICAL BLOCK LUMBAR SYMPATHETIC BLOCK PUDENDAL BLOCK PERINEAL INFILTRATION Effects of Analgesia on the Progress of Labor Nonobstetric Drug Therapy during Pregnancy and Lactation DRUG CLASSIFICATION DURING PREGNANCY AND LACTATION Analgesic Drugs during Pregnancy and Lactation CHAPTER 57 Pain and Sickle Cell Disease SAMIR K. BALLAS

Introduction HISTORY NATURE OF THE SICKLE MUTATION CLASSIFICATION OF SICKLE CELL SYNDROMES GENOTYPES Pathophysiology VASO-OCCLUSION CELLULAR DEHYDRATION ADHESION TO VASCULAR ENDOTHELIUM INFLAMMATION AND REPERFUSION INJURY GENETIC MARKERS 134

OTHER FACTORS Classification of Sickle Cell Pain Syndromes Acute Sickle Cell Pain Syndromes THE VASCULAR OCCLUSIVE CRISIS Predisposing Factors Precipitating Factors Phases of the Acute Vaso-occlusive Crisis The Prodromal Phase The Initial Phase The Established Phase The Resolving Phase The Relapsing or Postdromal Phase ACUTE CHEST SYNDROME ACUTE ABDOMINAL PAIN SYNDROMES Right Upper Quadrant Pain Syndromes Left Upper Quadrant Syndrome Other Acute Abdominal Painful Episodes HAND–FOOT SYNDROME (DACTYLITIS) PRIAPISM ACUTE MULTIORGAN FAILURE Chronic Sickle Cell Pain AVASCULAR NECROSIS LEG ULCERS INTRACTABLE PAINFUL EPISODES NEUROPATHIC PAIN Management of Sickle Cell Pain NONPHARMACOLOGIC MANAGEMENT OF PAIN PHARMACOLOGIC MANAGEMENT OF PAIN Nonopioids and Sickle Cell Disease Opioids and Sickle Cell Disease Adjuvants and Sickle Cell Disease Management of Pain at Home Outpatient Management of Sickle Cell Pain Pain Management in the Day Unit Pain Management in the Emergency Department 135

Management of Sickle Cell Pain in the Hospital Specific Approaches to Treatment Preventive Therapies Induction of Fetal Hemoglobin Hydroxyurea Hydroxyurea and the HUG Trials Benefits and Side Effects of Hydroxyurea Other Novel Approaches to Therapy CURATIVE THERAPIES Allogeneic Hematopoietic Stem Cell Transplant Gene Therapy Conclusion CHAPTER 58 Pain in HIV SVETLANA FAKTOROVICH AND DAVID M. SIMPSON

Prevalence of Pain in HIV/AIDS Pain in Women with HIV/AIDS Pain in Children with HIV/AIDS Specific Pain Syndromes in HIV/AIDS GASTROINTESTINAL PAIN OROPHARYNGEAL PAIN ESOPHAGEAL PAIN ABDOMINAL PAIN ANORECTAL Chest Pain Syndromes CARDIAC PAIN PULMONARY/PLEURITIC PAIN CHEST WALL PAIN Musculoskeletal Pain ARTHROPATHY OSTEOPOROSIS Neurologic Manifestations PERIPHERAL NEUROPATHY DISTAL SYMMETRIC POLYNEUROPATHY TREATMENT OF HIV-ASSOCIATED SENSORY 136

NEUROPATHY INFLAMMATORY DEMYELINATING POLYNEUROPATHY MONONEURITIS MULTIPLEX PROGRESSIVE POLYRADICULOPATHY INFLAMMATORY MYOPATHIES Headache PRIMARY HEADACHES SECONDARY HEADACHES Management of Pain EVALUATION GUIDELINES PAIN MEASUREMENT/ASSESSMENT TOOLS MULTIMODAL TREATMENT APPROACH PHARMACOLOGIC TREATMENT Acetaminophen Nonsteroidal Anti-inflammatory Drugs Opioid Analgesics Antidepressant Agents Anticonvulsants Topical Capsaicin Cannabinoids Recombinant Human Nerve Growth Factor Combination Pharmacotherapy NONPHARMACOLOGIC THERAPIES UNDERTREATMENT OF PAIN BARRIERS TO PAIN MANAGEMENT Summary CHAPTER 59 The Treatment of Chronic Pain in Patients with History of Substance Abuse HOWARD A. HEIT AND DOUGLAS L. GOURLAY

Principle of Balance THE IMPORTANCE OF THE DEFINITIONS Basic Science of the Disease of Addiction BINARY CONCEPT OF PAIN AND ADDICTION PAIN AND OPIOID ADDICTION—A CONTINUUM 137

APPROACH SEPARATING THE “MOTIVE” FROM “BEHAVIOR” WHEN DEALING WITH PAIN AND ADDICTION OPIOIDS FOR ANALGESIA OR OPIOID-STABILIZING EFFECT? Recommendations for Terminating Opioid Therapy Assessment Tools Universal Precautions in Pain Medicine THE 10 PRINCIPLES OF UNIVERSAL PRECAUTIONS IN PAIN MEDICINE PATIENT TRIAGE Treating the Pain Patient on Opioid Agonist Treatment The Treatment of Pain and Suffering in Our Society Conclusion CHAPTER 60 Compliance Monitoring in Chronic Pain Management DOUGLAS L. GOURLAY AND HOWARD A. HEIT

How Communication Influences Compliance Assessment Interpreting Aberrant Behavior POTENTIAL TREATMENT TRAPS IN COMPLIANCE MONITORING Borrowing from Tomorrow to Pay for Today Avoiding Excessive Pill Loads Using Pill Load Limits to Modify Behavior Compliance Monitoring Tips and Traps Urine Drug Testing in Pain Medicine SPECIMEN CHOICE WHOM TO TEST FREQUENCY OF TESTING TESTING STRATEGIES PRESUMPTIVE VERSUS DEFINITIVE TESTING LIMITATIONS OF TEST INTERPRETATION Dealing with Unexpected Urine Toxicology Results Decision to Terminate Opioid Therapy FUTURE CONSIDERATIONS 138

VISCERAL PAIN CHAPTER 61 Headache PETER J. GOADSBY

General Principles PRIMARY HEADACHE SYNDROMES ANATOMY AND PHYSIOLOGY SECONDARY HEADACHE MIGRAINE Clinical Features Frequent Migraine Principles of Management of Migraine Nonpharmacologic Management of Migraine Preventive Treatments of Migraine Acute Attack Therapies of Migraine Medication Overuse TENSION-TYPE HEADACHE Clinical Features Pathophysiology Management TRIGEMINAL-AUTONOMIC CEPHALALGIAS Cluster Headache Managing Cluster Headache PAROXYSMAL HEMICRANIA SHORT-LASTING UNILATERAL NEURALGIFORM HEADACHE ATTACKS WITH CONJUNCTIVAL INJECTION AND TEARING OR CRANIAL AUTONOMIC ACTIVATION OTHER PRIMARY HEADACHES Primary Stabbing Headache Primary Cough Headache Primary Exertional Headache Primary Sex Headache Hypnic Headache Primary Thunderclap Headache Hemicrania Continua 139

New Daily Persistent Headache Low Cerebrospinal Fluid Volume Headache Raised Cerebrospinal Fluid Pressure Headache Posttraumatic Headache OTHER IMPORTANT FORMS OF SECONDARY HEADACHE Giant Cell Arteritis Cervicogenic Headache ACKNOWLEDGMENT CHAPTER 62 Noncardiac Chest Pain RONNIE FASS AND TAKAHISA YAMASAKI

Epidemiology Natural History Pathophysiology GASTROESOPHAGEAL REFLUX DISEASE LINKED ANGINA ESOPHAGEAL DYSMOTILITY SUSTAINED ESOPHAGEAL CONTRACTIONS ESOPHAGEAL HYPERSENSITIVITY ALTERED AUTONOMIC ACTIVITY PSYCHOLOGICAL COMORBIDITY Diagnosis of Noncardiac Chest Pain CARDIOLOGY EVALUATION GERD-RELATED NCCP BARIUM ESOPHAGRAM UPPER ENDOSCOPY AMBULATORY 24-HOUR ESOPHAGEAL pH MONITORING THE WIRELESS pH SYSTEM THE PROTON PUMP INHIBITOR TEST MULTICHANNEL INTRALUMINAL IMPEDANCE ESOPHAGEAL DYSMOTILITY ESOPHAGEAL MANOMETRY PROVOCATIVE TESTING EDROPHONIUM (TENSILON) TEST 140

ERGONOVINE STIMULATION TEST PENTAGASTRIN STIMULATION TEST Sensory Testing of the Esophagus ACID PERFUSION TEST (BERNSTEIN TEST) ELECTRICAL STIMULATION INTRALUMINAL ULTRASONOGRAPHY BALLOON DISTENSION ESOPHAGEAL EVOKED POTENTIALS BRAIN IMAGING SENSORY TESTING—PITFALLS IN STUDY DESIGN PSYCHOLOGICAL EVALUATION Treatment GERD-RELATED NCCP NON–GERD-RELATED NCCP PAIN MODULATORS Trazodone Serotonin Norepinephrine Reuptake Inhibitors Selective Serotonin Reuptake Inhibitors Adenosine Antagonists Octreotide Benzodiazepines ENDOSCOPIC TREATMENT AND SURGERY FOR NCCP JOHREI THERAPY PSYCHOLOGICAL TREATMENT FUTURE THERAPY CHAPTER 63 Abdominal, Peritoneal, and Retroperitoneal Pain DAVID JUSTIN LEVINTHAL AND KLAUS BIELEFELDT

Clinical Approach to Abdominal Pain PAIN LOCALIZATION AND CHARACTER TIME COURSE CONTEXTUAL INFORMATION PHYSICAL EXAMINATION DIAGNOSTIC TESTING IN ABDOMINAL PAIN Mechanisms of Visceral Pain 141

VISCERAL NOCICEPTION CENTRAL PROCESSING OF SOMATIC AND VISCERAL PAIN SENSITIZATION AND VISCERAL HYPERSENSITIVITY Susceptibility Factors GENETIC FACTORS ADVERSE LIFE EVENTS AND STRESS PSYCHIATRIC DISEASES MICROBIAL COLONIZATION Biomarkers of Abdominal Pain Treatment of Abdominal Pain LIFESTYLE MODIFICATIONS PATIENT–PROVIDER RELATIONSHIP PLACEBO RESPONSE OPIOIDS NONOPIOID ANALGESICS NEUROMODULATORS ANTIDEPRESSANTS PSYCHOLOGICAL THERAPIES BLOCKING AFFERENT PATHWAYS SMOOTH MUSCLE RELAXANTS ACID SUPPRESSANTS ALTERING THE MICROBIOME SEROTONIN SUBSTANCE P COMPLEMENTARY AND ALTERNATIVE MEDICINE THERAPY Conclusion CHAPTER 64 Pelvic Pain in Females KATY VINCENT AND JANE MOORE

Acute Pelvic Pain INTRODUCTION OVERVIEW OF ASSESSMENT GYNECOLOGIC FACTORS 142

Pelvic Inflammatory Disease Adnexal Pathology Hematometra/Hematocolpos Acute Exacerbation of Chronic Pelvic Pain COMPLICATIONS SPECIFIC TO PREGNANCY Ectopic Pregnancy Miscarriage Fibroid Degeneration Ovarian Cyst Accident Ligamentous Stretch Urinary Retention and Uterine Incarceration COMPLICATIONS OF ASSISTED CONCEPTION Ovarian Hyperstimulation Syndrome Pelvic Infection Dysmenorrhea NONSTEROIDAL ANTI-INFLAMMATORY DRUGS HORMONAL TREATMENTS SURGICAL TREATMENTS NONPHARMACOLOGIC INTERVENTIONS Mittelschmerz Chronic Pelvic Pain INTRODUCTION FACTORS ASSOCIATED WITH CHRONIC PELVIC PAIN Social Abuse Psychological Personality OVERVIEW OF ASSESSMENT History Examination Investigations Therapeutic Trial Diagnostic Laparoscopy Empirical Treatment THE IMPORTANCE OF VISCERAL HYPERSENSITIVITY IN 143

CHRONIC PELVIC PAIN GYNECOLOGIC FACTORS IN CHRONIC PELVIC PAIN Endometriosis Adenomyosis Adhesions Chronic Pelvic Inflammatory Disease Pelvic Venous Congestion GASTROINTESTINAL FACTORS IN CHRONIC PELVIC PAIN Irritable Bowel Syndrome Constipation UROLOGIC FACTORS IN CHRONIC PELVIC PAIN Interstitial Cystitis/Bladder Pain Syndrome Urethral Syndrome MUSCULOSKELETAL FACTORS IN CHRONIC PELVIC PAIN Fibromyalgia Trigger Points Pelvic Floor Abnormalities Hernia Sacroiliac Joint Pain NEUROLOGIC FACTORS IN CHRONIC PELVIC PAIN Pudendal Neuropathy Neuropathy Secondary to a Pfannenstiel Incision Dyspareunia OVERVIEW Vaginismus Vulval Pain Syndromes Conclusion CHAPTER 65 Pelvic Pain in Males ANDREW BARANOWSKI

Taxonomy and Phenotyping Chronic Pelvic Pain CLASSICAL PATHOLOGIES PELVIC PAIN SYNDROMES AND NONPELVIC PAIN 144

SYNDROMES Male Urogenital Pain Syndromes MALE-SPECIFIC PELVIC PAIN SYNDROMES SUBCLASSIFICATION OF THE PELVIC PAIN SYNDROMES BY ORGAN THE IMPORTANCE OF TAXONOMY AND PHENOTYPING Epidemiology INCIDENCE/PREVALENCE Prostate Pain Syndrome Scrotal Pain Syndrome Penile Pain Syndrome PRECIPITATING FACTORS Mechanisms DIFFERENCES BETWEEN VISCERAL AND NONVISCERAL SOMATIC PAINS PERIPHERAL MECHANISMS CENTRAL MECHANISMS MUSCLES AND PELVIC PAIN Pelvic Muscle Pain Syndromes Spinal and Abdominal Muscle Pain Syndromes PELVIC NERVES AND PAIN Peripheral Nerve Pain Syndromes Functional Problems and Male Pelvic Pain Psychological Consequences of Male Pelvic Pain Male Urogenital Pelvic Pain Syndromes—Treatment SEX DIFFERENCES AND THERAPIES SPECIFIC PAIN SYNDROME TREATMENTS Prostate Pain Syndrome Scrotal/Testicular/Epididymal Pain Syndromes GENERIC TREATMENT APPROACH Psychology and Sexual Counseling Trigger Point Therapy Nerve Blocks Surgery Drugs 145

Neuromodulation Overview and Conclusion REGIONAL PAIN CHAPTER 66 Cranial Neuralgias MUHAMMAD HASSAN MAJEED AND ZAHID H. BAJWA

Classical Trigeminal Neuralgia HISTORY EPIDEMIOLOGY ETIOLOGY AND PATHOPHYSIOLOGY SYMPTOMS AND SIGNS DIFFERENTIAL DIAGNOSIS TREATMENT Treatment—Medical Management Treatment—Nerve and Neurolytic Blockade Treatment—Surgical Painful Trigeminal Neuropathy MULTIPLE SCLEROSIS NEOPLASM HERPES ZOSTER AND POSTHERPETIC NEURALGIA Etiology Epidemiology Symptoms and Signs Diagnosis Treatment Nervus Intermedius Neuralgia ETIOLOGY SYMPTOMS AND SIGNS DIAGNOSIS TREATMENT Glossopharyngeal Neuralgia ETIOLOGY SYMPTOMS AND SIGNS DIAGNOSIS TREATMENT 146

Vagal Neuralgia ETIOLOGY SYMPTOMS AND SIGNS DIAGNOSIS TREATMENT Other Terminal Branch Neuralgias Other Cranial Neuralgia–Related Causes of Pain: Anesthesia Dolorosa ETIOLOGY SYMPTOMS AND SIGNS DIAGNOSIS TREATMENT Conclusion CHAPTER 67 Facial Pain ALAA ABD-ELSAYED, PAMELA J. HUGHES, AND AHMED M.T. RASLAN

Trigeminal and Other Cranial Nerve Neuropathic Conditions TRIGEMINAL NEUROPATHY Trigeminal Neuralgia Type 1 Trigeminal Neuralgia Type 2 Symptomatic Trigeminal Neuralgia Neuropathic Trigeminal Neuralgia Postherpetic Trigeminal Neuralgia Deafferentation Trigeminal Neuralgia Atypical Facial Pain GLOSSOPHARYNGEAL NEURALGIA NERVUS INTERMEDIUS NEURALGIA Odontogenic and Temporomandibular Joint Disorders ODONTOGENIC PAIN Steps for Diagnosis Dental Findings Oral Soft Tissue Findings Radiographic Examination TEMPOROMANDIBULAR DISORDERS Chronic Headache Disorders Causing Facial Pain 147

PRIMARY HEADACHE CONDITIONS Migraine Headache Tension Headache Cluster Headache Exertional Headache Hypnic Headache Secondary Headache Conditions MEDICATION OVERUSE HEADACHE SINUS HEADACHES HEAD INJURY HEADACHES SHORT-LASTING, UNILATERAL, NEURALGIFORM HEADACHE ATTACKS WITH CONJUNCTIVAL INJECTION AND TEARING SHORT-LASTING, UNILATERAL, NEURALGIFORM HEADACHE ATTACKS WITH CRANIAL AUTONOMIC FEATURES PAROXYSMAL HEMICRANIAS CONTACT POINT HEADACHE CHAPTER 68 Neck and Arm Pain ANITA H. HICKEY AND ZAHID H. BAJWA

Anatomy of the Neck and Arm CERVICAL SPINE Ligaments of the Cervical Spine MUSCULATURE OF THE NECK THE VERTEBRAL CANAL VERTEBRAL ARTERIES CERVICAL NERVES THE CERVICAL AND BRACHIAL PLEXUS PECTORAL GIRDLE AND SHOULDER ANATOMY Epidemiology of Neck and Arm Pain Evaluation of the Patient HISTORY AND PHYSICAL EXAMINATION History Location/Radiation 148

Onset Modifying Factors and Drug History Associated Symptoms Family History Age and Psychosocial History Past Medical History and Review of Systems Surgical History Physical Examination LABORATORY EVALUATION RADIOGRAPHIC STUDIES Common Causes of Neck and Arm Pain MECHANICAL NECK PAIN AND CERVICOGENIC HEADACHE Cervical Spondylosis and Radiculopathy Cervicogenic Headache DIFFUSE IDIOPATHIC SKELETAL HYPEROSTOSIS CERVICAL RADICULOPATHIES UPPER EXTREMITY PERIPHERAL NERVE ENTRAPMENT SYNDROMES AND BRACHIAL PLEXUS NEUROPATHY Carpal Tunnel Syndrome Cubital Tunnel Syndrome LESIONS OF THE BRACHIAL PLEXUS Acute Brachial Plexus Neuritis Thoracic Outlet Syndrome CHAPTER 69 Chest Wall Pain NARASIMHA R. GUNDAMRAJ AND STEVEN H. RICHEIMER

General Considerations Anatomy of the Chest Wall SKELETAL STRUCTURES OF THE CHEST WALL Thoracic Spine Ribs Sternum JOINTS OF THE CHEST WALL INTERCOSTAL SPACES 149

INTERCOSTAL NERVES Neoplastic Chest Wall Pain EPIDURAL SPINAL CORD COMPRESSION SUPERIOR VENA CAVA SYNDROME COSTOPLEURAL SYNDROME Nonneoplastic Chest Wall Pain NEUROPATHIC PAIN Neuropathic Pain of Central Origin Peripheral Neuropathic Chest Wall Pain CHEST WALL PAIN OF SKELETAL ORIGIN Abnormalities of the Thoracic Spine Costochondral Dislocation Chest Wall Pain of Sternal Origin Chest Wall Pain of Myofascial Origin Breast Pain Postsurgical Chest Wall Pain CHEST PAIN AND PSYCHOLOGICAL FACTORS CHEST WALL PAIN OF CARDIAC ORIGIN Conclusion CHAPTER 70 Lower Extremity Pain GAGAN MAHAJAN AND DAVE LOOMBA

Lumbosacral Plexopathy NEOPLASMS RADIATION-INDUCED PLEXOPATHY DIABETIC AND NONDIABETIC LUMBOSACRAL RADICULOPLEXUS ABSCESS RETROPERITONEAL HEMATOMA ANEURYSMS TRAUMA OBSTETRIC-RELATED PLEXOPATHY Specific Nerve Entrapment Syndromes LATERAL FEMORAL CUTANEOUS NERVE ENTRAPMENT Etiology 150

Symptoms and Signs Diagnosis Treatment FEMORAL NERVE ENTRAPMENT Etiology Symptoms and Signs Diagnosis Treatment SAPHENOUS NERVE ENTRAPMENT Etiology Symptoms and Signs Diagnosis Treatment OBTURATOR NERVE ENTRAPMENT Etiology Symptoms and Signs Diagnosis Treatment SCIATIC NERVE ENTRAPMENT Etiology Symptoms and Signs Diagnosis Treatment FIBULAR (PERONEAL) NERVE ENTRAPMENT Etiology Symptoms and Signs Diagnosis Treatment Foot Pain PES PLANUS Etiology Symptoms and Signs Diagnosis and Treatment PES CAVUS Etiology 151

Symptoms and Signs Diagnosis and Treatment PLANTAR FASCIITIS Etiology Symptoms and Signs Diagnosis and Treatment HEEL PAD DEFICIENCY Etiology Symptoms and Signs Diagnosis and Treatment TARSAL TUNNEL SYNDROME Anatomy Etiology Symptoms and Signs Diagnosis Treatment LISFRANC JOINT INSTABILITY Etiology Symptoms and Signs Diagnosis Treatment POSTERIOR TIBIAL TENDON INSUFFICIENCY Etiology Symptoms and Signs Diagnosis Treatment DORSAL FOOT GANGLIA Etiology Symptoms and Signs Diagnosis and Treatment METATARSALGIA Etiology Symptoms and Signs Diagnosis Treatment 152

HALLUX VALGUS Etiology Symptoms and Signs Diagnosis Treatment HALLUX RIGIDUS Etiology Symptoms and Signs Diagnosis Treatment INTRACTABLE KERATOSIS Etiology Symptoms and Signs Diagnosis Treatment SESAMOIDITIS Etiology and Pathophysiology Symptoms and Signs Diagnosis Treatment GOUT Etiology Symptoms and Signs Diagnosis Treatment INTERDIGITAL (MORTON’S) NEUROMA Etiology Symptoms and Signs Diagnosis HAMMERTOES Etiology Diagnosis Treatment CLAW TOE DEFORMITY Etiology 153

Diagnosis Treatment HARD CORN (CLAVUS DURUM) Treatment SOFT CORN (CLAVUS MOLLUM) Treatment INGROWN TOENAIL (ONYCHOCRYPTOSIS) Treatment NECK AND LOW BACK PAIN CHAPTER 71 Neck Pain ANDREW J. ENGEL AND NIKOLAI BOGDUK

Definition Referred Pain CERVICOGENIC HEADACHE Pursuing Diagnosis TRAUMA ACUTE NECK PAIN Serious Conditions Inflammatory Disorders Widespread Pain Rare Conditions Spurious Conditions Unknown CHRONIC NECK PAIN Cervical Disk Stimulation Medial Branch Blocks Prevalence WHIPLASH Etiology Clinical Features Diagnosis CERVICOGENIC HEADACHE Differential Diagnosis Diagnosis 154

Sources Minimally Invasive Tests Prevalence Treatment NECK PAIN Conservative Therapy Injections Interventional Pain Medicine CERVICOGENIC HEADACHE Summary CHAPTER 72 Acute Low Back Pain WADE KING AND NIKOLAI BOGDUK

Introduction DEFINITION REFERRED PAIN CAUSES Management Algorithm TRIAGE Medical History Psychological and Social History Physical Examination Other Examination Ancillary Investigations Formulation INITIAL MANAGEMENT Pain REVIEW VIGILANCE REINFORCEMENT Yellow Flags Discussion Conclusion CHAPTER 73 Chronic Low Back Pain WADE KING AND NIKOLAI BOGDUK

155

Introduction DEFINITION REFERRED PAIN SOURCES CAUSES Lumbar Intervertebral Disks Lumbar Zygapophysial Joints PREVALENCE REFUTED CAUSES ACCEPTED CAUSES UNTESTED CAUSES Assessment MEDICAL HISTORY PSYCHOSOCIAL HISTORY PHYSICAL EXAMINATION REVIEW OF PREVIOUS INVESTIGATIONS Provisional Diagnosis Ancillary Investigations CLEARANCE NOT INDICATED MAGNETIC RESONANCE IMAGING DISK STIMULATION SINUVERTEBRAL NERVE BLOCKS LUMBAR MEDIAL BRANCH BLOCKS SACROILIAC JOINT BLOCKS SACRAL LATERAL BRANCH BLOCKS Treatment GENERAL TREATMENTS DRUG THERAPY Paracetamol (Acetaminophen) Nonsteroidal Anti-inflammatory Drugs Muscle Relaxants Benzodiazepines Antidepressants Pregabalin 156

Opioids PHYSICAL MODALITIES Physiotherapy Massage Traction Manual Therapy McKenzie Therapy Transcutaneous Electrical Nerve Stimulation Other Physical and Electrical Modalities Lumbar Supports Exercise Therapy SIMPLE NEEDLE TREATMENTS Acupuncture Trigger Point Injection Prolotherapy BACK SCHOOL PSYCHOLOGICAL INTERVENTIONS MULTIDISCIPLINARY PAIN MANAGEMENT FUNCTIONAL RESTORATION SPECIFIC, TARGETED TREATMENTS Discogenic Pain Zygapophysial Joint Pain Sacroiliac Pain INVASIVE TREATMENTS Implanted Devices Spinal Surgery Conclusion CHAPTER 74 Surgery for Low Back Pain YOUSSEF GHABRIAL AND NIKOLAI BOGDUK

Rationale Effectiveness BEFORE EVIDENCE-BASED MEDICINE ADVENT OF EVIDENCE-BASED MEDICINE SINCE EVIDENCE-BASED MEDICINE 157

Discussion CHAPTER 75 Failed Back Surgery JEROME SCHOFFERMAN

Causes of Failed Back Surgery MISMATCH: SURGERY NEEDED VERSUS SURGERY PERFORMED (“WRONG SURGERY”) INCOMPLETE EVALUATION AND/OR DIAGNOSIS (“RESIDUAL PATHOLOGY”) COMPLICATIONS TECHNICAL FAILURE RESIDUAL PATHOLOGY Spinal Pathology Extraspinal Pathology RECURRENT PATHOLOGY NEW PATHOLOGY Structural Etiologies of Failed Back Surgery FORAMINAL STENOSIS PAINFUL DISK (DISCOGENIC PAIN) DISK HERNIATION FACET JOINT PAIN SACROILIAC JOINT PAIN SPINAL STENOSIS AND AXIAL LOW BACK PAIN NEUROPATHIC PAIN EPIDURAL FIBROSIS DECONDITIONING Psychological Factors in Failed Back Surgery (“Right Patient”) Establishing the Diagnosis ROLE OF THE HISTORY Preoperative Versus Current Pain Location of Pain (Especially Low Back Pain Versus Leg Pain) Response to Mechanical Changes Quality of Pain TIME COURSE OF APPEARANCE OF PAIN Preoperative Low Back Pain or Leg Pain Never Improves or 158

Early Onset of Old Symptoms New Leg Pain Soon after Surgery Pain Improves but Recurs 1 to 6 Months after Surgery Pain Improves but Recurs and Is Different ROLE OF RADIOLOGIC EVALUATION OF FAILED BACK SURGERY ROLE OF DIAGNOSTIC INJECTIONS Anesthetic Injections Provocation Disk Injections (Discography) Treatments NONSPECIFIC TREATMENTS Rehabilitation and Exercise Medications SOME OF THE SPECIFIC TREATMENTS FOR SPECIFIC DISORDERS Discogenic Pain Facet Joint Pain Sacroiliac Joint Pain Spinal Stenosis Neuropathic Pain Lysis of Adhesions Psychological Interventions Reoperation CHAPTER 76 Psychological Screening of Candidates for Spine Surgery or Placement of Implanted Devices ROBERT EDWARDS AND ROBERT N. JAMISON

Introduction SPINAL SURGERY SPINAL CORD STIMULATION AND INTRATHECAL DRUG DELIVERY SYSTEMS AFFECTIVE DISORDERS AS PREDICTORS OF OUTCOME SOMATIZATION PAIN SENSITIVITY ANGER 159

Cognitive Factors COPING STRATEGIES Behavioral Factors EARLY-LIFE TRAUMA AND ABUSE SUBSTANCE ABUSE COMPONENTS OF PSYCHOLOGICAL EVALUATIONS VALIDATED PSYCHOLOGICAL MEASURES Pain Intensity Measures Mood and Personality Functional Capacity and Activity Interference Measures Pain Beliefs ELECTRONIC PAIN ASSESSMENT PROGRAMS Conclusion PA R T F I V E Methods for Symptomatic Control

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PHARMACOLOGIC THERAPIES CHAPTER 77 Rational Pharmacotherapy for Pain ARTHUR G. LIPMAN

Drugs Are Both Underused and Overused in Pain Management Pharmacotherapy Alone Is Rarely Optimal Therapy for Chronic Pain EVERY USE OF MEDICATION FOR PAIN IS AN EXPERIMENT PATIENT PREFERENCE: SYMPTOM CONTROL VERSUS SIDE EFFECTS WHENEVER POSSIBLE TREAT THE CAUSE OF THE PAIN SYNERGISM AND POTENTIATION OUTCOMES ANALYSES OF PAIN PHARMACOTHERAPY APPROVED DRUGS AND DRUGS FOR NONAPPROVED USES RATIONAL PHARMACOTHERAPY Conclusion CHAPTER 78 Nonsteroidal Anti-inflammatory Drugs and Acetaminophen ADAM C. YOUNG AND ASOKUMAR BUVANENDRAN

Mechanism of Action PROSTAGLANDIN SYNTHESIS AND PHARMACOLOGY CENTRAL SITES OF ACTION PERIPHERAL SITES OF ACTION COX-1 AND COX-2 SELECTIVITY Induction of COX-2 Pharmacokinetics ABSORPTION Oral Injectables Topical Intranasal DISTRIBUTION ELIMINATION PATHOPHYSIOLOGIC CONDITIONS AFFECTING THE 161

KINETICS OF NSAIDS Renal Failure Hepatic Disease Specific Drugs SALICYLATES Aspirin Diflunisal ACETIC ACID DERIVATIVES Indomethacin Sulindac Tolmetin and Etodolac Ketorolac Diclofenac PROPIONIC ACID DERIVATIVES Ibuprofen Ketoprofen Fenoprofen Naproxen Oxaprozin OXICAM DERIVATIVES Meloxicam COX-2 SELECTIVE NSAIDs Celecoxib Etoricoxib Valdecoxib and Parecoxib ACETAMINOPHEN NSAID Combination Medications SIDE EFFECTS, WARNINGS, AND CONTROVERSIES Cardiovascular Effects Allergy and Hypersensitivity Gastrointestinal Toxicity Hematologic Effects Renal Toxicity Hepatic Toxicity Central Nervous System Effects 162

Surgical Complications Conclusion DEDICATION CHAPTER 79 Opioid Analgesics CHARLES E. INTURRISI, DAVID S. CRAIG, AND ARTHUR G. LIPMAN

Classification Based on Interactions with an Opioid Receptor Classification Based on Opioid Agonist or Antagonist Activity Opioid Pharmacodynamics CELLULAR, SYNAPTIC, AND CIRCUIT LEVEL EVENTS THAT INHIBIT PAIN TRANSMISSION The Pharmacodynamic Effects of Opioids Central Nervous System Opioid Effects ANALGESIA MOOD EFFECTS SEDATION NAUSEA AND VOMITING RESPIRATORY DEPRESSION CONSTRICTION OF THE PUPIL ANTITUSSIVE EFFECT HYPOTHALAMIC EFFECTS CENTRAL NERVOUS SYSTEM EXCITATION OPIOID TOLERANCE, DEPENDENCE, AND ADDICTION THE OPIOID-TOLERANT PATIENT AND OPIOID-INDUCED HYPERALGESIA Clinically Observable Tolerance Proposed Mechanisms of Tolerance THE OPIOID-DEPENDENT PATIENT THE OPIOID-ADDICTED PATIENT WITH PAIN PERIPHERAL EFFECTS OF OPIOIDS EFFECTS ON SMOOTH MUSCLE AND THE CARDIOVASCULAR SYSTEM PRURITUS OPIOID EFFECTS IN PREGNANCY AND ON THE NEONATE 163

ROUTES FOR OPIOID ADMINISTRATION ALTERNATIVE NONINVASIVE ROUTES SUBLINGUAL ADMINISTRATION EPIDURAL, INTRATHECAL, AND INTRAVENTRICULAR ADMINISTRATION Characteristics of Specific Opioids MORPHINE HYDROMORPHONE METHADONE LEVORPHANOL OXYMORPHONE OXYCODONE FENTANYL MEPERIDINE CODEINE HYDROCODONE PROPOXYPHENE TRAMADOL TAPENTADOL PENTAZOCINE, NALBUPHINE, AND BUTORPHANOL BUPRENORPHINE Abuse-Deterrent Opioid Formulations Selecting among the Opioids for Clinical Use Conclusions and Insights into the Future of Opioids for Pain BIASED LIGANDS DEDICATION CHAPTER 80 Skeletal Muscle Relaxants and Analgesic Balms AUSIM CHAGHTAI AND CHARLES E. ARGOFF

Skeletal Muscle Relaxants MECHANISM OF ACTION Types of Skeletal Muscle Relaxants CENTRALLY ACTING SEDATIVE-HYPNOTIC MUSCLE RELAXANTS Chlorzoxazone 164

Metaxalone Methocarbamol Carisoprodol ANTIHISTAMINE MUSCLE RELAXANT Orphenadrine Citrate TRICYCLIC ANTIDEPRESSANT-LIKE MUSCLE RELAXANT Cyclobenzaprine γ-AMINOBUTYRIC ACID AGONIST MUSCLE RELAXANTS Diazepam Baclofen CENTRAL α2 AGONIST MUSCLE RELAXANTS Tizanidine Acute Low Back Pain Chronic Low Back Pain Topical Analgesic Balms TOPICAL COUNTERIRRITANTS Conclusion CHAPTER 81 Neuropathic Pain Pharmacotherapy ELON EISENBERG, SIMON VULFSONS, AND DAVID M. PETERSON

Antidepressants TRICYCLIC ANTIDEPRESSANTS SELECTIVE SEROTONIN AND NOREPINEPHRINE REUPTAKE INHIBITORS SELECTIVE SEROTONIN REUPTAKE INHIBITORS Antiepileptics PREGABALIN GABAPENTIN CARBAMAZEPINE OXCARBAZEPINE LAMOTRIGINE VALPROATE OTHER ANTICONVULSANTS Opioids 165

Tramadol Tapentadol NMDA Receptor Antagonists Systemic Sodium Channel Blockers Simple Analgesics Nonsteroidal Anti-inflammatory Agents Topical Agents CAPSAICIN TOPICAL LIDOCAINE PATCHES TOPICAL KETAMINE Cannabinoids Drug Combinations Future Drugs Evidence-Based Recommendations for Drug Therapy in Neuropathic Pain Intrathecal Drugs for Neuropathic Pain Neuropathic Pain—Not Only Pharmacotherapy CHAPTER 82 Local Anesthetics MICHAEL M. BOTTROS, LARA WILEY CROCK, AND SIMON HAROUTOUNIAN

Physicochemical Properties of Local Anesthetics MOLECULAR STRUCTURE CHIRALITY ACID–BASE BALANCE LIPOPHILIC–HYDROPHILIC BALANCE Local Anesthetic Pharmacology PHARMACODYNAMICS PHARMACOKINETICS Absorption Distribution Biotransformation and Excretion Effects of Disease States on Local Anesthetic Pharmacokinetics Regional Administration of Local Anesthetics for Pain Relief DIFFERENTIAL BLOCKADE SITE OF INJECTION 166

Neuraxial Anesthesia Peripheral Nerve Blockade Intravenous Regional Anesthesia Infiltration Anesthesia Topical Anesthesia POTENCY, ONSET, AND DURATION pH ADJUSTMENT OF LOCAL ANESTHETICS VASOCONSTRICTOR EFFECT MIXTURES OF LOCAL ANESTHETICS SPECIAL STATES: PREGNANCY Systemic Administration of Local Anesthetics for Pain Relief INTRAVENOUS LIDOCAINE FOR ACUTE POSTOPERATIVE PAIN INTRAVENOUS LIDOCAINE FOR CHRONIC NEUROPATHIC PAIN Adverse Effects SYSTEMIC TOXICITY ALLERGIES METHEMOGLOBINEMIA Prolonged-Duration Local Anesthetics PSYCHOLOGICAL TECHNIQUES CHAPTER 83 Anger and Pain R. JOSHUA WOOTTON

Cultural Background Psychoanalytic Background Current Research in Anger and Its Relation to Pain PHYSIOLOGIC MECHANISMS IN ANGER AND PAIN RESEARCH PSYCHOLOGICAL CONSTRUCTS IN ANGER AND PAIN RESEARCH ANGER MANAGEMENT STYLE Anger-In Anger-Out Opioid Deficit Hypothesis and the Role of Endogenous Opioid 167

Functioning Measurement of Anger STATE-TRAIT ANGER EXPRESSION INVENTORY-2 THE TARGETS AND REASONS FOR ANGER IN PAIN SUFFERERS MULTIDIMENSIONAL ANGER INVENTORY NOVACO ANGER SCALE AND PROVOCATION INVENTORY ANGER DISORDERS SCALE MINNESOTA MULTIPHASIC PERSONALITY INVENTORY2-RESTRUCTURED FORM Psychotherapeutic Management CONSIDERATIONS IN THE SELECTION OF PSYCHOTHERAPY BEHAVIORAL AND COGNITIVE-BEHAVIORAL THERAPIES Summary CHAPTER 84 Cognitive-Behavioral Therapy for Chronic Pain LAYNE A. GOBLE, CHRISTOPHER D. SLETTEN, TAYLOR CROUCH, AND KELLY BARTH

Introduction HISTORY AND DEVELOPMENT OF COGNITIVEBEHAVIORAL THERAPY FOR PAIN EVIDENCE FOR COGNITIVE-BEHAVIORAL THERAPY FOR CHRONIC PAIN Components of Cognitive-Behavioral Therapy for Chronic Pain CHRONIC PAIN PSYCHOEDUCATION Education about the Neurobiology of Chronic Pain Resetting Expectations about the Outcomes of Chronic Pain— the A-B-C Model Changing Behaviors—SMART Method RELAXATION TECHNIQUES BEHAVIORAL ACTIVATION AND TIME-BASED PACING SLEEP HYGIENE COGNITIVE RESTRUCTURING 168

COMMUNICATION SKILLS MAINTENANCE AND RELAPSE PREVENTION Maintaining Treatment Gains THIRD-WAVE THERAPIES—ACCEPTANCE AND COMMITMENT THERAPY TREATING COMORBID CONDITIONS Depression and Anxiety Posttraumatic Stress Disorder COGNITIVE-BEHAVIORAL THERAPY WITHIN INTERPROFESSIONAL PAIN PROGRAMS AND PAIN REHABILITATION PROGRAMS Effectiveness of Interprofessional Pain Management Programs and Pain Rehabilitation Programs COGNITIVE-BEHAVIORAL THERAPY TO PREVENT THE TRANSITION FROM ACUTE TO CHRONIC PAIN Summary CHAPTER 85 Pain and Anxiety and Depression LIN YU AND LANCE M. McCRACKEN

Prevalence of Anxiety and Depressive Disorders in Chronic Pain Impact of Anxiety and Depressive Disorders on Functioning The Interaction of Anxiety, Depression, and Chronic Pain THE FEAR-AVOIDANCE MODEL A Contextual Behavioral Approach to Anxiety and Depressive Disorders Treatment of Anxiety and Depressive Disorders EVIDENCE FROM PHARMACOLOGIC APPROACHES EVIDENCE FROM PSYCHOLOGICAL APPROACHES COGNITIVE-BEHAVIORAL THERAPY FOR CHRONIC PAIN: EFFECTS ON DEPRESSION AND ANXIETY Developments in Cognitive Behavioral Therapy Summary CHAPTER 86 Hypnosis JEANNE HERNANDEZ

History of Hypnosis in Pain and Symptom Control 169

Hypnosis by Definition CONSCIOUS, UNCONSCIOUS, AND CONTENT OF CONSCIOUSNESS Central Mechanisms CENTRAL MECHANISMS OF HYPNOSIS HIGH AND LOW HYPNOTIZABILITY CENTRAL MECHANISMS OF HYPNOTIC ANALGESIA Pain as a Plastic Experience Testing Hypnotizability Current Research and Applications of Medical Hypnosis for Pain EFFICACY AND EFFECTIVENESS REVIEW OF RESEARCH STUDIES ACCORDING TO PAIN PROBLEMS OR SITUATIONS Perioperative and Procedural Uses Complex Regional Pain Syndrome Phantom Limb Pain Burns Dentistry Pediatric Pain Irritable Bowel Syndrome Headaches Cancer Osteoarthritis Medical Hypnosis Techniques PRINCIPLES OF PREPARATION, INDUCTION, AND SUGGESTIONS COMMON INDUCTION PROCEDURES SUGGESTIONS AND IMAGERY Chronic Pain Management ERICKSONIAN NATURALISTIC APPROACHES TO PAIN AND SYMPTOM MANAGEMENT Conclusions CHAPTER 87 Group Therapy for Chronic Pain MELISSA A. DAY AND BEVERLY E. THORN

170

Rationale and Basic Considerations of Group Treatment for Pain EVIDENCE FOR EFFICACY OF GROUP TREATMENT FOR CHRONIC PAIN MANAGEMENT GROUP VERSUS INDIVIDUAL TREATMENT GROUP COGNITIVE-BEHAVIORAL THERAPY VERSUS WAIT-LIST, TREATMENT AS USUAL, OR OTHER GROUP TREATMENTS BEHAVIORAL VERSUS EXERCISE AND PHYSICAL THERAPY GROUP TREATMENTS MINDFULNESS-BASED APPROACHES TO PAIN MANAGEMENT ACCEPTANCE-BASED APPROACHES TO PAIN MANAGEMENT Factors Affecting Psychotherapeutic Outcome THE IMPORTANCE OF COGNITIVE CHANGE COMPLIANCE WITH HOMEWORK AND SKILLS PRACTICE TO MAINTAIN TREATMENT GAINS IMPORTANCE OF THERAPIST SKILL AND ADEQUATE TIME WITH THERAPIST IMPORTANCE OF GROUP PROCESS Advantages of Group Treatment EFFICIENCY AND COST-EFFECTIVENESS SOCIAL PROXIMITY AND SUPPORT VICARIOUS LEARNING AND MODELING OF COLLABORATIVE APPROACH INTERPERSONAL GROUP PROCESS Practical Issues OPEN VERSUS CLOSED GROUPS LENGTH OF GROUP NUMBER OF PARTICIPANTS INDIVIDUALS WHO MAY BE INAPPROPRIATE FOR GROUPS Summary and Conclusions Future Directions Appendix 87.1: Search Strategies 171

CHAPTER 88 Motivating Chronic Pain Patients for Behavioral Change AKIKO OKIFUJI, EMILY HAGN, CHRISTINA ELISE BOKAT, AND DENNIS C. TURK

Neural Mechanisms of Motivation Concept of Readiness to Change: Transtheoretical Model of Behavior Change MOTIVATION ENHANCEMENT THERAPY Help Patients Recognize the Problems and Goals DECISIONAL BALANCE SELF-MOTIVATIONAL STATEMENTS What Not to Do in Motivation Enhancement Therapy Dealing with Setbacks and Resistance SIMPLE REFLECTION AMPLIFIED REFLECTION DOUBLE-SIDED REFLECTION AGREEMENT WITH TWIST PERSONAL CHOICE AND CONTROL SHIFTING FOCUS Research Outcomes Volitional Approach: Implementation Intentions IMPLEMENTATION INTENTIONS: OUTCOMES Conclusion PHYSICAL AND OTHER NONINTERVENTIONAL THERAPEUTIC MODALITIES CHAPTER 89 Basic Concepts in Biomechanics and Musculoskeletal Rehabilitation MAUREEN YOUNG SHIN NOH, BENJAMIN C. SOYDAN, AND ANAND B. JOSHI

Basic Considerations KINETIC CHAIN THEORY ADVERSE NEURAL TENSION Lower Limb Upper Limb NEUROMUSCULAR CONTROL BIOMECHANICAL CONSIDERATIONS IN THE SETTING OF COMMON PHYSICAL EXAMINATION TECHNIQUES 172

ENDURANCE Biomechanical Considerations in Common Musculoskeletal Pain Syndromes CERVICALGIA PERISCAPULAR AND THORACIC PAIN LUMBAR PAIN SACROILIAC AND HIP GIRDLE PAIN Conclusion CHAPTER 90 Pain Rehabilitation STEVEN P. STANOS AND WILSON J. CHANG

Historical Overview: Pain Rehabilitation and Functional Restoration HISTORY OF PAIN REHABILITATION HISTORY OF FUNCTIONAL RESTORATION AND WORK REHABILITATION WHAT IS PAIN REHABILITATION? STAKEHOLDERS IN REHABILITATION Models of Rehabilitation BIOPSYCHOSOCIAL APPROACH VERSUS BIOMEDICAL MODEL FOR PAIN MANAGEMENT TREATMENT APPROACHES: PAIN REHABILITATION Acute Rehabilitation More Comprehensive Team Models: A Pain Continuum Multidisciplinary Treatment Interdisciplinary Treatment Outcomes of Multi- and Interdisciplinary Treatment Programs Team Building and Stakeholder Coordination CASE MANAGEMENT APPLYING TEAM VALUES Assessment, Goal Setting, and Progression through Treatment PAIN REHABILITATION PRINCIPLES Rehabilitation Specialists: Activities and Conceptual Models THE THERAPIST’S ROLE: BUILDING AN EFFECTIVE THERAPEUTIC RELATIONSHIP INCORPORATING BEHAVIORAL APPROACHES IN PAIN 173

REHABILITATION PHYSICAL THERAPY THERAPEUTIC EXERCISE EXERCISE PRESCRIPTION OCCUPATIONAL THERAPY Activities of Daily Living Pacing PAIN PSYCHOLOGY RELAXATION TRAINING Work Rehabilitation: Work Conditioning and Work Hardening OUTCOMES OF WORK CONDITIONING AND WORK HARDENING PROGRAMS Measuring Physical Capacity FUNCTIONAL CAPACITY TESTING FUNCTIONAL CAPACITY TESTING UTILITY What Does an “Invalid” Test Mean? Role of Opioid Management in Pain Rehabilitation Conclusion CHAPTER 91 Assessment and Treatment of Substance Use Disorders ANDREW J. SAXON, JAMES P. ROBINSON, AND MARK D. SULLIVAN

Assessment and Treatment of Substance Use Disorders—Addiction Medicine Perspective SCREENING AND RECOGNITION History Physical Examination Laboratory Self-report Questionnaires PRESCRIPTION DRUG MONITORING PROGRAM DIAGNOSTIC ASSESSMENT Co-occurring Psychiatric Disorders MONITORING DURING ONGOING PAIN TREATMENT TREATMENT AND/OR REFERRAL Brief Interventions Specialty Substance Use Disorders Treatment 174

Medically Supervised Withdrawal Opioid Maintenance Treatment Intensive Outpatient Treatment Inpatient Treatment Specific Behavioral Treatments Pharmacotherapies Conceptions of Opioid Use Disorder—The Pain Medicine Perspective HISTORY OF OPIOID USE FOR CHRONIC PAIN AS IT RELATES TO IDENTIFYING OPIOID USE DISORDER IMPLICATIONS FOR THE IDENTIFICATION OF OPIOID USE DISORDER CLINICAL PREVENTION AND MANAGEMENT OF OPIOID USE DISORDER IN PATIENTS RECEIVING OPIOIDS FOR CHRONIC PAIN Conclusions: Bridging the Gap between Addiction and Pain Medicine CHAPTER 92 Biophysical Agents for Pain Management in Physical Therapy ROGER J. ALLEN

Superficial Thermal Agents THERMOTHERAPY CRYOTHERAPY Light Therapy LASER MONOCHROMATIC INFRARED ENERGY Therapeutic Ultrasound Electrical Current TRANSCUTANEOUS ELECTRICAL NERVE STIMULATION INTERFERENTIAL CURRENT IONTOPHORESIS Somatosensory Desensitization Emerging Interventions MANUAL LYMPHATIC DRAINAGE CUPPING 175

MIRROR THERAPY AND GRADED MOTOR IMAGERY Conclusion CHAPTER 93 Exercise Therapy for Low Back Pain ELLEN McGOUGH AND JOYCE M. ENGEL

Individualized Exercise Programs MUSCULOSKELETAL EXAMINATION FOR LOW BACK PAIN DESIGNING INDIVIDUALIZED EXERCISE PROGRAMS EXERCISE RECOMMENDATIONS BASED ON THE CLINICAL COURSE Acute Lower Back Pain Subacute Lower Back Pain RECURRENT LOWER BACK PAIN STAGE OF MANAGEMENT PERSISTENT LOWER BACK PAIN STAGE OF MANAGEMENT Quota Programs for Exercise Dosage RELAPSE MANAGEMENT THE APPLICATION OF COMMON EXERCISE APPROACHES FOR LOWER BACK PAIN Specific Exercise Global Exercise Psychological and Educational Approaches Evidence to Support Exercise Therapy for Lower Back Pain EVIDENCE FOR SPECIFIC EXERCISE APPROACHES Efficacy of Spinal Stabilization Exercises Efficacy of Directional Preference Exercises EVIDENCE FOR USING CLASSIFICATION SYSTEMS FOR EXERCISE SELECTION Matching the Exercise Program to the Patient EVIDENCE FOR GLOBAL EXERCISE APPROACHES Conclusion CHAPTER 94 Complementary and Integrative Health CHARLES A. SIMPSON

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What Is Complementary and Integrative Health? The Divide FRINGE MEDICINE AND QUACKERY “UNORTHODOX” MEDICINE COMPLEMENTARY AND ALTERNATIVE MEDICINE COMPLEMENTARY AND INTEGRATIVE HEALTH BRIDGING THE DIVIDE: ONE KIND OF MEDICINE WHAT IS DIFFERENT ABOUT COMPLEMENTARY AND ALTERNATIVE MEDICINE? WHO USES COMPLEMENTARY AND INTEGRATIVE HEALTH? CATEGORIZING COMPLEMENTARY AND INTEGRATIVE HEALTH THERAPIES Why Consider Complementary and Integrative Health Therapies in Pain Management? CHALLENGES OF EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE THERAPIES The Complementary and Integrative Health Therapies: The Evidence BIOLOGICALLY BASED THERAPIES Manipulation Therapeutic Massage Natural Medicine Therapies Body Awareness Therapy Breath Pattern Retraining Prolotherapy The Tensegrity Model The Fascia Model Trigger Point Manipulation ENERGY-BASED THERAPIES Veritable Energy Therapies Putative Energy Therapies Biofield Therapies Conclusion IMPLANTED ELECTRICAL STIMULATORS 177

CHAPTER 95 Stimulation of the Peripheral Nervous System for Pain Relief MATTHEW S. WILLSEY, SRINIVAS CHIRAVURI, LYNDA J. YANG, AND PARAG G. PATIL

Pathophysiology and Mechanisms of Analgesia Stimulation Technologies Implantation Techniques OPEN SURGICAL PLACEMENT PERCUTANEOUS PLACEMENT WITH FLUOROSCOPIC GUIDANCE PERCUTANEOUS PLACEMENT WITH ULTRASOUND GUIDANCE PLACEMENT AT THE NERVE ROOT/DORSAL ROOT GANGLION Patient Selection and Preoperative Workup Clinical Indications and Outcomes EXTREMITY PAIN Peripheral Nerve Stimulation Brachial and Lumbar Plexus Stimulation Dorsal Root Ganglion Stimulation TRUNCAL PAIN Axial Back Pain Pelvic and Groin Pain Other Truncal Pain Syndromes HEADACHE AND FACIAL PAIN Occipital Neuralgia Migraine Headache Cluster Headache Trigeminal Neuralgia and Facial Pain Complications PERIPHERAL NERVE STIMULATION PERIPHERAL FIELD STIMULATION DORSAL ROOT GANGLION STIMULATION Conclusion and Future Directions CHAPTER 96 Spinal Cord Stimulation 178

RICHARD B. NORTH AND BENGT LINDEROTH

History Basic Science of Conventional Spinal Cord Stimulation INTRODUCTION NEUROPHYSIOLOGY AND NEUROCHEMISTRY Basic Science of New Spinal Cord Stimulation Waveforms HIGH-FREQUENCY SPINAL CORD STIMULATION BURST SPINAL CORD STIMULATION MODERATE CHANGES OF CONVENTIONAL SPINAL CORD STIMULATION PARAMETERS COMPUTER MODELING STUDIES CONVENTIONAL SPINAL CORD STIMULATION MECHANISMS IN ISCHEMIC PAIN PERIPHERAL VASCULAR DISEASE SPINAL CORD STIMULATION FOR ANGINA PECTORIS AND CARDIAC DISEASE MECHANISMS OF SPINAL CORD STIMULATION IN VISCERAL ABDOMINAL PAIN Indications NEUROPATHIC PAIN ISCHEMIC PAIN VISCERAL PAIN AND DYSFUNCTION Potential Beneficial Outcomes TECHNICAL GOAL CLINICAL GOALS Prognostic Factors Patient Selection Technique Screening Trial SCREENING ELECTRODE CHOICE ELECTRODE POSITIONING PARAMETER ADJUSTMENT PROCEDURAL RISK REDUCTION TRIAL DURATION REMOVAL OF TRIAL ELECTRODE Device Options 179

CHOICE OF ELECTRODE CHOICE OF PULSE GENERATOR PROGRAMMING A SPINAL CORD STIMULATION SYSTEM Patient Management SPINAL CORD STIMULATION PATIENT PRECAUTIONS Spinal Cord Stimulation Treatment Challenges CLINICAL FAILURE BIOLOGIC FAILURE PSYCHOLOGICAL FAILURE TECHNICAL FAILURE EQUIPMENT FAILURE Cost-effectiveness Spinal Cord Stimulation Challenges CHAPTER 97 Deep Brain and Motor Cortex Stimulation JIMMY CHEN YANG, ATHAR N. MALIK, AND EMAD N. ESKANDAR

Deep Brain Stimulation BASIC CONSIDERATIONS EFFICACY OF DEEP BRAIN STIMULATION SURGICAL TECHNIQUE Motor Cortex Stimulation BASIC CONSIDERATIONS EFFICACY OF MOTOR CORTEX STIMULATION SURGICAL TECHNIQUE Transcranial Magnetic Stimulation BASIC CONSIDERATIONS EFFICACY OF REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION FOR PAIN Conclusion INTERVENTIONAL PAIN MANAGEMENT CHAPTER 98 Diagnostic and Therapeutic Nerve Blocks MICHELE CURATOLO AND NIKOLAI BOGDUK

Common Principles 180

PHYSICIAN PATIENT PREPARATION CONTRAINDICATIONS COMPLICATIONS Systemic Effects Physiologic Effects Damage to Nonneural Structures Damage to Nerves PROCEDURE Blind Techniques Fluoroscopy-Guided Techniques Computed Tomography–Guided Techniques Ultrasound-Guided Techniques Test Blocks Prognostic Blocks SPINAL NERVE BLOCKS SYMPATHETIC BLOCKS Diagnostic Blocks PRINCIPLES Controls Criteria for Positive Response APPLICATIONS Nerve Blocks for Cervical Zygapophysial Joint Pain Nerve Blocks for Lumbar Zygapophysial Joint Pain Other Diagnostic Nerve Blocks Diagnostic Intra-articular Blocks Therapeutic Nerve Blocks Conclusion CHAPTER 99 Epidural Steroid Injections TIMOTHY PHILIP MAUS AND NIKOLAI BOGDUK

Definition Background Techniques 181

CAUDAL INJECTIONS: TECHNIQUE CAUDAL INJECTIONS: EVIDENCE CAUDAL INJECTIONS: ADVERSE EVENTS INTERLAMINAR INJECTIONS: TECHNIQUE NONIMAGE-GUIDED INTERLAMINAR TECHNIQUE: EVIDENCE IMAGE-GUIDED INTERLAMINAR TECHNIQUE: EVIDENCE INTERLAMINAR TECHNIQUE: ADVERSE EVENTS TRANSFORAMINAL INJECTIONS TRANSFORAMINAL INJECTIONS UNDER FLUOROSCOPIC GUIDANCE: EVIDENCE TRANSFORAMINAL INJECTIONS: DETERMINANTS OF EFFICACY TRANSFORAMINAL INJECTIONS: ADVERSE EVENTS TRANSFORAMINAL INJECTIONS UNDER COMPUTED TOMOGRAPHY GUIDANCE: EVIDENCE, ADVERSE EVENTS TRANSFORAMINAL EPIDURAL STEROID INJECTIONS: THEIR ROLE IN TREATING THE RADICULAR PAIN PATIENT CHAPTER 100 Intrathecal Drug Delivery in the Management of Pain EDGAR ROSS AND DAVID ARCELLA

History of the Development of Intrathecal Drug Delivery Systems Basic Pharmacology of Intrathecal Drug Administration Selection of Agents for Intrathecal Drug Delivery Specific Agents for Intrathecal Drug Delivery OPIOIDS Morphine Hydromorphone Fentanyl and Sufentanil Opioid-Induced Hyperalgesia and Intrathecal Opioids LOCAL ANESTHETICS α2-ADRENERGIC AGONISTS 182

CALCIUM CHANNEL ANTAGONISTS N-METHYL-D-ASPARTATE RECEPTOR ANTAGONISTS γ-AMINOBUTYRIC ACID AGONISTS GABAPENTIN SOMATOSTATIN AND SOMATOSTATIN ANALOGUES TRICYCLIC ANTIDEPRESSANTS ACETYLCHOLINESTERASE INHIBITORS ADENOSINE NITRIC OXIDE PROSTAGLANDIN INHIBITORS CALCITONIN GENE-RELATED PEPTIDE ANTAGONISTS SUBSTANCE P ANTAGONISTS Patient Selection for Intrathecal Drug Delivery Trialing Techniques for Intrathecal Drug Delivery Implantable Pump Technology SURGICAL TECHNIQUE OF PUMP IMPLANTATION Complications of Spinal Drug Delivery SURGICAL COMPLICATIONS Wound Hematoma/Seroma and Epidural Hematoma Infectious Complications Cerebrospinal Fluid Leak and Postdural Puncture Headache Neurologic Injury DEVICE-RELATED COMPLICATIONS Catheter and Pump Problems Complications Associated with Refill of the Pump Reservoir PHARMACOLOGIC COMPLICATIONS AND DRUGRELATED SIDE EFFECTS Side Effects of Intrathecal Opioids Opioid Tolerance Intrathecal Inflammatory Masses (Intrathecal Granuloma) Drug Withdrawal Patient Outcomes and Intrathecal Drug Infusion CANCER PAIN INTRATHECAL DRUG DELIVERY FOR CHRONIC NONCANCER PAIN 183

Conclusion ACKNOWLEDGMENT CHAPTER 101 Intradiscal Therapies for Low Back Pain YAKOV VOROBEYCHIK AND NIKOLAI BOGDUK

Discogenic Pain Pathology Therapies ABLATION Ramus Communicans Lesions Intranuclear Radiofrequency PERCUTANEOUS INTRADISCAL RADIOFREQUENCY THERMOCOAGULATION Intradiscal Electrothermal Therapy L’DISQ Coblation Biacuplasty CHEMICAL THERAPIES Intradiscal Steroids Etanercept Methylene Blue Antibiotics Proliferants BIOLOGICS Sealant Platelet-Rich Plasma α2 Macroglobulin Stem Cells Discussion CHAPTER 102 Neurolytic Blockade for Noncancer Pain JOHN MACVICAR AND NIKOLAI BOGDUK

Introduction DEFINITION PRINCIPLES 184

HISTORY AND TRENDS LIMITATIONS Chemical Neurolytic Blockade PRINCIPLES PHENOL ALCOHOL APPLICATIONS GLYCEROL Cryoneurotomy Thermal Radiofrequency INTRODUCTION PHYSICS PATHOLOGY PHYSIOLOGY APPLICATIONS Trigeminal Neuralgia Central Ablative Procedures Medial Branch Neurotomy Sacral Lateral Branch Neurotomy Discussion SURGICAL APPROACHES CHAPTER 103 Surgery of the Peripheral Nervous System as a Treatment for Pain JAMES MICHAEL MOSSNER AND PARAG G. PATIL

Peripheral Neurectomy BASIC CONSIDERATIONS Pathophysiology of Neuropathic Pain Rationale for Neuroma Relocation Surgery CLINICAL CONSIDERATIONS Preoperative Evaluation Operative Technique INDICATIONS AND OUTCOMES FOR TREATMENT OF NEUROPATHIC PAIN Amputation Stump Pain Intercostal and Intercostobrachial Pain 185

Perineal and Inguinal Pain Meralgia Paresthetica Saphenous Neuralgia Morton’s Neuroma General Results of Neurectomy for Neuropathic Pain INDICATIONS AND OUTCOMES FOR TREATMENT OF NOCICEPTIVE PAIN Axial Spine Pain Extremity Joint Pain Pelvic Pain Cancer Pain Nerve Entrapment Release BASIC CONSIDERATIONS Pathophysiology of Nerve Entrapment Pain Nerve Entrapment and Systemic Disease CLINICAL CONSIDERATIONS Preoperative Evaluation Operative Technique INDICATIONS AND OUTCOMES Entrapments of the Median Nerve Entrapments of the Ulnar Nerve Entrapments of the Radial Nerve Entrapment of the Suprascapular Nerve Thoracic Outlet Syndrome Entrapments of the Lower Extremities Dorsal Rhizotomy and Ganglionectomy BASIC CONSIDERATIONS CLINICAL CONSIDERATIONS Preoperative Evaluation Operative Technique INDICATIONS AND OUTCOMES Cranial and Cervical Pain Occipital Neuralgia Thoracic Pain Postsurgical Truncal Pain 186

Sacral Pain Extremity Pain Visceral Pain Axial Spine Pain Postherpetic Neuralgia Sympathectomy BASIC CONSIDERATIONS Sympathetic Efferents Sympathetically Maintained Pain CLINICAL CONSIDERATIONS Preoperative Evaluation Operative Techniques INDICATIONS AND OUTCOMES POSTOPERATIVE COMPLICATIONS Conclusion CHAPTER 104 The Surgical Management of Trigeminal Neuralgia MATTHEW K. MIAN, SARAH K. BICK, PRATIK A. TALATI, AND EMAD N. ESKANDAR

Patient Presentation Anatomy Pathophysiology Evaluation for Surgery Microvascular Decompression OUTCOMES Percutaneous Rhizotomy OUTCOMES Percutaneous Radiofrequency Rhizotomy Percutaneous Balloon Compression Radiosurgery OUTCOMES Conclusions CHAPTER 105 Ablative Neurosurgical Procedures for Chronic Pain BENJAMIN L. GRANNAN, MUHAMED HADZIPASIC, AND EMAD N. ESKANDAR

Dorsal Root Entry Zone Lesioning 187

INDICATIONS ANATOMY AND PHYSIOLOGY TECHNIQUE OUTCOMES Cordotomy INDICATIONS ANATOMY AND PHYSIOLOGY TECHNIQUE OUTCOMES Cingulotomy INDICATIONS ANATOMY AND PHYSIOLOGY TECHNIQUE OUTCOMES Thalamotomy INDICATIONS ANATOMY AND PHYSIOLOGY TECHNIQUES OUTCOMES Ablative Procedures of the Brainstem INDICATIONS ANATOMY AND PHYSIOLOGY TECHNIQUES OUTCOMES Conclusion PA R T S I X Provision of Pain Treatment CHAPTER 106 Interdisciplinary Chronic Pain Management: Overview and Lessons from the Public Sector JENNIFER L. MURPHY AND MICHAEL E. SCHATMAN

History of Interdisciplinary Chronic Pain Management EMPIRICAL SUPPORT FOR INTERDISCIPLINARY CHRONIC PAIN MANAGEMENT THEORETICAL BASIS OF THE INTERDISCIPLINARY 188

APPROACH COMPOSITION OF THE INTERDISCIPLINARY TEAM AND ROLES OF MEMBERS The Process of Interdisciplinary Chronic Pain Management Interdisciplinary Chronic Pain Management in Veterans Healthcare Administration: Overview of a Model System Future Considerations for Interdisciplinary Chronic Pain Management Conclusion CHAPTER 107 Spine Clinics JAMES D. KANG, HAI V. LE, AND KENNETH C. NWOSU

Treatment Components Treatment Providers CONSERVATIVE CARE GATEKEEPERS PAIN MANAGEMENT PSYCHOLOGY PHYSICAL THERAPY OCCUPATIONAL THERAPY SPINE SURGERY CHRONIC PAIN MANAGEMENT PROGRAM POTENTIAL BENEFITS OF A SPINE SPECIALTY CLINIC COORDINATION OF CARE RESEARCH AND EDUCATION Conclusion CHAPTER 108 Pain Management in Primary Care WILLIAM C. BECKER AND MATTHEW J. BAIR

Introduction PREVALENCE OF PAIN IN THE UNITED STATES ECONOMIC IMPLICATIONS OF CHRONIC PAIN CHRONIC PAIN MANAGEMENT: THE STATUS QUO SEARCHING FOR SOLUTIONS A New Approach to Chronic Pain Management WHO TREATS CHRONIC ILLNESS? WHY PRIMARY CARE IS INVOLVED? 189

TREATING CHRONIC PAIN IN THE PRIMARY CARE SETTING—WHY A CHALLENGE? Training in Pain Disagreement among Experts—To Treat and Not to Treat Barriers to Treating Pain Addressing Barriers to Care MYTHS AND BIASES PATIENT RESISTANCE REGULATORY SCRUTINY PATIENT EXPECTATIONS Pain Practitioner: A Primary Care Model TRAINING COLLABORATION WITH PAIN SPECIALISTS NEW FOCUS ASSESSMENT AND EVALUATION DURING SHORT VISITS THE 15-MINUTE OFFICE VISIT Validating the Patient Assessment Tools Substance Misuse Screening Goal Setting and Plan of Action PHARMACOLOGIC TREATMENT REFERRAL TO AN ADDICTION SPECIALIST MOTIVATING BEHAVIOR CHANGE IN PATIENTS WITH CHRONIC PAIN Conclusion CHAPTER 109 Pain Management at the End of Life JUDITH A. PAICE

Introduction PALLIATIVE CARE HOSPICE Pain Syndromes Common at the End of Life CANCER NONCANCER DIAGNOSES Pain Assessment at the End of Life 190

CHALLENGES IN PAIN ASSESSMENT PAIN ASSESSMENT IN THE COGNITIVELY IMPAIRED PAIN ASSESSMENT IN THOSE UNABLE TO COMMUNICATE PAIN MEASUREMENT IN RESEARCH CONDUCTED AT END OF LIFE Pain Management Strategies at End of Life ROUTES OF DRUG DELIVERY Oral, Sublingual, Transmucosal, and Buccal Routes Transmucosal Immediate-Release Fentanyl Products Enteral and Rectal Parenteral Spinal (Epidural/Intrathecal) Topical Transdermal INTRACTABLE PAIN OR UNMANAGEABLE ADVERSE EFFECTS OF TREATMENT Effect of Organ Dysfunction on Pharmacokinetics Myoclonus Intractable Pain at End of Life Fears of Hastening Death Suffering and Existential Distress NONPHARMACOLOGIC TECHNIQUES Palliative Sedation Conclusion C H A P T E R 11 0 Ethical Principles that Support Decision Making in Pain Management: The Case of Stopping Opioids FAYE M. WEINSTEIN, CLAUDIA KOHNER, AND STEVEN H. RICHEIMER

Background MEDICAL ETHICS AND ERIKSON’S GOLDEN RULE TRUST MUTUALITY MORALS AND ETHICS Case Vignettes and Analysis 191

CASE 1: OPIOID-INDUCED HYPERALGESIA Background and First Attempt at Change of Treatment Plan to Opioid Cessation Physician Consultation with a Colleague Modification in Engagement with Patient and Treatment Plan following the Consultation and Reflection Analysis CASE 2: CHANGE IN THE CENTERS FOR DISEASE CONTROL AND PREVENTION GUIDELINES Background Analysis CASE 3: OPIOID PRESCRIPTIONS FROM OTHER PHYSICIANS FOUND IN CHECK OF STATE DRUG MONITORING PROGRAM Background Analysis Building Trust through Mutuality DIALOGUE EMPATHY NARRATIVE MEDICINE Conclusion C H A P T E R 111 Training Pain Specialists JAMES P. RATHMELL AND JAN VAN ZUNDERT

The Evolution of Pain Medicine as a Subspecialty Pain Medicine as a Primary Medical Specialty Training in Pain Medicine in Europe Training and Credentialing in Interventional Pain Medicine Conclusion ACKNOWLEDGMENTS C H A P T E R 11 2 Emergencies in the Pain Clinic CHRISTOPHER GILLIGAN, MILAN P. STOJANOVIC, RAMSEY SABA, AND JAMES P. RATHMELL

The American Society of Anesthesiologists Closed Claims Project Bleeding Complications 192

Infectious Complications Local Anesthetic Systemic Toxicity UNINTENDED DESTINATIONS FOLLOWING LOCAL ANESTHETIC ADMINISTRATION VASOVAGAL REACTIONS Complications Associated with Intrathecal Drug Delivery OPIOID WITHDRAWAL Anaphylactic and Anaphylactoid Reactions CATASTROPHIC NEURAL INJURIES AND THE ADMINISTRATION OF PARTICULATE STEROIDS Conclusion C H A P T E R 11 3 Pain Management in the Emergency Department JAMES R. MINER

The Prevalence of Pain in the Emergency Department The Assessment of Pain in the Emergency Department Oligoanalgesia in the Emergency Department Pain and Opioid Abuse in the Emergency Department Definitions Pain and “Drug-Seeking Behavior” in the Emergency Department Pain and Substance Abuse in the Emergency Department: A Balanced Perspective The Example of Sickle Cell Disease Pain Treatment and Procedural Sedation in the Emergency Department Specific Treatment Modalities NONOPIOIDS OPIOIDS PATIENT-CONTROLLED ANALGESIA ALTERNATIVE DELIVERY ROUTES PROCEDURAL SEDATION AND ANALGESIA Evolving Emergency Department Pain Management Practice Conclusion C H A P T E R 11 4 Pain Management in the Intensive Care Unit CURTIS N. SESSLER, KIMBERLY VARNEY GILL, AND KRISTIN MILLER

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Pain, Analgesia, and Critical Illness Evaluation and Monitoring of Pain in the Intensive Care Unit Managing Pain and Analgesia in the Intensive Care Unit PHARMACOLOGIC TREATMENT OF PAIN IN THE INTENSIVE CARE UNIT: PARENTERAL OPIOIDS Fentanyl Hydromorphone Morphine Remifentanil PHARMACOLOGIC TREATMENT OF PAIN IN THE INTENSIVE CARE UNIT: ADJUVANT THERAPY Ketamine Methadone Other Analgesics and Adjuvant Agents NONPHARMACOLOGIC MANAGEMENT OF PAIN IN THE INTENSIVE CARE UNIT REGIONAL ANESTHETIC APPROACHES TO PAIN IN THE INTENSIVE CARE UNIT Integrated Analgesia Management in the Intensive Care Unit ANALGOSEDATION IN THE INTENSIVE CARE UNIT ANALGESIA AS A COMPONENT OF COMPREHENSIVE BUNDLED INTENSIVE CARE UNIT CARE Pain and Analgesia at the End of Life in the Intensive Care Unit Conclusions ACKNOWLEDGMENTS C H A P T E R 11 5 The Future of Pain Medicine: An Epilogue SCOTT M. FISHMAN AND JAMES P. RATHMELL

Index

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PART ONE

Basic Considerations CHAPTER 1 Intellectual Milestones in Our Understanding and Treatment of Pain G.F. GEBHART In order to treat something we first must learn to recognize it. —Sir William Osler1

Through the ages, pain and suffering have been the primary reasons why patients sought medical care. But what pain is (an independent sense, an emotion, an experience, . . . ) has been considered and argued by philosophers and investigators alike to the present day. The International Association for the Study of Pain (www.iasp-pain.org) defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.” Pain is always a subjective, personal, and unpleasant experience. This chapter reviews ideas and concepts about pain, including how our mental constructs shape our understanding, and then treatment of this complex experience we call pain. This chapter closes with a discussion of how the medical subspecialty is evolving within the broader context of medical specialization and thoughts for future development.2

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Pain Understood as Part of a Larger Philosophy or Worldview Since the beginning of time, humans have been born through a painful process, and the experience of suffering remains universal. The meaning of pain reflects the contemporary spirit of the age and, therefore, has changed over recorded history as worldviews changed. Among the earliest systems of pain management, dating back to the Stone Age, was Chinese acupuncture, theoretically based on the philosophy of imbalances of yin and yang affecting qi and blood flow. Thousands of years ago, Egyptians considered the experience of pain to be a god or disincarnate spirit afflicting the heart, which was conceptualized as the center of emotion. Galen, and later Aristotle, described pain as an emotional experience, or “a passion of the soul.”3 An important concept dating from antiquity that persisted until the 19th century was the theory of importance of the four humors. This worldview was espoused by Greek philosophers in approximately 400 BC and later applied to medicine by Hippocrates, who described humors as related to one of the four constitutions, shown in Table 1.1. Seasonal changes evoked pain, and certain disorders, such as migraine, were associated with specific humors (e.g., excessive cold humors thought to result in a mucus discharge requiring application of “hot effusions” to the head). TABLE 1.1 Relationships in Antiquity between the Four Humors, Elements, Constitutions, and Seasons4 Black bile Earth Dry, cold Autumn

Blood Air Hot, wet Spring

Phlegm Water Cold, wet Winter

Yellow bile Fire Hot, dry Summer

Consistent with this ideology was the custom of treating pain by applying “opposites” such as hot applications to the head to counterbalance and evacuate “cold” humors of headaches.5 Based on the humor theory and treatment by “opposites” was a technique called cupping. Warm suction cups were applied to the skin that on cooling resulted in raised reddened welts thought to “draw out” any unbalanced 196

humors.6 Later, during the Middle Ages, coincident with the spread of Christianity, pain, not surprisingly, was explained in a spiritual, religious context. Medieval life has been described as short, cheap, and brutish, especially for the lower classes, with pain accepted as the universal lot of mankind. Little is known of how pain was actually treated during this period, but a suffering Christ, martyred saints, and the concept of physical pain in purgatory originated around the 12th century AD.6,7 Commonly revered was the iconography of tortured saints with ecstatic faces depicting pain as a spiritual discipline bringing the saints closer to God, relieved primarily by prayer and meditation. A clear example of pain as ennobling was St. Ignatius Loyola’s habit of wearing ropes and chains cutting into the skin and encouraging other humiliations of the flesh to enhance his spiritual development.3 An interesting example of pain as a function of the sociologic concepts of the day is the rise and fall of the diagnosis of hysteria, common in the 17th century and virtually nonexistent today. Thomas Sydenham (Fig. 1.1), in 1681, wrote, “Of all chronic diseases hysteria—unless I err—is the commonest.”8 The cardinal symptom of this condition was unexplained pain. In mid-19th century Europe and America, hysteria was virtually everywhere, found in every community. Invalids, mostly females, filled homes, spas, and convalescent facilities at the turn of the 19th century. This mysterious syndrome, afflicting only middle and upper class females, was treated by complete social isolation, confinement to bed, and a total prohibition on any form of intellectual activity, even sewing or reading (CP Gilman as quoted in Rey9). As the social situation and educational opportunities for women improved, this disorder almost totally disappeared, a public health success on the order of magnitude of the eradication of yellow fever. In the 21st century, fibromyalgia, although a commonly diagnosed condition in Western countries, interestingly enough, is either underreported or not significantly present in Asian and developing country populations.

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FIGURE 1.1 Thomas Sydenham. (Courtesy of the National Library of Medicine.)

Another very clear link between mental state and the perception and control of pain is apparent in the work of the German physician Franz Anton Mesmer. In 1766, he published his doctoral dissertation entitled “On the Influence of the Planets on the Human Body,” describing animal (or life spirit) magnetism as a force to cure many ills.10 He used iron magnets to treat various diseases, amplifying the magnetic fields with room-sized Leyden jars. His demonstrations of his technique, combining hypnotism with spectacle, included the wearing of brightly colored robes in dimly lit ritualistic séances, with soft music playing from a glass harmonium. He invoked magnetic power with poles either held or waved over the patient and his techniques were an early rival to ether anesthesia as a way to relieve pain during surgical procedures.11 Mesmerism was such a common form of pain therapy during his day that Robert Liston reportedly exclaimed after the successful administration of ether anesthesia in an early above-knee operation, “This Yankee Dodge beats mesmerism hollow.”12 Mesmerism was based on the larger generally accepted theory 198

of vitalism which posited that every part of a living thing was endowed with sensibility. The energy or force which animated a living organism was capable of being stimulated or consumed. In disease, pain was necessary to produce a “crisis” which rid the patient of original pain by stimulating the diminishing energy.6 A further development of the link between mind and body and the understanding of pain was the landmark development of Freudian theory in understanding subconscious influences on pain perception and behavior. The link between the unconscious mind and physical sensation in hysterical conversion disorders was posited as an explanation for psychogenic pain and continues to be influential today. This conceptual paradigm was expanded in the 1970s by the psychiatrist George L. Engel who demonstrated the link between chronic pain and psychiatric illness.13 Later, psychiatrists, psychologists, and social scientists, including Thomas Szasz,14 Allan Walters,15 and Harold Merskey,16 explored social situations, psychological character traits, and the effects of past life experiences in understanding chronic pain in patients. Depression, stress, and personality, in addition to physiologic mechanisms, have proven to be critical grounds for investigation and therapy. From these early studies, investigating the mind–body interface of pain grew the cognitivebehavioral school of pain therapy in the 1980s that is widely employed today, emphasizing the development of coping mechanisms to deal with chronic pain as a basic component of interdisciplinary pain programs. The concept of pain, not only as a physiologic response to stimuli but as a more complicated construct, incorporating social, behavioral, and psychological responses as well, is an intellectual milestone that has inspired a wealth of investigations and patient treatment options. New areas of investigation now include pain in relationship to social setting, gender, national, ethnic, and racial background as well as differences in coping ability and psychiatric comorbidities. Considerations of vocational and legal environment as well as family and interpersonal dynamics are also relevant to the understanding and care of individual patients. This global philosophy of pain as only part of an entire life experience can best be summed up in the words of Alexander Pope in his Essay on Man in 1733: 199

Say what the use, were finer optics giv‘n, T’ inspect a mite, not comprehend the heav‘n? Or touch, if tremblingly alive all o‘er, To smart and agonize at ev‘ry pore? Or, quick effluvia darting thro‘ the brain, Die of a rose in aromatic pain?17

Mechanistic Views of Pain In counterpoint to the holistic philosophical consideration of pain was mechanism, the philosophical mind set suggesting that the human body functions as a simple machine with pain being the result of its malfunction.18 This viewpoint is clearly seen in Descartes’ Passions of the Soul in 1649 where he compares a human being to a watch: [T]he difference between the body of a living man and that of a dead man is just like the difference between, on the one hand, a watch or other automaton (that is, a self-moving machine) when it is wound up and contains in itself the corporeal principle of the movements for which it is designed . . . ; and, on the other hand, the same watch or machine when it is broken and the principle of its movement ceases to be active.19 How did the mechanistic view of the body develop and even supersede traditional theologic and philosophical explanations for pain? Early anatomical studies were conducted beginning with Galen of Pergamum (130–201 AD) and Avicenna (Fig. 1.2), the Persian Muslim polymath (980–1037 AD), forming an intellectual basis for pain as an actual physical sensation rather than as a mental, spiritual dilemma. Later, in the 14th through 17th centuries, the Renaissance cultural movement questioned the basis of all knowledge, including ideas about the human body and the experience of pain. Empiricism and the development of scientific inquiry with direct observation into the mysteries of life became the basis for advances in both medical understanding and treatment, including the now commonly accepted neurologic basis of pain. Extended wars on the continent between France and Spain resulted in bullet and musket ball injuries that tore the skin, forcing surgical removal and amputation. 200

Wounds were bound and foreign bodies extracted, originally posited to prevent leakage of the “vital force” or to inhibit the entrance of animal spirits into the injured body. Gradually, direct observation of the circulation of the blood by William Harvey20 in 1628 and the direct anatomical studies of Descartes (Fig. 1.3)19 in 1662, elucidating sensory physiology became the theoretical basis for further exploration in the 18th and 19th centuries.

FIGURE 1.2 Avicenna. (Courtesy of the National Library of Medicine.)

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FIGURE 1.3 René Descartes. (Courtesy of the National Library of Medicine.)

19TH CENTURY—PAIN AS A SPECIFIC SENSE In 1811, Charles Bell (Fig. 1.4), an anatomist in Edinburgh, Scotland, published a monograph in which he described new and important evidence for the specificity of function of peripheral nerves. Bell proposed differences in function between the dorsal and ventral roots of the spinal cord, writing that “. . . the nerves of sense and nerves of motion . . . are distinct . . .”21 Bell’s discovery that ventral root stimulation controlled muscle contraction was followed by François Magendie’s (Fig. 1.5) report in 1822 that sectioning posterior (dorsal) nerve roots resulted in paralysis and insensibility of the corresponding limbs, confirming that the dorsal roots are afferent.22 The result of these discoveries regarding the functions of the spinal roots is now known as the Bell-Magendie law (confirmed in 1831 by Johannes Müller).

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FIGURE 1.4 Sir Charles Bell. (Courtesy of the National Library of Medicine.)

FIGURE 1.5 François Magendie. (Courtesy of the National Library of Medicine.)

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Johannes Müller (Fig. 1.6)23 was a precocious and influential German investigator who advanced in 1826 at the age of 25 years the Law of Specific Nerve Energies, which laid out the basic concept of modern sensory physiology (cf. Handwerker and Brune24). Müller’s “law” emphasized that the quality of sensation depends not on the stimulus but on the sense organ and sensory pathway stimulated. Müller’s law was not advanced in the context of pain as he was studying at that time vision. He considered the sensation of sound to be the “specific energy” of the acoustic nerve, and the sensation of light the particular “energy” of the visual nerve. In 1858, Moritz Schiff25 established, based on studies of the effects of spinal cord lesions, that separate spinal pathways conveyed tactile, temperature, and pain sensations. On the basis of his studies, Schiff proposed that pain was an independent sensation (a specific sense). Schiff’s findings were subsequently confirmed and extended by CharlesÉdouard Brown-Séquard and Sir William Richard Gowers, establishing the importance of spinal pathways for conducting information about painful stimuli applied in the periphery.

FIGURE 1.6 Johannes Müller. (Courtesy of the National Library of Medicine.)

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Alfred Goldscheider (Fig. 1.7) and Max von Frey (Fig. 1.8) were contemporaries, adversaries, and also important to the history of pain research.24 Their divergent interpretations and conclusions from their research fostered and supported debate about the “pain” sensitivity of pressure points in skin well into the 20th century. In 1881, Goldscheider, a German army physician, demonstrated in his dissertation (and independently of the Swedish physiologist Magnus Blix), spatially discontinuous warm and cold spots in the skin, thus confirming Müller’s Law of Specific Nerve Energies. Goldscheider reported that stimulation of a cold point always produced the sensation of cold whether activated by a cold metal rod or by electrical stimulation. Goldscheider also reported that stimulation of temperature points did not produce a sensation of pain and advanced therefore the existence of tactile and pain points in skin.24,26

FIGURE 1.7 Alfred Goldscheider. (Courtesy of the National Library of Medicine.)

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FIGURE 1.8 Max von Frey. (Courtesy of the National Library of Medicine.)

Max von Frey was a systematic and methodical investigator interested in the skin as a sense organ and who today is largely (and incorrectly) credited with first documenting “pain points” in skin (Fig. 1.9). Using pig bristles and horsehairs of various diameters and stiffness, thus requiring different forces to bend when applied perpendicular to the skin, von Frey carefully mapped pressure points (Druckpunkte) and pain points (Schmerzpunkte) on the back of the hand.24,27 Max von Frey believed that the critical event producing pain from the skin was excitation of painconducting nerve fibers in peripheral nerves and that different types of sensory spots (warm, cool, pressure, pain) were associated with distinct structural elements in the skin. In the aggregate, at the turn of the 20th century, it was generally agreed that skin contained a number of nonuniformly distributed, distinct receptive end organs, each representing a particular kind of sensibility—pressure, warmth, cold and pain—and each responding only to its appropriate stimulus (termed subsequently by 206

Sherrington as its adequate stimulus).

FIGURE 1.9 Pain points in the skin.

AFFERENT SIGNALING In the latter part of the 19th century and into the 20th century, however, arguments against pain as a specific skin sense were advanced. In particular, the advent of electrophysiology as a research approach contributed specific information about afferent fiber types (i.e., A and C fibers) and their responses to applied stimuli. The pioneering contributions of anatomists and physiologists in this period of time, several of whom were subsequently recognized with Nobel Prizes for revealing the structure and physiology of the nervous system (e.g., Adrian, Erlanger, Gasser, Golgi, Ramón y Cajal, Sherrington), were relevant to but did not specifically focus on pain (cf. Perl28). The contributions of the eminent British physiologist, Charles Scott Sherrington (Fig. 1.10), however, are remarkable for several reasons. Aware that pain commonly arises from injured tissue, Sherrington avoided labeling stimuli based on their physical character, instead naming stimuli that threatened or caused tissue damage “nocuous” (noxious). Importantly, he understood the distinction between pain and the neural encoding of noxious events, which he termed nociception, and named the sense organ in skin that responded to noxious stimuli a nociceptor.29,*

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FIGURE 1.10 Charles Scott Sherrington. (Courtesy of the National Library of Medicine.)

Alfred Goldscheider, who initially supported the existence of pain sensory points, subsequently denied their existence and instead adopted the idea that pain arose from intense stimulation of pressure points. This “intensity theory” did not survive evidence that intense, even maximal stimulation of sense organs that respond to innocuous stimuli does not generate pain-associated reactions. In light of these and other evidence, John Paul Nafe, an American psychologist, formalized what became referred to as pattern theory. He posited that all sensation arises from the spatial and temporal patterns of responses of afferent neurons rather than the result of activation of specific receptors or pathways.30 In 1955, Sinclair31 and Weddell32 expanded the concept, emphasizing that all afferent endings, except those innervating hair follicles, are similar, and it is only the pattern that is important in sensory discrimination. Based largely on clinical observations, other investigators focused on the role of the spinal dorsal horn, suggesting that pain resulted from the “summation” of afferent inputs rather than the “intensity” of the input or its spatiotemporal pattern. The American physician, William K. Livingston, suggested that pathologic input from the body activates reverberating circuits in spinal interneurons that subsequently can be triggered by normally innocuous afferent input (cf. Melzack and Wall33). The concept of central summation, coupled with growing appreciation of spinal modulation of afferent input, led to the introduction in 1965 by 208

Ronald Melzack and Patrick Wall of a new theory of pain, the gate control theory.

GATE CONTROL THEORY As reviewed earlier, specificity, intensity, and pattern theories about pain were not entirely exclusive in the writings of Goldscheider and von Frey. Even Müller, whose “laws” underlie the foundation of “specificity theory,” understood that peripheral nerves did not feel pain and that it was their excitation of the central nervous system that determined modality and quality of sensation. Although Goldscheider embraced concepts of “intensity theory,” he also was aware of the notion of central inhibition, a component of pattern and summation theories of pain. The complexity of pain, today recognized as comprising sensory, emotional, and drive state components, however, could not be adequately explained as either a specific (“labeled line”) pathway, spatiotemporal pattern of afferent input, or central summation of inputs. These often conflicting paradigms were reviewed and critically evaluated, and the prevailing basic and clinical evidence formulated as a new theory of pain by the Canadian psychologist Melzack and the British physiologist Wall (Figs. 1.11 and 1.12) while working together at the Massachusetts Institute of Technology.33 The gate control theory most directly challenged specificity theory and generated both high praise and strong opposition to the underlying assumptions on with the theory was based (cf. Perl28). The gate control theory was (and remains) heuristically important, providing (1) a conceptual framework that challenged long-held views about pain mechanisms as well as (2) an experimentally testable model that continues to the present day to stimulate research into mechanisms of pain. The basic proposition of the theory is that information arriving in the spinal cord via C fibers is modulated through presynaptic inhibition exerted by Aβ fibers. The gate was placed by Melzack and Wall in the substantia gelatinosa and, importantly, its output modulated by supraspinal influences.34 Many of the underlying assumptions of the gate control theory were immediately challenged and then or since shown to be incorrect (cf. Perl28). For example, specific end organs that encode intensities of noxious stimuli (nociceptors) have been widely documented in virtually all tissues, the 209

roles of A and C fibers in pain are far more complex than envisioned in 1965, and the spinal dorsal horn substantia gelatinosa is not the location of a presynaptic “gate” for pain. Like Müller’s Law of Specific Nerve Energies, introduction of the gate control theory was a seminal event in the pain field that has shaped thinking and research to the present day. It is now more than 50 years since its introduction, having been cited nearly 5,500 times through 2017, and remains a facile means of “explaining” pain to the layman.

FIGURE 1.11 Ronald Melzack, PhD. (Courtesy of MIT Museum.)

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FIGURE 1.12 Patrick D. Wall, MD. (Courtesy of MIT Museum.)

Treatments for Pain The rationale for choosing one form of pain treatment over another more often reflects the philosophical worldview of the physician more than the patient’s presenting condition. Physicians who are focused on the patient’s adaptation to life might focus on issues of lifestyle, stress, and emotional upheaval and assist the patient to work toward more adaptive behavioral responses to their pain. Physicians who see pain in mechanistic terms most likely will look for the anatomic foci of pain and be confounded if the source of the suffering is unclear. In the first, older, historical paradigm, pain is a part of an entire life and the enhancing adaptation to life is also needed to manage painful conditions. In the second, a specific anatomical or physiologic lesion is sought with therapy specifically directed toward the underlying pathology.

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Cognitive Treatment for Pain The fundamental significance of the word pain in English is derived from the Latin word poena, meaning punishment, and its relief was through prayer.35 This reflects the supposed cause of the pain being harm inflicted by the powers above for putative wrongdoing. Prior to the 18th century, nonspecific therapies were employed for many types of pain, including acupuncture, the application of humoral opposites, bloodletting, purging, topical and oral herbal compounds, and distraction by creating a competing, more severe pain. To better define why patients experienced pain and, presumably, how to treat it, physicians attempted classification by causes. However, treatment options were still limited. During the Roman emperor Trajan’s time, a noted physician recorded 13 causes of pain. Avicenna, a noted Muslim healer in the early 11th century, described 15 separate causes. And Hahnemann, the founder of homeopathy, listed 75.36 However, nonspecific treatments such as mesmerism and hypnotism, and even general anesthetics, were based on a whole body cure rather than a mechanistic view of pain. Later, cognitive-behavioral therapy and palliative care focused on the care of the whole person as a human being in need of adaptive coping skills. Early work in the 1950s by Engel, based on Freud’s theoretical ideals, explored the link between suffering from pain and psychiatric diagnosis. Merskey and Spear, in the mid-1960s, confirmed that chronic pain patients also often had coexisting psychiatric morbidity.13 Henry Beecher, in the battlefields of World War II, observed that seriously wounded soldiers reported less pain than civilian patients in the Massachusetts General Hospital recovery room. Their injury may have been subjectively interpreted as a cause of removal from harm and their return home as a war survivor. Later, however, these same patients would complain loudly about a minor insult such as venous puncture, causing Beecher to conclude that the experience of pain was derived from a complex interaction between physical sensation, cognition, and an emotional reaction.37 Dame Cicely Saunders (Fig. 1.13), founder of the hospice movement in Great Britain and throughout the world, championed the idea of “total pain” emphasizing the holistic concept of patient-centered pain 212

management.38 Similarly, John Bonica (Fig. 1.14) instituted in 1947 a multidisciplinary approach to treat pain in World War II veterans with complex multifocal persistent pain. Cultivating the multidisciplinary approach to pain management, Bonica later organized a multidisciplinary conference held in Issaquah, Washington, in May 1973 that was attended by more than 300 pain clinicians and researchers of various disciplines. Discussions among attendees at this meeting provided the impetus for the foundation on which the International Association for the Study of Pain was established.39

FIGURE 1.13 Dame Cicely Saunders. (Courtesy of St Christopher’s Hospice.)

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FIGURE 1.14 Dr. John J. Bonica. (Courtesy of the Wood Library Museum of Anesthesiology.)

Pharmacologic Treatment of Pain The development of pharmacology as a science parallels the treatment of painful conditions by medications. Alcohol and morphine were proven antidotes to pain. In the mid-17th century, Thomas Sydenham concocted laudanum, the ubiquitous mix combining sherry, wine, opium, saffron, cinnamon, and clove and used to treat everything from dysentery to hysteria and gout. In South America, coca leaves were in common use, both as an orally chewed remedy for altitude sickness and physical pain and as a topical treatment. The alkaloid cocaine was isolated by Albert Niemann40 in his 1860s autoexperimentation and was originally touted as a cure for alcohol and morphine addiction. Carl Koller,41 in 1884, demonstrated the local anesthetic effects of cocaine in reducing corneal movement during eye surgery. As chemical analysis became more sophisticated, opium, a long known 214

treatment for pain, was studied by the pharmacist Serturner who isolated “the soporific principle” from the compound in 1806. Despite being wellknown to herbalists, the first scientific report of the power of willow derivatives was reported in a paper to the Royal Society of Medicine in London in 1763 by the Reverend Edmund Stone from Chipping Norton, Oxfordshire.42 The overuse of quinine in the early 19th century led to a shortage of the Peruvian cinchona trees, and therefore, there were increased efforts to isolate, characterize, and then commercially synthesize pain-relieving compounds. In 1829, the French pharmacist Henri Leroux extracted the active compound in willow leaves and bark that had been used in application to painful joints. Later, in 1873, Charles von Gerhardt prepared salicylic acid by combining sodium salicylate with acetyl chloride to produce acetylsalicylic acid, or aspirin. The benefit of adding the acetyl group was decreased irritation to mucous membranes of the mouth, esophagus, and stomach and avoidance of the bitter alkaloid taste.43 Clinically, the benefits of this newly synthesized product were reported in treating acute rheumatism by Thomas J. MacLagan in 1876, over a century after Reverend Stone’s first report.44 Two other landmarks that marked clear leaps forward in the pharmacologic treatment of pain were the development of the hypodermic needle by Rynd45 and the syringe by Wood (RD Mann as cited in Birk46), permitting injection of analgesics and anesthetics. Morton’s 1846 landmark demonstration of ether anesthesia, following Crawford Long’s earlier application of ether anesthesia in 1843, marked a new era of surgical anesthesia.

Anatomically Specific Treatments for Pain In contrast, the majority of the treatment options for pain in the last two centuries have been inspired by specificity theory and its refined derivatives. Surgical cures have been employed for pain relief by interruption of specific sensory tracts in neurotomies, division of the anterolateral column of the spinal cord, dorsal roots excision, thalamectomy, mesencephalic lesioning, psychosurgical lobotomies, and 215

other procedures that specifically alter the anatomy of the central nervous system. This paradigm shift developed over time, paralleling the scientific advances in understanding the mechanisms of pain transmission. As knowledge of the importance of the central nervous system in the transmission of pain increased, cures based on this new science proliferated. An early treatment, neurocompression, was developed by James Moore, a Glasgow-born London surgeon. In 1784, he demonstrated that compression of specific nerves provided anesthesia in patients via clamps in both upper and lower limbs, inducing reversible neurapraxia to anesthetize a limb.47 Before his time, Ambroise Paré (1510–1590), the great French surgeon of the Renaissance and “physician to the kings of France,” linked observable injury to the development of chronic pain. He not only sustained a prolific medical practice but wrote 10 books of surgery (Dix Livres de la Chirurgie). These books were based on his extensive experience in treating gun and sword wounds and the pain that attended them.48 He was the first to describe pain after the amputation of limbs, 300 years before the conceptualization of “phantom limb pain” was ever expressed. Remarkably, contrary to the current philosophy of his time, he resisted the prevailing wisdom that pain was either inevitable and to be passively tolerated or in some way the will of God to be accepted by man as a path to holiness by actively treating pain in his suffering patients. Some of his innovations included the development of prosthetic devices for missing limbs, a steam bath chair for urethral stone pain, and combinations, called “allodynes,” of opium and other drugs to treat the symptoms of pain.11 Other compassionate physicians observing their tormented pain patients, primarily as a result of catastrophic war injuries, continued to develop options to treat pain out of necessity. The US Civil War resulted in untold numbers of soldiers who suffered damaged nerves after amputation and injury, with resultant chronic “nerve” disease. The persistent burning pain long after the initial injury was first called reflex paralysis by Silas Weir Mitchell (Fig. 1.15) in 1864. Dr. Mitchell, born in Philadelphia as the seventh physician within three generations, was told at an early age by his physician father, “You are wanting in nearly all the qualities that go to 216

make a success in medicine.” Despite this, he graduated from Jefferson Medical College in 1848 and, at the outbreak of hostilities in 1861, was placed in charge of Turner’s Lane Hospital in Philadelphia, a 400-bed hospital for nervous diseases. With colleagues, William Williams Keen Jr. and George Read Morehouse, he personally transported railroad cars full of wounded soldiers from the Gettysburg battlefield and undertook their care. Based on daily patient observation and review of literally thousands of pages of careful clinical notes, he described causalgia for the first time in 1864 in the work Gunshot Wounds and Other Injuries of Nerves.49–51

FIGURE 1.15 Silas Weir Mitchell, MD. (Courtesy of the National Library of Medicine.)

An early example of injecting specific nerves to produce analgesia was the work of Schloesser in 1903. He injected alcohol to produce longlasting interruption of neural conduction in patients with convulsive facial tics, obtaining paralysis that lasted from days to a month. He recommended lytic injections for the patients with clinical supraorbital neuralgia and tic douloureux.52 217

Later, war injuries in World War I soldiers inspired a practical French surgeon, René Leriche, to study pain and its treatment in various forms of pathology. He identified patients with sympathetic nerve injuries—his “pariahs of pain”—that he treated by injecting the local anesthetic procaine and surgical sympathectomy, which later became standard therapy in the 1930s. He was a clinician’s clinician, describing pain from direct personal observation: “Physical pain is not a simple affair of an impulse, traveling at a fixed rate along a nerve. It is the resultant of a conflict between a stimulus and the whole individual.”53 Following the theory of pain arising from specific nerve injuries, surgeons in the 1920s performed nerve ablation procedures for chronic unexplained pain syndromes. Following this model, anesthesiologists experimented with various local anesthetic nerve blocks to provide analgesia for surgery. The first nerve block clinic for pain relief was started by Emery Rovenstine at Bellevue Hospital in New York City, New York, in 1936.54 Eleven years later, the first nerve block clinic in the United Kingdom was established at University College Hospital in London.55 Current therapies based on central nervous system plasticity modulating input from peripheral nerves include spinal cord stimulation, sympathetic nerve blocks, radiofrequency modulation (both pulsed and lesioning), and cognitive therapies and are now commonly available in modern pain practice.

The Specialty of Pain Medicine How did pain as a medical specialty and physicians specializing in the diagnosis and treatment of pain conceive of chronic pain as an original and new field of clinical practice? A sociologist, Isabelle Baszanger, observed two clinics in Paris that had very different constructs of pain and pain treatment, which she described as the two poles of pain. The first—“curing through techniques”—considers pain as a function of physiologic abnormalities, with diagnosis aimed at confirming the pathology and using medication and technical therapies to treat it. As more technologic possibilities develop, the treatments become more focused and 218

sophisticated. The second pole is “healing through adaptation,” which considers pain a poorly adaptive behavior, and therefore, behavioral and cognitive therapies are necessary to alleviate pain and suffering.56 Whereas Emery A. Rovenstine established in 1936 one of the first outpatient clinics devoted to the treatment of chronic pain,57 the founding father of interdisciplinary pain care was John J. Bonica, who established in 1947 in Seattle the first multidisciplinary clinic to treat the pain in wounded World War II veterans. He published the first edition of his comprehensive textbook, Management of Pain, in 1953.7 His clinical practice increased and gained support after aligning with the University of Washington in Seattle in 1960. As his reputation grew, he encouraged other centers to recognize and treat pain as an integral part of health care.58 He then proceeded to work internationally to foster the study and treatment of pain. He was the driving force behind the Issaquah, Washington, multidisciplinary pain conference in 1973 which, as noted earlier, led to the subsequent establishment of the International Association for the Study of Pain. This association currently represents over 60 scientific disciplines in active research and clinical practice in a wide variety of pain related fields. The journal, Pain, supported by this organization, foreshadowed the numerous peer reviewed scholarly publications now focused on all levels of pain research.59 The American Board of Anesthesiology (ABA) approved a certificate of added qualification in pain management in 1991, followed by subspecialty certification from the American Board of Psychiatry and Neurology (ABPN) and the American Board of Physical Medicine and Rehabilitation (ABPMR) in 2000.60 It is an exciting time for the study and treatment of pain. New research approaches, including elegant molecular biologic and genetic approaches and imaging techniques that allow real-time investigation of information processing in the nervous system with improved resolution and power, are informing our improved understanding of pain mechanisms and central nervous system contributions to the experience of pain. The chapters that follow in this, the 5th edition of Bonica’s Management of Pain, highlight the impressive developments in the understanding and managing of pain.

ACKNOWLEDGMENTS 219

This is an updated version of this chapter written originally by Dr. Doris Cope for the 4th edition of Bonica’s Management of Pain. *It should be appreciated that theories about pain as a specific sense were advanced largely based on stimulation of the skin and assumed/implied to apply generally to other tissues. It is now known that stimuli adequate to produce pain differ in different tissues and that nociceptors are heterogeneous.

References 1. Weiner RS. Innovations in Pain Management: A Practical Guide for Clinicians. Orlando, FL: Paul M. Deutsch Press, Inc; 1990. 2. Benedelow GA, Williams SJ. Transcending the dualisms toward a study of pain. Soc Health Ill 1995;17(2):139–165. 3. Birk RK. The history of pain management. Hist Anesth Soc Proc 2006;36:37–46. 4. Keirsey D. Please Understand Me II: Temperament, Character, Intelligence. Del Mar, CA: Prometheus Nemesis Book Co, Inc; 1998. 5. King H. The early anodynes: pain in the ancient world. In: Mann RD, ed. The History of the Management of Pain. Lancaster, United Kingdom: Parthenon Publishing Group Ltd; 1988:51– 60. 6. Rey R. Christianity and pain in the Middle Ages. In: The History of Pain. Cambridge, MA: Harvard University Press; 1955:48–49. 7. Bonica JJ. The Management of Pain. Philadelphia: Lea & Febiger; 1953:23. 8. Epistolary dissertation (1681). In: RG Latham, trans-ed. The Works of Thomas Sydenham, M.D. London: Sydenham Society; 1848–1850:85. 9. Rey R. The history of pain. Gilman CP, ed. The Living of Charlotte Perkins Gilman: An Autobiography. New York: D. Appleton-Century Co; 1935:96. 10. Colquhoun JC, ed. Report of the Experiments on Animal Magnetism Made by a Committee of the Medical Section of the French Royal Academy of Sciences, Read at the Meetings of the 21st and 28th of June 1831. Edinburgh: Whittaker; 1833. 11. Zimmermann M. The history of pain concepts and treatment before IASP. In: Merskey H, Loeser JD, Dubner R, eds. The Paths of Pain, 1975–2005. Seattle, WA: IASP Press; 2005:1– 21. 12. Squire WW. On the introduction of ether inhalation as an anesthetic in London. Lancet 1888;22:1220–1221. 13. Engel GL. Psychogenic pain. Med Clin North Am 1958;42(6):1481–1496. 14. Szasz TS. Pain and Pleasure: A Study of Bodily Feelings. London: Taistock; 1957. 15. Walters A. Psychogenic regional pain alias hysterical pain. Brain 1961;84:1–18. 16. Merskey H. Psychiatric patients with persistent pain. J Psychosom Res 1965;9:299–309. 17. Pope A. An Essay on Man. Epistle I. An Essay on Man in Four Epistles. Whitefish, MT: Kessinger Publishing, LLC; 2004. 18. Sawday J. Engines of the Imagination: Renaissance Culture and the Rise of the Machine. London: Routledge; 2007. 19. Descartes R. L’Homme. Paris, France: C. Angot; 1664. 20. Harvey W. Exercitatio Anatomica de Motu Cordis et Sanguinis in Animalibus. Padua, Italy: University of Padua; 1628. 21. Bell C. Idea of a New Anatomy of the Brain: Submitted for the Observations of His Friends. London: Strahan & Preston; 1811.

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22. Magendie F. Experiments on the spinal nerves. J Exp Phys Pathol 1822;2:276–279. 23. Müller J. Handbuch der Physiologie des Menschen. Koblenz, Germany: J Hölscher; 1837. 24. Handwerker HO, Brune K. Deutschsprachige Klassiker der Schmerzforschung [Classical German contributions to pain research]. Haßfurt, Germany: Tagblatt–Druckerei KG; 1987. 25. Schiff M. Lehrbuch der Physiologie des Menschen. I. Muskel und Nervenphysiologie. Lahr, Germany: Verlag von M. Schauenburg & Co; 1859. 26. Goldscheider A. Die spezifische Energie der Gefühlsnerven der Haut. Prakt Derm 1884;3:283. 27. Rey R. Von Frey and the theory of specificity. In: Rey R, ed. The History of Pain. Cambridge, MA: Harvard University Press; 1955:215–218. 28. Perl E. Pain mechanisms: a commentary on concepts and issues. Prog Neurobiol 2011;94:20– 38. 29. Sherrington CS. The Integrative Action of the Nervous System. Cambridge, United Kingdom: Cambridge University Press; 1906. 30. Nafe JP. A quantitative theory of feeling. J Gen Psychol 1929;2:199–211. 31. Sinclair DC. Cutaneous sensation and the doctrine of specific energy. Brain 1955;78:584–614. 32. Weddell G. Somesthesis and the chemical senses. Ann Rev Psychol 1955;6:119–136. 33. Melzack R, Wall PD. Pain mechanisms: a new theory. Science 1965;150:971–979. 34. Mendell L. Constructing and deconstructing the gate theory of pain. Pain 2014; 155:210–216. 35. Parris W. The history of pain medicine. In: Raj PP, ed. Practical Management of Pain. 3rd ed. St. Louis, MO: Mosby; 2000:4. 36. Fülöp-Miller R. Triumph Over Pain. Paul E, Paul C, trans-eds. New York: Literary Guild of America; 1938. 37. Beecher HK. Pain in men wounded in battle. Ann Surg 1946;123:96–105. 38. Clark D. Total pain: disciplinary power and the power in the work of Cicely Saunders, 1958– 1967. Soc Sci Med 1999;49:727–736. 39. Liebeskind JC, Meldrum ML. John J. Bonica. World champion of pain. In: Jensen TS, Turner JA, Wiesenfeld-Hallin Z, eds. Proceedings of the Eighth World Congress on Pain: Progress in Pain Research and Management. Vol 8. Seattle, WA: IASP Press; 1997:19–32. 40. Niemann A. Über einer organische Base in der Coca. Annalen Chemie 1860;114:213. 41. Koller C. On the use of cocaine for producing anaesthesia on the eye. Lancet 1884;2:990. 42. Leake CD. An Historical Account of Pharmacology to the Twentieth Century. Springfield, IL: Charles C. Thomas; 1975. 43. Fairley P. The Conquest of Pain. London: Michael Joseph; 1978. 44. Andermann AAJ. Physicians, fads, and pharmaceuticals: a history of aspirin. McGill J Med 1996;2(2):1–19. 45. Rynd F. Neuralgia—introduction of fluid to the nerve. Dublin Med Press 1845;13:167. 46. Birk RK. The history of pain management. Hist Anesth Soc Proc 2006;36:37–46. 47. Moore J. A Method of Preventing or Diminishing Pain in Several Operations of Surgery. London: T. Cadell; 1784. 48. Malgaigne JF. Oeuvres completes d’Ambroise Paré. Paris, France: Baillière; 1840–1841. 49. Mitchell SW, Morehouse GR, Keen WW. Gunshot Wounds and Other Injuries of Nerves. Philadelphia: J.B. Lippincott & Co; 1864. 50. Mitchell SW. Civilization and pain. JAMA 1892;18:108. 51. Mitchell SW. Injuries to Nerves and Their Consequences. Philadelphia: J.B. Lippincott & Co; 1872. 52. Schloesser. Heilung periphärer Reizzustände sensibler und motorischer Nerven. Klin Monatsbl Augenheilkd 1903;41:244. 53. Leriche R. La Chirurgie de la Douleur. Paris, France: Masson; 1937. 54. Rovenstine EA, Wertheim HM. Therapeutic nerve block. JAMA 1941;117:1599–1603.

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55. Swerdlow M. The early development of pain relief clinics in the UK. Anaesthesia 1992;47:977–980. 56. Baszanger I. Deciphering chronic pain. Soc Health Ill 1992;14(2):181–215. 57. Cousins M. History of neural blockade and pain management. In: Cousins MJ, Bridenbaugh PO, eds. Neural Blockade in Clinical Anesthesia and Management of Pain. 3rd ed. Philadelphia: Lippincott-Raven; 1998:21–22. 58. Bonica JJ. Basic principles in managing chronic pain. Arch Surg 1977;112(6):783. 59. Bond MR, Dubner R, Jones LE, et al. The history of the IASP: progress in pain since 1975. In: Merskey H, Loeser JD, Dubner R, eds. The Paths of Pain, 1975–2005. Seattle, WA: IASP Press; 2005:23–32. 60. Fishman S, Gallager RM, Carr DB, et al. The case for pain medicine. Medicine 2004;5(3):281–286.

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CHAPTER 2 Pain Terms and Taxonomies of Pain DENNIS C. TURK and AKIKO OKIFUJI The inherent subjectivity of pain presents a fundamental impediment to increased understanding of its mechanisms and control. The language used by any two individuals attempting to describe a similar injury and their pain experience often varies markedly. Similarly, clinicians and clinical investigators commonly use multiple terms that at times have idiosyncratic meanings. Needless to say, appropriate communication requires a common language and a classification system that is used in a consistent fashion. Thus, we have two primary goals in this chapter: (1) to provide definitions for many commonly used terms in the pain literature, in an effort to bring about consistency and thereby improve communication, and (2) to describe and discuss different classification systems or taxonomies that have been used or proposed, in an attempt to improve communication and bring consistency to research and treatment of patients reporting pain.

Definition of Commonly Used Pain Terms Discussions of pain involve many terms. The meaning and connotation of these different terms may vary widely. For example, some authors use the term pain to relate to a stimulus, others to a thing, and still others to a response. Such inconsistent usage creates difficulties in communication. As Merskey1 noted, it would be most convenient and helpful if there were some consensus on technical meanings and usage. Based on this belief, the editors of the two editions of the International Association for the Study of Pain (IASP) Classification of Chronic Pain included a set of definitions of commonly used pain terms2,3 (note that a third adaptation of chronic pain for the International Classification of Diseases 11th revision [ICD-11] 223

does not include any listing of definitions).4 In the second edition of this text, Bonica reproduced a list of the terms and in some cases provided annotations. We adopt a similar strategy. We follow the convention of IASP; we begin with the definition of pain and then proceed alphabetically. Terms preceded by an asterisk come directly from the IASP descriptions of pain terms.3 *Pain: An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage (emphasis added). It should be noted that some have argued that inclusion of the phrase “described in terms of such damage” is problematic because it assumes an ability to verbally communicate that may not be present in very young children and individuals with limitations in their verbal abilities.5 They also suggest that the use of the term unpleasant may trivialize the experience which may greatly exceed the unpleasant nature of the experience. Moreover, the original IASP definition fails to incorporate advanced knowledge as to the important role of cognitive, social, and contextual factors. Williams and Craig5 suggest a revised definition, “Pain is a distressing experience associated with actual or potential tissue damage with sensory, emotional, cognitive, and social components,”(p2420) to take these factors into consideration. Pain, acute/chronic†: Definitions of acute, chronic, recurrent, and cancer pain are not specifically included in the IASP list of pain terms. We believe, however, that it is important to clarify these because they are commonly used in the literature. Traditionally, the distinction between acute and chronic pain has relied on a single continuum of time, with some interval since the onset of pain used to designate the onset of acute pain or the transition point when acute pain becomes chronic. The two most commonly used chronologic markers used to denote chronic pain have been 3 months and 6 months, most recently by IASP as lasting longer than 3 months4 since the initiation of pain; however, these distinctions are arbitrary. Moreover, these criteria do not take into consideration intensity of pain, the severity and nature of its impact on functioning or treatment-seeking behaviors, or whether pain must be present every day or how frequent it occurs in this interval. These features are important because they may influence estimates of the 224

prevalence of pain and effects on physical activity and treatment requirements and may explain some of the inconsistencies reported. Another criterion for chronic pain is “pain that extends beyond the expected period of healing.” This is relatively independent of time because it considers pain as chronic even when it has persisted for a relatively brief duration. Unfortunately, how long the expected process of healing will (or should) take is ambiguous. One suggestion has been to differentiate “chronic pain” from “impactful chronic pain.”6,7 Some hold that pain that persists for long periods of time in the presence of ongoing pathology should be considered an extended “acute” pain state. In this case, treatment targets the underlying pathology. This is not to encourage a Cartesian dualistic perspective of pain that treats mind and body as independent entities with distinctive functions. Historically, such distinction led to a faulty assumption of acute pain as “real,” whereas chronic pain without known pathology was suspect and viewed as being merely “functional.” As the IASP definition clearly states, any pain, acute or chronic, regardless of the presence of identifiable tissue damage, is an unpleasant experience, inherently influenced by various cognitive, affective, and environmental factors. We hold that the weighing of psychological and environmental factors is often greater in chronic pain than acute pain, and the importance of these factors escalates over time, contributing to the experience of pain and associated disability.8 We propose conceptualizing acute and chronic pain on two dimensions: time and physical pathology. Figure 2.1 schematically depicts this twodimensional conceptualization of acute and chronic pain. From this perspective, any case falling above the diagonal line (short duration or high physical pathology) is acute pain, whereas cases falling below the diagonal line (low physical pathology or long duration) suggest chronic pain. The perspective presented in Figure 2.1 leads to the following definitions of acute and chronic pain.

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FIGURE 2.1 Pictorial representation of acute and chronic pain.

Acute pain: Acute pain is the physiologic response to and experience of noxious stimuli that can become pathologic, is normally sudden in onset, is time-limited, and motivates behaviors to avoid potential or actual tissue injury.9 Pain is elicited by the injury of body tissues and activation of nociceptive transducers at the site of local tissue damage. The local injury alters the response characteristics of the nociceptors and perhaps their central connections and the autonomic nervous system in the region. In general, the state of acute pain lasts for a relatively limited time and remits when the underlying pathology resolves (however, see the following definition of central sensitization). This type of pain often serves as the impetus to seek health care, and it occurs following trauma, some disease processes, and invasive interventions. Chronic pain: May be elicited by an injury or disease but is likely to be perpetuated by factors that are both pathogenetically and physically remote from the originating cause. Chronic pain extends for a long period of time and/or represents low levels of underlying pathology that does not explain the presence and extent of pain (e.g., mechanical back pain, fibromyalgia [FM] syndrome). There have been suggestions that chronic pain in the apparent absence of pathology may be attributable to modification of nerves and sensitization of the peripheral or central nervous system. There have also been suggestions that genetic factors and prior life experiences might predispose some to develop chronic pain problems following an initiating insult that resolves in others who do not have the predisposition. 226

Just as the brain is modified by experience, especially in early life, the brain may alter the way noxious information is processed to reduce or augment its impact on subjective awareness. Chronic pain frequently is the impetus for people to seek health care. Currently available treatments are rarely capable of totally eliminating the noxious sensations and thereby “curing” chronic pain. Because the pain persists, it is likely that environmental, emotional, and cognitive factors will interact with the already sensitized nervous system, contributing to the persistence of pain and associated illness behaviors (see following description of pain behaviors). It is also possible that, just as the brain is modified by experience, especially in early life, the brain may alter the way noxious information is processed to reduce or augment its impact on subjective awareness. The acute–chronic pain continuum is based solely on duration. There is an implication that those with chronic pain will have progressed from an acute pain state to a chronic pain state and that once the threshold to chronic pain is crossed, it becomes fixed and relatively immutable with the implication that worsening, and deterioration over time is inevitable. The reality in contrast is there in the presence of considerable variability within individuals who have transitioned into the classification based on arbitrary time points. A range of psychosocial, behavioral, and contextual factors as well as physical ones will influence the adaptation and responses to pain.8 Cancer pain: Pain associated with cancer includes pain associated with disease progression as well as treatments (e.g., chemotherapy, radiotherapy, surgery) that may damage the nervous system. Although some contend that pain associated with neoplastic disease is unique, in the majority of instances, we view it as fitting within our description of acute and chronic pain, as depicted in Figure 2.1. Moreover, pain associated with cancer can have multiple causes, namely, disease progression, treatment, and co-occurring diseases (e.g., arthritis). Regardless of whether the pain associated with cancer stems from disease progression, treatment, or a cooccurring disease, it may be either acute or chronic. Thus, we do not advocate a separate classification of cancer pain as distinct from acute and chronic pain. Some concerns have also been raised regarding the common usage of 227

chronic malignant and chronic benign pain4; often, pain unrelated to cancer is implicitly view as “benign” to distinguish it from cancer-related pain. Certainly, people who have pain associated with neoplastic disease experience a unique and disease-specific situation, but from a mechanistic perspective, there may be little to substantiate continued use of this dichotomy. Moreover, patients who have chronic noncancer pain who are told that their pain is “benign” may feel denigrated because, from their perspective, the inference is that their pain is not a serious concern. Recurrent pain: Episodic or intermittent occurrences of pain, with each episode lasting for a relatively short period of time but recurring across an extended period of time (e.g., migraine headaches, tic douloureux, sickle cell crisis, dysmenorrhea). Our distinction between acute and chronic pain using the integration of the dimensions of time and pathology does not specifically include recurrent pain. In the case of recurrent pain, patients may experience episodes of pain interspersed with periods of being completely pain-free. Although recurrent pain may seem acute because each pain episode (e.g., headache) is of relatively short duration, the pathophysiology of many recurrent pain disorders (e.g., migraine) is not well understood. Syndromes characterized by recurrent acute pain share features in common with both acute and chronic pain. The fact that these syndromes extend over time, however, suggests that psychosocial and behavioral factors, not only physical pathology, may be major contributors to emotional and behavioral responses. IASP4 now includes recurrent pain lasting longer than 3 months within its definition of chronic pain. However, it is not clear whether multiple episodes lasting several days within 3 months would meet the chronic pain criterion or whether the pain must last at least 3 months. That is, would multiple migraines in a 3-month period be chronic even if there were pain-free periods within the 3 month period? Transient pain: Pain elicited by activation of nociceptors in the absence of any significant local tissue damage. This type of pain is ubiquitous in everyday life and is rarely a reason to seek health care. It is seen in the clinical setting and only in incidental or procedural pain, such as during a venipuncture or injection. This type of pain ceases as soon as the stimulus is removed. There are situations where sources of transient 228

pain may be treated by providers with preventive analgesic or topical medication. Acceptance: A choice to acknowledge pain experiences (intensity, thoughts, emotions) and to cease efforts to control them while simultaneously engaging in valued behaviors, particularly when control efforts have let to restrictions. Addiction: A behavioral pattern of substance, including prescribed medication, abuse characterized by overwhelming involvement with the use of a drug (i.e., compulsive use), the securing of its supply, and a high tendency to relapse. The compulsive use of the drug results in physical, psychological, and/or social harm to the user, and use continues despite this harm. (See also physical dependence.) *Allodynia: Pain due to a stimulus that does not normally provoke pain. Analgesia: Absence of the spontaneous report of pain or pain behaviors in response to stimulation that would normally be expected to be painful. The term implies a defined stimulus and a defined response. Analgesic responses can be tested in nonhuman as well as humans. *Anesthesia dolorosa: Spontaneous pain in an area or region that is anesthetic. Breakthrough pain: A transient increase in pain to greater than moderate intensity superimposed on baseline pain that is fairly well managed. Breakthrough pain includes (1) incident pain that may arise from some activity or physical function (e.g., coughing, ambulating), (2) pain that routinely increases as the duration of analgesic medication is reaching its limit (end-of-dose failure), and (3) spontaneous exacerbation of a stable level of pain for nonspecific reasons. Catastrophizing: A cognitive and emotional process that involves magnification of pain-related stimuli, feelings of helplessness, and a negative orientation to pain and life circumstances. Catastrophizing has been shown to be an important predictor of response to both acute and chronic pain.10 *Central pain: Pain initiated or caused by a primary lesion or dysfunction in the central nervous system. Central sensitization: Increase in the excitability and responsiveness of neurons in the spinal cord. Central sensitization may explain the 229

persistence of pain beyond the removal or resolution of the initiating stimulus. Chronic widespread pain: A complex condition with a range of disabling physical and psychological symptoms that does not fit neatly into any medical specialty and has a myriad of possible causes and triggers, both physical and psychological. A set of disparate disorders is often lumped into chronic widespread pain including nonradicular back pain, FM, irritable bowel syndrome, pelvic pain, temporomandibular disorders (TMD), and tension-type headache. This diagnosis is based on the presence and distribution of symptoms in the absence of another defined pathologic process: The features in the history or clinical examination are generally more important than laboratory investigations. *Complex regional pain syndrome type 1 (formerly reflex sympathetic dystrophy): A syndrome that usually develops after an initiating noxious event, is not limited to the distribution of a single peripheral nerve, and is apparently disproportionate to the inciting event. It is associated at some point with evidence of edema, changes in skin blood flow, abnormal pseudomotor activity in the region of the pain, or allodynia or hyperalgesia. Specific criteria for the diagnosis of complex regional pain syndrome (CRPS) have been proposed.11 *Complex regional pain syndrome type 2 (formerly causalgia): A syndrome of sustained burning pain, allodynia, and hyperpathia following a traumatic nerve lesion, often combined with vasomotor dysfunction and later trophic changes. Conditioned pain modulation: Altered endogenous pain modulation is considered as a mechanism involved with diverse chronic pain syndromes (e.g., TMD, FM, chronic tension-type headache, and irritable bowel syndrome). It is assessed by measuring phasic pain response after a conditioned tonic pain stimulus. Conditioned pain modulation is at least partially mediated by the diffuse noxious inhibitory control (DNIC) system characterized by inhibition of wide dynamic range neurons in the dorsal horn of the spinal cord by heterosegmental noxious afferent input.12 Cost–benefit analysis: Evaluation of the costs and effects of an intervention in a common, usually monetary unit. The standardization of unit has an advantage because it permits comparisons across dissimilar 230

intervention programs. On the other hand, the conversion of treatment effects to monetary units may not always be feasible. Estimation of the cost to outcome ratio is possible, as are comparisons between interventions using the rates of improvement (e.g., return to work) with common denominators. Cost-effectiveness analysis: Estimation of treatment outcome entails criteria other than monetary terms, such as lives saved or return to work. An intervention is cost-effective when it satisfies one of the following conditions: 1. It is more effective than an alternative modality at the same cost; 2. It is less costly and at least as effective as an alternative modality; 3. It is more effective and more costly than an alternative treatment, but the benefit exceeds the added cost; or 4. It is less effective and less costly, but the added benefit of the alternative is not worth the additional cost. Disability: Any restriction or loss of capacity to perform an activity in the manner or within the range considered normal for a human being, such as climbing stairs, lifting groceries, or talking on a telephone. It is a taskbased concept that involves both the person and the environment. Disability is essentially a social and not a medical term or classification. Level of disability should be determined only after a patient has reached maximum medical improvement following appropriate treatment and rehabilitation. *Dysesthesia: An unpleasant abnormal sensation, whether spontaneous or evoked. *Hyperalgesia: An increased response to a stimulus that is normally painful. *Hyperesthesia: Increased sensitivity to stimulation, excluding special senses. *Hyperpathia: A painful syndrome characterized by an abnormally painful reaction to a stimulus, especially a repetitive stimulus, as well as an increased threshold. *Hypoalgesia: Diminished pain in response to a normally painful stimulus. Hypochondriasis: An excessive preoccupation with bodily sensations 231

and fears that they represent serious disease despite reassurance to the contrary. Impairment: Any loss of use of, or abnormality of, psychological, physiologic, or anatomical structure or function that is quantifiable. It is not equivalent to disability. Impairment is to disability as disease is to illness. Malingering: A conscious and willful feigning or exaggeration of a disease or effect of an injury in order to obtain a specific external gain. It is usually motivated by external incentives such as financial compensation, avoiding work, or obtaining drugs. Maximum medical improvement: The state beyond which additional medical treatment is unlikely to produce an improvement in function. Minimum clinically important difference (MCID): The magnitude of reduction in pain or related problems that a patient would consider minimally important. In considering the determination of clinically important differences, two different aspects of the interpretation of clinical trial results must be distinguished. One is establishing the difference in the magnitude of response between the treatment and control groups that will be considered large enough to establish the scientific or therapeutic importance of the results. The other is establishing what change in the outcome measure represents a meaningful difference for patients. This later consideration has come to be referred to as the minimum clinically important difference. The development of criteria for determining what are important changes in an individuals’ scores on the outcome measures used in chronic pain trials would provide clinicians and researchers with essential methods for evaluating treatment responses of individuals in clinical trials and clinical practice. Such individual-level criteria make it possible to conduct responder analyses that classify each trial participant as “improved,” “stable,” or “worse” on the basis of validated criteria of important change. (See description of patient global impression of change.) Multidisciplinary (interdisciplinary) pain center: An organization of health care professionals and basic and applied scientists that includes research, teaching, and patient care related to acute and chronic pain. It includes a wide array of health care professionals including physicians, 232

psychologists, nurses, physical therapists, occupational therapists, and other specialty health care providers. Multiple therapeutic modalities are available. These centers provide evaluation and treatment and are usually affiliated with major health science institutions. *Neuralgia: Pain in the distribution of a nerve or nerves. *Neuritis: Inflammation of a nerve or nerves. *Neurogenic pain: Pain initiated or caused by a primary lesion, disease, dysfunction, or transitory perturbation in the somatosensory nervous system.13 It may be spontaneous or evoked, as an increased response to a painful stimulus (hyperalgesia), a painful response to a painful stimulus (hyperalgesia), or a painful response to a normally nonpainful stimulus (allodynia). Neuropathic pain: Pain arising as a direct consequence of a lesion or disease affecting the somatosensory system.14 *Neuropathy: A disturbance of function or pathologic change in a nerve: in one nerve, mononeuropathy; in several nerves, mononeuropathy multiplex; if diffuse and bilateral, polyneuropathy. Nocebo: Negative treatment effects induced by a substance or procedure containing no toxic or detrimental substance. Nociception: Activation of sensory transduction in nerves by thermal, mechanical, or chemical energy impinging on specialized nerve endings. The nerve(s) involved conveys information about tissue damage to the central nervous system. *Nociceptor: A receptor preferentially sensitive to tissue trauma or to a stimulus that would damage tissue if prolonged. *Noxious stimulus: A stimulus that is capable of activating receptors for tissue damage. Pain behavior: Verbal or nonverbal actions understood by observers to indicate that a person may be experiencing pain and suffering. These actions may include audible emissions (e.g., signs, moans); facial expressions (e.g., grimacing); abnormal postures or gait (e.g., limping, bracing, moving in a guarded fashion); motor behavior (e.g., rubbing a body part); use of prosthetic devices; avoidance of activities; and verbal indications of pain, distress, and suffering. An important feature is the observable nature of these behaviors that can be subjected to the 233

conditioning process. Once conditioned, the same behavior is exhibited as a learned response rather than expression of actual pain experience. Thus, pain behavior can either reflect internal experience of pain or is exhibited as a learned behavior in response to certain cues. Pain clinic: Facilities focusing on diagnosis and management of patients with pain problems. It may specialize in specific diagnoses or pain related to a specific area of the body. Pain relief: Report of reduced pain after a treatment. It does not require reduced response to a noxious stimulus and is not a synonym for analgesia. The term applies only to humans. Pain threshold: The least level of stimulus intensity perceived as painful. In psychophysics, this is defined as a level of stimulus intensity that a person recognizes as painful 50% of time. *Pain tolerance level: The greatest level of noxious stimulation that an individual is willing to tolerate. Pain sensitivity range: The difference between the pain threshold and the pain tolerance level. *Paresthesia: An abnormal sensation whether spontaneous or evoked. Patient global impression of change (PGIC): Patients’ overall evaluation of improvement or worsening of symptoms over the course of treatment. This measure is often a single-item rating by patients on a scale, often 5-point or 7-point scale that ranges from “very much improved” to “very much worse” with “no change” as the midpoint. *Peripheral neurogenic pain: Pain initiated or caused by a primary lesion or dysfunction or transitory perturbation in the peripheral nervous system. Physical dependence: A pharmacologic property of a drug (e.g., opioid) characterized by the occurrence of an abstinence syndrome following abrupt discontinuation of the substance or administration of an antagonist. It does not imply an aberrant psychological state or behavior or addiction. Placebo: An inert substance or procedure without a specified therapeutic ingredient that is provided as a treatment. It is frequently used to control patients’ expectations for the efficacy in testing a treatment. Placebo effects: Refers to the positive benefit(s) from a placebo (i.e., 234

inert) preparation or procedure when such benefit is generally achieved only with an active treatment intervention. Active treatments also are likely to have a placebo component that augments the active component associated with the treatment. Plasticity, neural: Nociceptive input leading to structural and functional changes that may cause altered perceptual processing and contribute to pain chronicity. Pseudoaddiction: Refers to drug-seeking behavior or misuse by patients who have severe pain and are undermedicated or who have not received other effective pain treatment interventions. Such patients may appear preoccupied with obtaining opioids, but the preoccupation reflects a need for pain relief and not drug addiction. Pseudoaddictive behavior differs from true addictive behavior because when higher doses of opioid are provided, the patient does not use these in a manner that persistently causes sedation or euphoria, the level of function is increased rather than decreased, and the medications are used as prescribed without loss of control over use. Psychogenic pain: Report of pain attributable primarily to psychological factors usually in the absence of any objective physical pathology that could account for pain. This term is commonly used in a pejorative sense. It often suggests a Cartesian dualism and is not usually a helpful method of describing a patient. Quality of life/health-related quality of life: Quality of life (QOL) refers to an individual’s perception of his or her position in life in the context of the culture and value systems in which he or she lives and in relation to his or her goals, expectations, standards, and concerns. Concerns with this all-encompassing description have led a number of investigators to use a more circumscribed construct, health-related quality of life (HRQOL). Although HRQOL has been used interchangeably with terms such as health status and functional status, HRQOL is a narrower term than QOL because it does not include aspects of work, environmental conditions, housing, and other variables that are often considered relevant to QOL but that do not involve health directly.7 Rehabilitation: Restoration of an individual to maximal physical and mental functioning in light of his or her impairment. 235

Residual functional capacity: The capacity to perform specific social and work-related physical and mental activities following rehabilitation related to impairment or when a condition has reached a point of maximum medical improvement. Resilience: Capacity and dynamic process of adaptively overcoming stress and adversity while maintaining normal psychological and physical functioning.15 Summed pain intensity difference (SPID): A strategy for combining relief magnitude and duration in a single score. It is calculated by the sum of the time-weighted pain intensity difference (difference between current pain and pain at baseline) multiplied by the interval between ratings. Symptom magnification: Conscious or unconscious exaggeration of symptom severity in an attempt to convince an observer that one is truly experiencing some level of pain. It differs from malingering as it is an effort to be believed, not necessarily to achieve a positive outcome (i.e., secondary gain) such as financial compensation. Suffering: Reaction to the physical or emotional components of pain with a feeling of uncontrollability, helplessness, hopelessness, intolerability, and interminability. Suffering implies a threat to the intactness of an individual’s self-concept, self-identify, and integrity. Tolerance, drug: A physiologic state in which a person requires an increased dosage of a psychoactive substance to sustain a desired effect. Total pain relief (TOPAR): Is used in clinical trials to assess pain relief over time. It is a cumulative measure that is composed of the sum of time-weighted pain relief score multiplied by the interval between ratings. TOPAR is frequently used in clinical trials of medications designed to ameliorate pain. Wind-up: Slow temporal summation of pain mediated by C fibers due to repetitive noxious stimulation at a rate faster than one stimulus every 3 seconds. It may cause the person to experience a gradual increase in the perceived magnitude of pain.

Taxonomies The lack of a classification of chronic pain syndromes that is used on a

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consistent basis inhibits the advancement of knowledge and treatment of chronic pain and makes it hard for investigators as well as practitioners to compare observations and results of research. Bonica16 referred to this language ambiguity as “a modern tower of Babel.” In order to identify target groups, conduct research, prescribe treatment, evaluate treatment efficacy, and for policy and decision making, it is essential that some consensually validated criteria are used to distinguish groups of individuals who share a common set of relevant attributes. The primary purpose of such a classification is to describe the relationships of constituent members based on their equivalence along a set of basic dimensions that represent the structure of a particular domain. Infinite classification systems are possible, depending on the rationale about common factors and the variables believed to discriminate among individuals. The majority of the current taxonomies of pain are “expertbased” classifications.

EXPERT-BASED CLASSIFICATIONS OF PAIN Classifications of disease are usually based on a preconceived combination of characteristics (e.g., symptoms, signs, results of diagnostic tests), with no single characteristics being both necessary and sufficient for every member of the category, yet the group as a whole possesses a certain unity.17 Most classification systems used in pain medicine (e.g., ICD,18 classification and diagnostic criteria for headache disorders, cranial neuralgias, and facial pain,19 IASP Classification of Chronic Pain,2,4 CRPS,11 whiplash-associated disorders,20 and the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks [ACTTION]-American Pain Society Pain Taxonomy [AAPT]21 and ACTTION-American Pain Society-American Academy of Pain Medicine [AAPM] Pain Taxonomy [AAAPT]22) and dentistry (i.e., Research Diagnostic Criteria [RDC] for Temporomandibular Disorders23,24) are based on the consensus arrived at by a group of “experts.” In this sense, they reflect the inclusion or elimination of certain diagnostic features depending on agreement. “Expert-based” classification tends to result in preconceived categories and “force” individuals into the most appropriate one even if not all 237

characteristics defining the category are present. Expert-based classification systems do not explicitly state the mathematical rules that should exist among the variables used in order to assign a case to a specific category. In an ideal classification, the categories comprising the taxonomy should be mutually exclusive and completely exhaustive for the data to be incorporated. Every element in a classification should fit into one, and only one, place, and no other element should fit into that place. An example of such an ideal, natural taxonomy is the periodic table in chemistry. We can also develop artificial classifications such as a telephone directory. The criterion for the classification, namely, the sequence of letters in the alphabet, bears no relation to the people, addresses, and telephone numbers being classified; but it is quite satisfactory for the intended purpose.3 No classification in medicine or dentistry has achieved such aims. For example, the RDC (now Diagnostic Criteria as the RDC has been adopted for clinical diagnostic purposes based on the research evidence) for Temporomandibular Disorders23,24 includes eight different diagnoses. In one study, over 50% of the sample received three or more RDC diagnoses.25 Thus, the classifications or diagnoses are not mutually exclusive. The most commonly used classification system of pain is the ICD published by the World Health Organization. In the most recent draft edition, the ICD-10,22 conditions are classified along a number of different dimensions including causal agent; body system involved; pattern and type of symptoms; and whether or not they are related to the artificial intervention of an operation, time of occurrence or grouped as signs, symptoms, and abnormal clinical and laboratory findings. Within major groups, there are subdivisions by symptom pattern, the presence of hereditary or degenerative disease, extrapyramidal and movement disorders, location, and etiology. Overlapping occurs repeatedly in such approaches to categorization; thus, they are not ideal even if they serve a useful function. Recently, IASP has created its adaptation of the original IASP classification2 (described in the following discussion) in an effort to have chronic pain included within the ICD-114 (described in the following discussion). 238

Further complications arise when clinicians require a separate coding system. In the United States, for example, in addition to the ICD codes, a clinician must select current procedural terminology (CPT) coding schemes for billing purposes. This has created a tendency where the fulfillment of the CPT coding may dictate the ICD selections to justify the procedures. Such practices often needlessly create diagnoses and additional treatments for billing purposes only. It is clear that the classification of pain cannot approach the ideal found in chemistry or telephone books, but this is not unique to pain; it characterizes medical classification systems in general. Classification in medicine, dentistry, and psychology is pragmatic. It does not provide absolute truth but rather provides categories with which we can work to identify individuals with similar phenomena, prognoses, or causes.3 Currently, the majority of pain classifications in pain medicine rely on various parameters of pain experience such as anatomy, system, severity, duration, and etiology.

CLASSIFICATION BASED ON ANATOMY Several pain syndromes are classified by body location. For example, low back pain, pelvic pain, and headache, each refers to the specific location of symptoms. However, the extent to which the anatomy-based classification of pain is clinically meaningful is limited, at least partially, due to the lack of anatomically defined specificity in the neurophysiology of pain.

CLASSIFICATION BASED ON DURATION As previously discussed, one common way to classify pain is to consider it along a continuum of duration. Thus, pain associated with tissue damage, inflammation, or a disease process that is of relatively brief duration (i.e., hours, days, or even weeks), regardless of how intense, is frequently referred to as acute pain (e.g., postsurgical pain). Many pain problems can be classified as chronic. For example, pain that persists for extended periods of time (i.e., months or years), accompanies a disease process (e.g., rheumatoid arthritis), or is associated with an injury that has not resolved within an expected period of time (e.g., low back pain, phantom limb pain) are all referred to as chronic. As noted, however, a single dimension of 239

duration is inadequate because pathologic factors may be relatively independent of duration.

CLASSIFICATION BASED ON THE ETIOLOGY OF PAIN Another way to classify pain is based on etiology, by lumping a range of potentially disparate diagnoses within general categories, for example, somatogenic-psychogenic, nociceptive-neuropathic, and nociceptiveneuropathic-widespread. Historically, crude efforts were made to subdivide or classify patients reporting pain dichotomously based on the putative basis for their report. A classical approach to classify patients based the presence of physical pathology that to which the pain report was attributed—somatogenic versus pain with unknown physical pathology and with the implication on nonphysical causal mechanism such as psychopathology (psychogenic) or motivation to achieve some desired outcome such as disability attention or disability compensation (i.e., malingering), seeking of mood altering drugs, or avoidance of undesirable activities (e.g., work, homemaking responsibilities) (reinforcement). The processes by which clinicians determine whether pain is somatogenic or psychogenic are distinctive. The classification of somatogenic pain is established by identification of positive organic findings, whereas psychogenic pain is indicated only in the absence of positive signs. More recently, a dichotomous classification has been advocated by the AAPM26 with the somewhat analogous concepts of “eudynia” (good pain) and “maldynia” (bad pain). Eudynia (nociceptive pain) conceptualizes pain that serves as an alarm signal and that is mediated by specialized primary sensory neurons that respond to sufficiently intense thermal, mechanical, or chemical stimuli and transmit signals via well-defined pathways in the central nervous system. Eudynia is triggered and maintained by the presence of noxious stimuli. When local inflammation ensues, certain features of the nociceptive response are modified and magnified to aid healing and repair; hence, good pain. Little consideration is given to the involvement of psychosocial, behavioral, or contextual factors in the development, amplification, or maintenance of symptom or response to 240

treatment. In contrast, maldynia is classified when pain is reported to be present when neural tissues in the peripheral or central nervous system are directly damaged or become dysfunctional. Here, in contrast to eudynia, different sequence of events unfolds. Under these conditions, pain can manifest and eventually persist in the absence of typical nociceptive generators. Such pain can be considered maladaptive because it occurs in the absence of ongoing noxious stimuli and does not promote healing and repair. In the instance of maldynia, there is an acknowledgment that psychosocial, behavioral, and contextual factors may become enmeshed. Accordingly, the AAPM and other proponents in the pain medicine community have advanced the notion that under such conditions, pain becomes the disease process itself. Other variations on the dichotomous somatogenic versus psychogenic classification exist. For example, Portenoy27 proposed that three primary categories of pain be used: nociceptive, neuropathic, and psychogenic. In this system, somatogenic pain is subdivided into two subtypes that contrast with psychogenic pain. More recently, a suggested broad classification into subgroups has proposed three categories, namely, nociceptive, neuropathic, and widespread (sometimes referred to as central sensitivity syndromes, with the causal mechanisms of central nervous system plasticity and the resulting central sensitization, combining such apparently disparate diagnoses as back pain, FM, irritable bowel syndrome, pelvic pain, TMD, tension-type headaches).28,29

CLASSIFICATION BASED ON BODY SYSTEM Classification may focus on the body system involved. For example, Friction30 proposed the use of five categories, namely, myofascial, rheumatic, causalgic, neurologic, or vascular. In this case, patients are assigned to one of five rather than two or three categories as proposed by Portenoy.27 However, the decision regarding classification is still based on a single dimension system for the experience of pain.

CLASSIFICATION BASED ON SEVERITY Frequently, pain is classified unidimensionally on the basis of severity (0to 10-point scale with 0 = no pain and 10 = the worst pain that can be 241

imagined). That is, regardless of the scale’s level of measurement— nominal, ordinal, or interval—the construct involves a single dimension. When pain is classified on the basis of severity, it is dependent on the subjective report of patients. Assuming pain threshold is normally distributed, there will be significant variability among patients’ rating severity of what might be objectively the same nociceptive stimulation. Ratings of pain severity will be anchored to how questions are asked, and responses may vary widely depending on the question. For example, if the ratings associated with “pain right now,” “over the past week?” “usual severity,” “severity at its worst,” “severity at its lowest,” “during specific movements,” or “at rest?” pain severity may be very useful in evaluating individual patients but less so for comparison among groups.

CLASSIFICATION BASED ON FUNCTIONING The International Classification of Functioning, Disability and Health (ICF)31 aims to provide a standard framework for the comparison and understanding of health outcomes. For any given health outcome, including chronic pain, the ICF identified three main outcomes: impairment, activity limitations, and participation restrictions. To date, the efforts of the ICF have been largely focused on identification of common domains across measures that can be used to evaluate patients and treatment outcomes. It has less emphasis on classification of patients, but it can be used for this purpose. The empirical approach described in the following discussion can be readily applied to the ICF conceptual model.

CLASSIFICATION BASED ON INTENSITY AND FUNCTIONING The Emory Pain Estimate Model (EPEM) was the first attempt to integrate the biophysiologic and psychosocial domains in classifying pain patients.32,33 Brena and colleagues32,33 arbitrarily labeled the dimensions “pathology” and “behavior.” The pathology dimension included the quantification of physical examination procedures (e.g., ratings of joint mobility, muscle strength) as well as assigning numerical indices to reflect the extent of abnormalities determined from diagnostic procedures such as radiographic studies. The behavioral dimension comprises a composite of 242

activity levels, pain verbalizations, drug use, and measures of psychopathology based on the elevations of scales of the Minnesota Multiphasic Personality Inventory (MMPI). Using median divisions on the pathology and behavior dimensions, the EPEM defines four classes of chronic pain patients. Class I patients are characterized by higher scores on the behavior dimension and lower scores on the pathology dimension. The EPEM describes these patients as displaying low activity levels, high verbalizations of pain, prominent social and psychological malfunctions, and frequent misuse of medications. Class II patients are those who display lower scores on both the pathology and behavioral dimensions. These patients are described as displaying dramatized pain complaints with ill-defined anatomical patterns. However, they do not display significant behavioral dysfunction. Class III represents patients with higher scores on both dimensions, characterized as showing clear evidence of physical pathology and high intensity illness behavior. Finally, Class IV patients are those who have higher scores on the pathology dimension and a lower score on the behavior dimension, thus demonstrating competent coping in the presence of a physical pathologic condition. Although Brena and his colleagues32,33 appropriately emphasized the importance of integrating physical and psychological data in order to develop a classification system for chronic pain patients, some of the basic theoretical and quantitative characteristics of the EPEM are problematic. We see this framework as a conceptual model rather than an adequately operationalized empirical one. For example, from a theoretical standpoint, the inclusion of activity levels, pain verbalizations, and measures of psychopathology under a single dimension labeled “behavioral” is troubling because research shows that there is little association between pain behaviors and psychopathology. Thus, the behavioral dimension is most likely not unidimensional and, therefore, cannot measure behavior directly. Von Korff and colleagues34 developed a similar model, the Chronic Pain Grade, which integrates the conceptual approach of the EPEM but adds greater emphasis of empirical determination of criteria for subgroup classification and empirical validation. The Chronic Pain Grade classifies 243

patients into one of five categories: (1) pain-free, (2) low pain intensity and low disability, (3) high pain intensity and low disability, (4) low pain intensity and high disability, and (5) high pain severity and high disability. More recently, Deyo et al.6 have based the core data set that they recommend for research on back pain on the Chronic Pain Grade.

CLASSIFICATION BASED ON PROGNOSIS Chronic pain is typically viewed by definition as being fixed with progressive dysfunction over time; however, there is considerable variability in its course. An alternative view, based on prognosis such that chronic pain is defined by the risk, that clinically significant pain and associated dysfunction will be present at some future time point, where the likelihood of future pain and dysfunction is predicted by multiple biopsychosocial prognostic factors.35,36 As a consequence, subgroups of pain patient should be based on prognosis. This approach is based on several propositions. The first proposition is that chronic pain is better characterized by a failure of the resolution of pain and associated dysfunction rather than progression based on time. The argument is that severe pain, pain-related activity limitations, and emotional distress often used to characterize chronic pain are observable soon after pain onset. What typically differentiates “chronic pain” from “acute pain” is the lack of meaningful improvement. The second proposition is that the seeds of chronic pain can be observed early in the pain course. The third proposition is that varied prognostic indicators can be combined into a prognostic risk score and this risk score will predict clinically significant pain and dysfunction in the future better than pain duration in isolation. In this view, risk of future clinically significant pain is probabilistic and not immutable. In contrast, chronic pain status can change over time and that, rather than being hopeless, it can improve. We must exercise caution, however, because duration does have some prognostic value.37 Some classification system has included duration alongside prognostic indicators.38 Other classifications are consistent with the prognostic approach.34,39

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The conventional classifications of pain disorders based on anatomy, duration, and systems have drawn criticism for their deficiency in sensibility for guiding treatment or research.40 Woolf et al.40 support developing a mechanism-based classification of pain, proposing a potential list of pain mechanisms (Table 2.1). They argue that the list needs to include affective, behavioral, and cognitive factors relevant to pain, although they do not specify what these factors may be or how they would be incorporated within the proposed classification system. TABLE 2.1 Categories of Pain and Possible Mechanisms Transient Pain Nociceptor specialization Tissue Injury Pain Primary Afferent Sensitization Recruitment of silent nociceptors Alteration in phenotype Hyperinnervation CNS Mediated Central sensitization recruitment, summation, amplification Nervous System Injury Pain Primary Afferent Acquisition of spontaneous and stimulus-evoked activity by nociceptor axons and somata at loci other than peripheral terminals Alteration in phenotype CNS Mediated Central sensitization Deafferentation of second-order neurons Disinhibition Structural reorganization CNS, central nervous system. Adapted with permission from Woolf CJ, Bennett GJ, Doherty M, et al. Towards a mechanismbased classification of pain? (editorial). Pain 1998;77(3):227–229.

The mechanism-based classifications of pain differ from the conventional classification in that the former frees pain from diseases that may accompany reports of pain. Mechanism-based classification groups patients who are homogeneous in pain mechanisms but heterogeneous in disease conditions or diagnoses. Woolf et al.40 emphasize that their proposal is not to replace but rather to supplement the current system. 245

The basic premise underlying the mechanism-based classification of pain40 is helpful, both in guiding treatment and in bridging research to clinical practice in pain medicine. However, such a system is still at the conceptual stage. Ongoing efforts to synthesize findings from various areas of pain research will help to formulate this new classification system. This approach contrasts with our description of the use of two dimensions, time and severity, to distinguish acute and chronic pain (see Fig. 2.1). An explication of attempts to develop multidimensional classification systems incorporating features of several of the classifications is reviewed in the next section.

Multiaxial Classifications Ever since the gate control model underscored the importance of cognitive–evaluative and motivational–affective factors in the process of pain experience, the importance of integrating the psychosocial domains in the classification of pain has been proposed by a number of clinical investigators. However, as in other domains of pain medicine, the psychosocial classifications of pain have largely depended on psychiatric diagnoses to identify psychopathology. Although the psychiatrically defined classification of pain patients may help identify patients with specific psychiatric disorders, thereby directing treatments for those disorders, psychological classification systems aim to identify the specific psychosocial and behavioral contributions.

Empirically Based Classification of the Psychological Components of Pain Many taxonomies of pain recognize that the conceptualization and operationalization of cognitive, affective, and behavioral factors associated with pain merit consideration (e.g., IASP,4 AAPT21/AAAPT22 described in the following discussion). Numerous instruments assess pain-related psychosocial constructs, but most are unidimensional, inadequate for pain populations, or lack predictive validity for treatment outcomes. We describe one specific multidimensional, psychosocial classification system used primarily with patients with chronic pain conditions. The Multidimensional Pain Inventory (MPI)41 consists of a set of 246

empirically derived scales designed to assess chronic pain patients’ (1) pain severity, (2) pain interferes, (3) their dissatisfaction with present levels of functioning in main life domains, (4) appraisals of support received from significant others, (5) perceived life control, (6) their affective distress, and (7) activity levels. Turk and Rudy39 performed cluster analyses on a heterogeneous sample of chronic pain patients’ responses on the MPI scales. Three distinct profiles were identified: (1) dysfunctional (DYS): patients who perceived the severity of their pain to be high, reported that pain interfered with much of their lives, reported a higher degree of psychological distress due to pain, and reported low levels of activity; (2) interpersonally distressed (ID): patients with a common perception that significant others were not very supportive of their pain problems; and (3) adaptive copers (AC): patients who reported high levels of social support, relatively low levels of pain and perceived interference, and relatively high levels of activity. Reliable, external scales supported the uniqueness of each of the three subgroups of patients. Performing a 12-dimension Bayesian calculation to test goodness of fit can identify the profile that best fits a patient. The empirical–statistical approach has a distinct advantage of permitting judgments about how well an individual patient matches the central features of that classification. This is especially useful in complex pain syndromes that involve various clinical characteristics with large individual variability even within a single diagnostic group. Based on a set of patient characteristics, signs, and symptoms, a prototype for a diagnosis can be established. It is possible to statistically determine how close an individual case matches that prototype. Assume that a perfect match to a prototype is 0.99. A particular case may fit within the diagnosis but not be a perfect fit; thus, the fit might be 0.80. Some statistical rule can decide the minimum fit to the characteristics of the diagnosis; for example, 0.67. Thus, any two individuals with the same diagnosis must share certain characteristics but not necessarily all; the similarity of two patients with the same diagnosis has a statistical definition. Subsequent testing of the MPI profiles across various pain disorders suggests that the MPI psychosocial classification is independent of the conventionally defined pain syndromes, such as low back pain, TMD, 247

migraine headaches, FM, and pain associated with cancer. In other words, two patients whose pain pathologies are likely to differ (e.g., cancer and migraine headaches) could have a homogeneous psychological classification of pain. On the other hand, two patients, both having same type of TMD based on the RDC24 for comparable duration, may fare differently in the psychological classification of pain. Clinical trials using the MPI-based classification have yielded differential responses to a cognitive-behavioral approach.42,43 Such results strongly suggest that the psychosocial treatment components need to conform to the psychological classification of pain.44 A number of other empirical classifications based on patterns of psychosocial and behavioral factors have been reported.45,46 These approaches are similar but as with any empirically derived system that classification will depend on the variables assessed and entered into classification algorithms. We suggest that disease classification should reflect physical assessment leading to medical/physical treatment plans (e.g., 2), whereas that a psychosocial–behavioral taxonomy should determine complementary psychological treatment strategies. Both physical and psychosocial diagnoses are important in the person with a chronic pain syndrome. Several groups24,46,47 have proposed the use of a dual-diagnostic approach, whereby two diagnoses are assigned concurrently: physical and psychosocial–behavioral. Treatment could then target both simultaneously. A chronic pain patient might have diagnoses on two different but complementary taxonomies; for example, IASP and MPI-based classification. Thus, a patient might be classified as having CRPS type 1 of the upper extremity (203.X1, Axis I Region = upper shoulder and upper limbs, Axis II Systems = nervous, Axis III Temporal Characteristics of Pain: Pattern of Occurrence = none of the codes listed, Axis IV Intensity and Time of Onset = based on patient report, Axis V Etiology = trauma) on the IASP taxonomy and be classified DYS on the MPI-based taxonomy. Note that not all CRPS type 1 patients would be classified as DYS and not all DYS patients would have CRPS type 1. A second patient might have the same IASP diagnosis CRPS type 1 but be ID on the MPIbased classification. Conversely, patients might have quite different 248

classifications on the IASP system but have an identical MPI-based classification. The most appropriate treatment for these different groups might vary, with different complementary components of treatments addressing the physical diagnosis (IASP) and the psychosocial diagnosis (MPI-based).

COMPREHENSIVE, MULTIDIMENSIONAL CLASSIFICATION OF PAIN: INTERNATIONAL ASSOCIATION FOR THE STUDY OF PAIN TAXONOMY An alternative to the unidimensional approaches is a multidimensional approach that uses several relevant rather than a single dimension as the basis for developing the classification system and for assigning patients to a particular subgroup or diagnosis. The IASP has published an expertbased multiaxial classification of chronic pain1,2 intended to standardize descriptions of relevant pain syndromes and to provide a point of reference. The published taxonomy classifies chronic pain patients according to five axes based on the best published information and consensus: 1. Region of the body (Axis I), 2. System whose abnormal functioning could conceivably produce the pain (Axis II), 3. Temporal characteristics of pain and pattern of occurrence (Axis III), 4. Patient’s statement of intensity and time since onset of pain (Axis IV), and 5. Presumed etiology (Axis V) (Table 2.2). TABLE 2.2 International Association for the Study of Pain (IASP): Scheme for Coding Chronic Pain Syndromes Axis I: Regions Head, face, and mouth Cervical region Upper shoulder and upper limbs Thoracic region Abdominal region Lower back, lumbar spine, sacrum, and coccyx

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000 100 200 300 400 500

Lower limbs Pelvic region Anal, perineal, and genital region More than three major sites

600 700 800 900

Axis II: Systems Nervous system (central, peripheral, and autonomic) and special senses; physical disturbance or dysfunction Nervous system (psychological and social) Respiratory and cardiovascular systems Musculoskeletal system and connective tissue Cutaneous and subcutaneous and associated glands (breast, apocrine, etc.) Gastrointestinal system Genito-urinary system Other organs or viscera (e.g., thyroid, lymphatic hemopoietic) More than one system Unknown

00 10 20 30 40 50 60 70 80 90

Axis III: Temporal Characteristics of Pain: Pattern of Occurrence Not recorded, not applicable, or not known Single episode, limited duration (e.g., ruptured aneurysm, sprained ankle) Continuous or nearly continuous, nonfluctuating (e.g., low back pain) Continuous or nearly continuous, fluctuating (e.g., ruptured intervertebral disc) Recurring irregularly (e.g., headache, mixed type) Recurring regularly (e.g., premenstrual pain) Paroxysmal (e.g., tic douloureux) Sustained with superimposed paroxysms Other combinations None of the above

0 1 2 3 4 5 6 7 8 9

Axis IV: Patient’s Statement of Intensity: Time Since Onset of Pain Not recorded, not applicable, or not known Mild—1 mo or less Mild—1 to 6 mo Mild—more than 6 mo Medium—1 mo or less Medium—1 to 6 mo Medium—more than 6 mo Severe—1 mo or less Severe—1 to 6 mo Severe—more than 6 mo

.0 .1 .2 .3 .4 .5 .6 .7 .8 .9

Axis V: Etiology Genetic or congenital disorders (e.g., congenital dislocations) Trauma, operation, burns Infective, parasitic

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.00 .01 .02

Inflammatory (no known infective agent), immune reaction .03 Neoplasm .04 Toxic, metabolic (e.g., alcoholic neuropathy) anoxia, vascular, nutritional, endocrine, .05 radiation Degenerative, mechanical .06 Dysfunctional (including psychophysiologic) .07 Unknown or other .08 Psychological origin (e.g., conversion hysteria, depressive hallucination) .09 IASP Chronic Pain Syndromes A. Relatively generalized syndromes B. Relatively localized syndromes of the head and neck I. Neuralgias of the head and face II. Craniofacial pain of musculoskeletal origin III. Lesions of the ear, nose, and oral cavity IV. Primary headache syndromes, vascular disorders, and cerebrospinal fluid syndromes V. Pain of psychological origin in the head, face, and neck VI. Suboccipital and cervical musculoskeletal disorders VII. Visceral pain in the neck C. Spinal pain—spinal and radicular pain syndromes D. Spinal pain—spinal and radicular pain syndromes of the cervical and thoracic regions E. Local syndromes of the upper limbs and relatively generalized syndromes of the upper and lower limbs I. Pain in the shoulder, arm, and hand II. Vascular disease of the limbs III. Collagen disease of the limbs IV. Vasodilating functional disease of the limbs V. Arterial insufficiency in the limbs VI. Pain of psychological origin in the lower limbs F. Visceral and other syndromes of the trunk apart from spinal and radicular pain I. Visceral and other chest pain II. Chest pain of psychological origin III. Chest pain referred from abdomen or gastrointestinal tract IV. Abdominal pain of neurologic origin V. Abdominal pain of visceral origin VI. Abdominal pain syndromes of generalized diseases VII. Abdominal pain of psychological origin VIII. Diseases of the bladder, uterus, ovaries, and adnexa IX. Pain in the rectum, perineum, and external genitalia G. Spinal pain—spinal and radicular pain syndromes of the lumbar, sacral, and coccygeal regions I. Lumbar spinal or radicular pain syndromes II. Sacral spinal or radicular pain syndromes III. Coccygeal pain syndromes IV. Diffuse or generalized spinal pain V. Low back pain or psychological origin with referral

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H. Local syndromes of the lower limbs I. Local syndromes in the leg or foot: pain of neurologic origin II. Pain syndromes of the hip and thigh of musculoskeletal origin III. Musculoskeletal syndromes of the leg

This system establishes a five-digit code that assigns to each chronic pain diagnosis, a unique number. For example, the code for carpal tunnel syndrome is 204.X6. Thus, • 200 = REGION: upper shoulder and upper limbs • 00 = SYSTEM: the abnormal functioning is attributed to the nervous system • 4 = TEMPORAL CHARACTERISTICS: symptoms occur irregularly • X = PATIENT’S STATEMENT OF INTENSITY AND TIME SINCE ONSET: this will vary by patient • 06 = ETIOLOGY: degenerative, mechanical Table 2.3 contains the IASP scheme developed for the coding of chronic pain diagnoses. TABLE 2.3 List of Descriptions in Each Syndrome in the IASP Classification Definition Site System(s) involved Main features of the pain including its prevalence, age of onset, sex ratio if known, duration, severity, and quality Associated features; aggravating and relieving agents Signs Laboratory findings Natural course Complications Social and physical disability Pathology or other contributing factors Essential features and diagnostic criteria Differential diagnosis Code based on the five axes References (optional)

The IASP classification is the most comprehensive approach to classification of chronic pain syndromes. By design, the IASP classification is a heuristic, multiaxial guide that emphasizes the consideration of both signs and symptoms. Unfortunately, it excludes 252

assessment of psychosocial or behavioral data. Moreover, to be useful, any classification system must be reliable and valid, but as yet little published research has evaluated the reliability, validity, or utility of the IASP classification. What little evidence is available48 indicates that, although Axis I (body region) demonstrated reliable coding across examiners, Axis V (etiology) failed to achieve acceptable interrater reliability. The consistency (test–retest reliability) of the IASP taxonomy has yet to be established. Further research is needed in order to evaluate the psychometric properties of the classification system and to facilitate refinements of the system. The classifications we have described are only a few examples and are definitely not exhaustive. Specialists can arrive at classification categories based on clinical experience, published data, and consensus6,43 There is no single system for classifying pain patients that is universally accepted by clinicians or researchers. Furthermore, several problems associated with the current classification systems have generated debate and research concerning an alternative classification of pain. We provide several examples to illustrate different attempts to devise alternative taxonomies of pain and chronic pain patients. Recently, IASP proposed a classification of chronic pain for inclusion in the ICD-11.4 The classification includes seven categories (i.e., “primary”, cancer, postsurgical/posttraumatic, neuropathic, headache and orofacial, visceral, and musculoskeletal). The primary category is somewhat of a mixed back pain that cannot be explained by other chronic pain conditions and includes back pain that is neither identified as musculoskeletal or neuropathic, chronic widespread pain, FM, or irritable bowel syndrome. The primary category is consistent with the lumping of this set of disorders in the category of AAPM’s diagnosis of maldynia and central sensitivity disorders advocated by Clauw28 and Yunus29 among others. There may be some concern that this poorly defined category may imply the discredited psychogenic classification; that is, an artificial dichotomy where either the condition has a physical basis (somatogenic) or in the absence is psychogenic.

COMPREHENSIVE, MULTIDIMENSIONAL CLASSIFICATION OF PAIN: ACTTION-AMERICAN 253

PAIN SOCIETY AND ACTTION-AMERICAN PAIN SOCIETY-AMERICAN ACADEMY OF PAIN MEDICINE Recently, a consortium composed of ACTTION partnering with the American Pain Society to create chronic pain taxonomy (AAPT)21 and with the AAPM (AAAPT)22 to create an acute pain taxonomy. AAPT and AAAPT are evidence-based pain taxonomy in which a multidimensional diagnostic framework has been applied to the most prevalent and important chronic and acute pain conditions. A major impetus for the AAPT/AAAPT initiative derived from observing the transformative impact of evidence-based diagnostic classifications in related medical specialties. An essential characteristic of the AAPT multidimensional framework, taxonomy, and diagnostic criteria is that they are based on the best available evidence regarding symptoms, signs, mechanisms, and consequences rather than on expert opinion alone. This coordinated effort can be applied across all chronic pain conditions, and as has been true of other diagnostic criteria, AAPT will be revised periodically on the basis of accumulating evidence. Another critical aspect of the AAPT is that it reflects the multidimensional, biopsychosocial nature of chronic pain, in which psychological and social risk factors and consequences are integrated with neurobiologic mechanisms and outcomes. In addition, an essential characteristic is that the taxonomy is intended to be applicable for both research and clinical settings; it is recognized, however, that widespread clinical use is likely to develop gradually as the clinical utility of the criteria become apparent and as the evidence base increases. Finally, the initial version of AAPT is based on currently available evidence, and the goal is to systematically update the criteria on the basis of new evidence, especially the results of studies of reliability, validity, and neurobiologic mechanisms. AAPT therefore categorizes chronic pain conditions by organ system and anatomic structure, distinguishing peripheral and central neuropathic pain, musculoskeletal pain, spine pain, orofacial and head pain, and abdominal/pelvic/urogenital pain (Table 2.4). Because certain types of chronic pain cannot be included in one of these groups, an additional category for disease-related pain not classified elsewhere includes pain 254

associated with cancer and pain associated with sickle cell disease (pain associated with Lyme disease and with leprosy, among other conditions, would also be included in this group). It is important to emphasize that all types of headache were intentionally excluded from AAPT because the International Classification of Headache Disorders (ICHD)20 provides systematic, valid, and widely used diagnostic criteria for these conditions. TABLE 2.4 ACTTION-American Pain Society Pain Taxonomy (AAPT) for Chronic Pain Peripheral Nervous System Complex regional pain syndrome Painful peripheral neuropathies associated with diabetes, impaired glucose tolerance, and human immunodeficiency virus Postherpetic neuralgia Posttraumatic neuropathic pain, including chronic pain after surgery Trigeminal neuralgia Central Nervous System Pain associated with multiple sclerosis Poststroke pain Spinal cord injury pain Spine Pain Chronic axial musculoskeletal low back pain Chronic lumbosacral radiculopathy Musculoskeletal Pain Fibromyalgia and chronic myofascial and widespread pain Gout Osteoarthritis Rheumatoid arthritis Spondyloarthropathies Orofacial and Head Pain Headache disorders (see International Classification of Headache Disorders) Temporomandibular disorders Abdominal, Pelvic, and Urogenital Pain Interstitial cystitis Irritable bowel syndrome Vulvodynia Disease-Associated Pain Conditions Not Classified Elsewhere Pain associated with cancer: cancer-induced bone pain, chemotherapy-induced peripheral neuropathy, and pancreatic cancer pain Pain associated with sickle cell disease NOTE: The specific chronic pain conditions listed within each of the seven categories are those for which diagnostic criteria are included within AAPT and are not all of the chronic pain conditions

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that occur within these categories. This table is updated from (Fillingim et al.21). Reprinted from Dworkin RH, Bruehl S, Fillingim RB, et al. Multidimensional diagnostic criteria for chronic pain: introduction to the ACTTION-American Pain Society Pain Taxonomy (AAPT). J Pain 2016;17(9 Suppl):T1–T9. Copyright © 2016 by the American Pain Society. With permission.

The AAPT multidimensional framework comprises five dimensions that can be applied to all chronic pain conditions. This can be contrasted with the new IASP taxonomy where psychosocial factors are “optional specifiers” for each diagnoses beyond the classification of “chronic primary pain” where it is given a prominent role along with interference with activities and participation in social roles (somewhat of a departure from the original IASP taxonomy). An overview of these dimensions is presented in Table 2.4, and each is briefly summarized in this section (see also Fillingim et al.21). Other than prioritizing core diagnostic criteria, which is the first AAPT dimension, the order of the dimensions does not reflect their importance. Indeed, as noted earlier, it is anticipated that AAPT diagnostic criteria will ultimately be based on the mechanisms of the specific chronic pain conditions, whereas in the current version of the taxonomy, these mechanisms constitute the final dimension. Like the IASP classification, the AAPT also includes seven but somewhat different categories of chronic pain (i.e., peripheral nervous systems; central nervous system; spine; musculoskeletal; orofacial and head; visceral, pelvic, and urogenital; other [e.g., cancer, sickle cell]). Within the AAPT classification, psychological and behavioral factors are identified with all of the seven categories. Specifically, the AAPT classification incorporates five dimensions for each condition within the seven categories (Table 2.5). The AAAPT is being extended to acute pain, incorporating the same five dimensions, in this application for eight acute pain sets of conditions (i.e., acute surgical/procedural pain; acute trauma pain; acute musculoskeletal pain; acute visceral pain; cancer/immunemediated acute pain; acute neuropathic pain; acute orofacial pain; acute pain in pediatric, geriatric, and special populations).22 TABLE 2.5 The ACTTION-American Pain Society Pain Taxonomy Multidimensional Framework for Chronic Pain Dimension Description

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1. Core diagnostic criteria

2. Common features

3. Common medical and psychiatric comorbidities

4. Neurobiological, psychosocial, and functional consequences 5. Putative neurobiological and psychosocial mechanisms, risk factors, and protective factors

Symptoms, signs, and diagnostic test findings required for the diagnosis of the chronic pain condition. Includes differential diagnosis considerations. Additional information regarding the disorder, including common pain characteristics (e.g., location, temporal qualities, descriptors), nonpain features (numbness, fatigue), the epidemiology of the condition, and life span considerations, including those specific to pediatric and geriatric populations. These features are important in describing the disorder but are not components of the core diagnostic criteria. Medical and psychiatric disorders that commonly occur with the chronic pain condition. For example, major depression is comorbid with many chronic pain conditions. Also includes chronic overlapping pain conditions, that is, those chronic pain conditions that are comorbid with each other. Neurobiological, psychosocial, and functional consequences of chronic pain. Examples include sleep and mood disorders and pain-related interference with daily activities. Putative neurobiological and psychosocial mechanisms contributing to the development and maintenance of the chronic pain condition, including risk and protective factors. Examples include central sensitization, decreased descending inhibition, and somatosensory amplification.

Reprinted from Dworkin RH, Bruehl S, Fillingim RB, et al. Multidimensional diagnostic criteria for chronic pain: introduction to the ACTTION-American Pain Society Pain Taxonomy (AAPT). J Pain. 2016;17(9 Suppl):T1–T9. Copyright © 2016 by the American Pain Society. With permission.

INDUCTIVE EMPIRICALLY BASED CLASSIFICATIONS OF PAIN Those who advocate the use of empirically derived taxonomies maintain that quantitative analysis should define the relationships of contiguity and similarity among individuals. That is, the taxonomic system must reflect clinically relevant characteristics that exist in nature, defined by empirical methods rather than based on expert judgment and consensus. The American College of Rheumatology (ACR) proposed the first standard criteria that were empirically derived for the classification of FM in 1990. In a multicenter study,49 a group of FM experts from several medical centers collected FM-related variables and used those variables in an attempt to differentiate FM patients from patients with other types of chronic pain syndromes. The acceptable sensitivity and specificity were 257

achieved by two criteria: presence of widespread pain (i.e., above and below the waist, right and left side of the body, and along the midline) and at least 11 of 18 positive tender points upon palpation. Other symptoms commonly reported by FM patients, such as fatigue and stiffness, did not differentiate between FM and other types of chronic pain. Since publication, most subsequent research seems to conform to this classification system, making it a bit easier to compare results across studies. Nonetheless, debate remains about the extent that this classification contributes to clinical practice and the meaning of tender points and the necessity of the tender point criterion.50 Although the criteria were well acknowledged as the important step to standardize the nature of FM population, they were criticized by many as not quite capturing the disease entity well. It is important to acknowledge that all relevant factors cannot be measured by a single classification system. The use of an inductive approach depends on what the investigator chooses to include within the statistical analysis. Thus, in practice, the inductive approach to classification is not a totally objective process that is completely atheoretical. Furthermore, there are significant difficulties in defining a “pure” syndrome that is distinct from all the relevant illnesses when the syndrome itself is a multisymptom disorder. In a case of FM, one of the major criticisms of the empirically driven 1990 ACR criteria is that they fail to incorporate main feature of FM, such as fatigue, cognitive problem, and sleep disturbance. These main features are common in other disorders and do not necessarily differentiate FM from others; nevertheless, not taking these features into account seemed to diminish the validity of the classification. Purely inductive approach to empirically delineate a clinical syndrome may benefit therefore from incorporating clinically and theoretically meaningful approaches.

PSYCHOMETRIC CONSIDERATIONS The general utility of any proposed empirical taxonomy links closely to the psychometric properties (i.e., reliability, validity, and utility) of the measures, scales, or instruments used to derive the classification system. Because these are the building blocks used to generate profiles or clusters, the reliability and validity of the classification system depends, in part, on 258

the psychometric quality of the measures used. Because reliability and validity coefficients are generic terms, the specific psychometric techniques used to evaluate a measure’s “psychometric properties” require consideration. There are multiple ways to demonstrate the reliability and validity of measures. Therefore, the more psychometric support there is for a measure, the more likely it will perform well when used in taxometric identification and classification procedures. Additionally, replication of classification accuracy on new samples and demonstrating substantial, statistically significant differences across patient profiles for conceptually related measures external to the measures used to develop the profiles are some of the best ways to demonstrate the reliability and validity of empirically derived profiles. Evaluation of any classification should demonstrate reliability, validity, and utility prior to widespread adoption.

Conclusion Pain management specialists have witnessed rapid advances in the basic sciences and clinical arenas of pain medicine over the past three decades. Many pain-related terms, once a major source of confusion, have received clear definitions, aiding efficient and productive communication among researchers and clinicians. The classification systems that direct our research and clinical practice need to reflect the progress in our understanding of mechanisms, multifactorial integration, and outcome predictability of classification criteria. In this chapter, we have reviewed several conventional classifications as well as emerging classification systems that can supplement the conventional ones. The review of various classification systems suggests that the comprehensive taxonomy of pain require multifactorial assessments including physical, psychosocial, and behavioral components (see Table 2.5). The utility of any classification system depends on application. The important question is whether assignment of an individual to a class truly facilitates treatment decisions or predictions of future behavior. Several of the taxometric systems have demonstrated their utility to predict treatment outcome.45 The prognostic approach has some data supporting its use as an alternative to the traditional approach based on the acute–chronic duration

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continuum. In support of this, the multiaxial RDC for Temporomandibular Disorders has acquired sufficient data to warrant it being adopted as Diagnostic Criteria for Temporomandibular Disorders.24 Research is needed to demonstrate the validity of the newer IASP4 and AAPT21/AAAPT22 taxonomies. †The discussion describing the distinction between acute and chronic pain reflects on deliberations among the editors of the third edition of this volume.

References 1. Merskey H. Classification of chronic pain. Descriptions of chronic pain syndromes and definitions. Pain 1986;(suppl 3):345–356. 2. Merskey H, Bogduk N. Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. 2nd ed. Seattle, WA: IASP Press; 1994. 3. Merskey H. Classification and diagnosis of fibromyalgia. Pain Res Manag 1996;1:42–44. 4. Treede RD, Rief W, Barke A, et al. A classification of chronic pain for the ICD-11. Pain 2015;156:1003–1007. 5. Williams AC, Craig KD. Updating the definition of pain. Pain 2016;157:2420–2423. 6. Deyo RA, Dworkin SF, Amtmann D, et al. Report of the NIH Task Force on research standards for chronic low back pain. J Pain 2014:15:569–585. 7. Von Korff M, Dunn KM. Chronic pain reconsidered. Pain 2008;138:267–276. 8. Turk DC, Murphy TB. Chronic pain. In: Carr A, McNulty M, eds. The Handbook of Adult Clinical Psychology: An Evidence-Based Practice Approach. 2nd ed. London: Routledge; 2016:635–685. 9. Turk DC. Remember the distinction between malignant and benign pain? Well, forget it. Clin J Pain 2002;18:75–76. 10. Sullivan MJ, Thorn B, Haythornthwaite JA, et al. Theoretical perspectives on the relation between catastrophizing and pain. Clin J Pain 2001;17:52–64. 11. Harden RN, Bruehl S, Stanton-Hicks M, et al. Proposed new diagnostic criteria for complex regional pain syndrome. Pain Med 2007;8:326–331. 12. Yarnitsky D, Arendt-Nielsen L, Bouhassira D, et al. Recommendations on terminology and practice of psychophysical DNIC testing. Eur J Pain 2010;14:339. 13. Jensen TS, Baron R, Haanpää M, et al. A new definition of neuropathic pain. Pain 2011;152:2204–2205. 14. Treede RD, Jensen TS, Campbell JN, et al. Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology 2008;70:1630–1635. 15. Southwick SM, Bonanno GA, Masten AS, et al. Resilience definitions, theory, and challenges: interdisciplinary perspectives. Eur J Psychotraumatol 2014;5:25338. 16. Bonica JJ. The need of a taxonomy. Pain 1979;6:247–248. 17. Baron DN, Fraser PM. Medical applications of taxonomic methods. Br Med Bull 1968;24:236–240. 18. World Health Organization, ed. ICD-10: International Statistical Classification of Diseases and Related Health Problems. Vol 1. 10th rev ed. Geneva, Switzerland: World Health Organization; 1992. Available at: http:/www.who.int/classifications/icd/revision/contentmodel/en/. Accessed October 1, 2014.

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19. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Headache Classification Committee of the International Headache Society. Cephalalgia 1988; (8)(suppl 7):1–96. 20. Spitzer WO, Skovron ML, Salmi LR, et al. Scientific monograph of the Quebec Task Force on whiplash-associated disorders: redefining “whiplash” and its management. Spine (Phila Pa 1976) 1995;20(8)(suppl):1S–73S. 21. Fillingim RB, Bruehl S, Dworkin RH, et al. The ACTTION-American Pain Society Pain Taxonomy (AAPT): an evidence-based and multi-dimensional approach to classifying chronic pain conditions. J Pain 2014;15:241–249. 22. Kent ML, Tighe PJ, Belfer I, et al. The ACTTION-APS-AAM Pain Taxonomy (AAAPT) multidimensional approach to classifying acute pain conditions. J Pain 2017;18:479–489. 23. Dworkin SF, LeResche L. Research diagnostic criteria for temporomandibular disorders: review, criteria, examinations and specifications, critique. J Craniomandib Disord 1992;6:301–355. 24. Schiffman E, Ohrbach R, Truelove E, et al. Diagnostic criteria for temporomandibular disorders (DC/TMD) for clinical and dental research applications: recommendations of the International RDC/TMD Consortium Network and Orofacial Pain Special Interest Group. J Oral Facial Pain Headache 2014;28:6–27. 25. Zaki H, Rudy T, Turk D, et al. Reliability of Axis I research diagnostic criteria for TMD [abstract]. J Dent Res 1994;73:186. 26. Dickinson BD, Head CA, Gitlow S, et al. Maldynia: pathophysiology and management of neuropathic and maladaptive pain—a report of the AMA Council on Science and Public Health. Pain Med 2010;11:1635–1653. 27. Portenoy RK. Mechanisms of clinical pain. Observations and speculations. Neurol Clin 1989;7:205–230. 28. Clauw DJ. Fibromyalgia and related conditions. Mayo Clinic Proc 2015;90:680–692. 29. Yunus MB. Central sensitivity syndromes: a new paradigm and group nosology for fibromyalgia and overlapping conditions, and the related issue of disease versus illness. Semin Arthritis Rheum 2008;37:339–352. 30. Friction J. Medical evaluation of patients with chronic pain. In: Barber J, Adrian C, eds. Psychological Approaches to the Management of Pain. New York: Brunner/Mazel; 1982:37– 61. 31. World Health Organization. International Classification of Functioning, Disability and Health: ICF. Geneva, Switzerland: World Health Organization; 2001. 32. Brena S, Koch D. A “pain estimate” model for quantification and classification of chronic pain states. Anesth Rev 1975;2:8–13. 33. Brena S, Koch D, Moss R. Reliability of the “pain estimate” model. Anesth Rev 1976;3:28– 29. 34. Von Korff M, Ormel J, Keefe FJ, et al. Grading the severity of chronic pain. Pain 1992;50:133–149. 35. Dunn KM, Von Korff M, Croft PR. Defining chronic pain by prognosis. In: Hasenbring MI, Rusu AC, Turk DC, eds. From Acute to Chronic Back Pain: Risk Factors, Mechanisms, and Clinical Implications. Oxford, England: Oxford University Press; 2012:21–39. 36. Von Korff M, Miglioretti DL. A prognostic approach to defining chronic pain. Pain 2005;117:304–313. 37. Elliott AM, Smith BH, Hannaford PC, et al. Assessing change in chronic pain severity: the Chronic Pain Grade compared with retrospective perception. Br J Gen Pract 2002;52:269– 274. 38. Spitzer WO, LeBlanc FE, Dupuis M, et al. Scientific approach to the assessment and

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management of activity-related spinal disorders: a monograph for clinicians. Report of the Quebec Task Force on Spinal Disorders. Spine (Phila Pa 1976) 1987;12(7)(suppl):S1–S59. Turk DC, Rudy TE. Towards a comprehensive assessment of chronic pain patients. Behav Res Ther 1987;25:237–249. Woolf C, Bennett G, Doherty M, et al. Towards a mechanism-based classification of pain? Pain 1998;77:227–229. Kerns RD, Turk DC, Rudy TE. The West Haven-Yale Multidimensional Pain Inventory (WHYMPI). Pain 1985;23:345–356. Turk DC, Okifuji A, Sinclair JD, et al. Differential responses by psychosocial subgroups of fibromyalgia syndrome patients to an interdisciplinary treatment. Arthritis Care Res 1998;11:397–404. Turk DC, Rudy TE, Kubinski JA, et al. Dysfunctional patients with temporomandibular disorders: evaluating the efficacy of a tailored treatment protocol. J Consult Clin Psychol 1996;64:139–146. Turk DC. Customizing treatment for chronic pain patients: who, what, and why? Clin J Pain 1990;6:255–270. Rusu A, Boersma K, Turk DC. Reviewing the concept of subgroups in subacute and chronic pain and the potential of customizing treatments. In: Hasenbring MI, Rusu AC, Turk DC, eds. From Acute to Chronic Back Pain: Risk Factors, Mechanisms, and Clinical Implications. Oxford, United Kingdom: Oxford University Press; 2012:485–511. Turk DC. The potential of matching treatments to characteristics of chronic pain patients: lumping versus splitting. Clin J Pain 2005;21:44–55. Scharff L, Turk DC, Marcus DA. Psychosocial and behavioral characteristics in chronic headache patients: support for a continuum and dual-diagnostic approach. Cephalalgia 1995;15:216–223. Turk DC, Rudy TE. Toward an empirically derived taxonomy of chronic pain patients: integration of psychological assessment data. J Consult Clin Psychol 1988;56:233–238. Wolfe F, Smythe HA, Yunus MB, et al. The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum 1990;33:160–172. Clauw DJ. Fibromyalgia: update on mechanisms and management. J Clin Rheumatol 2007;13:102–109.

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CHAPTER 3 Peripheral Pain Mechanisms and Nociceptor Sensitization MICHAEL S. GOLD Pain has been categorized by duration (acute vs. chronic), location (superficial or deep; cutaneous, bone/joint, muscle, or viscera), and cause or type (inflammatory, neuropathic, cancer). Generally, activation of and/or ongoing activity in specific subpopulations of primary afferent neurons underlies the experience of pain regardless of how it is categorized. Accordingly, primary afferents are key players in understanding mechanisms of, and managing, pain. Sir Charles Sherrington anticipated by many decades the existence sensory receptors that respond to noxious stimuli, that he called nociceptors and thereby provided for us the operational definition of stimuli that are noxious (i.e., stimuli that damage or threaten damage of tissue). Two considerations are important to this discussion. First, Sherrington functionally defines the nociceptor by its response to a noxious stimulus (e.g., a nociceptive withdrawal reflex, pain). Second, the definition of an applied stimulus as noxious is based on the response to the stimulus applied to skin and subcutaneous structures. Sherrington’s definition of a nociceptor continues to the present day. However, the term has undergone change and challenge over the past 100 years and may be nearing the end of its utility in the face of the growing understanding of the heterogeneity in the neurons that may not fit so comfortably under this umbrella term. It is therefore important to consider, within the context of our current knowledge, how a nociceptor is defined, identified, and studied, as the interpretation of this information will directly affect the management of pain. All would agree that a nociceptor is a sensory receptor which, when activated or active, can contribute to the experience of pain. Nociceptors 263

are present in skin, muscle, joints, and viscera, although the density of innervation (i.e., the number and distribution of sensory endings) varies between and within tissues. As originally described by Sherrington, a nociceptor is the peripheral sensory terminal (i.e., the site of energy transduction—see following section), although commonly the term is used to also include the cell body (in a dorsal root, trigeminal, or nodose ganglion) and its central termination in the spinal cord or brainstem. Beyond this, agreement about important features of nociceptors is less uniform. One of the best examples of why this definition is becoming problematic is the observation that injury-induced changes in the central nervous system underlie the emergence of allodynia, pain in response to normally innocuous stimuli. Allodynia is problematic for this definition of nociceptor because pain is mediated by activity in low-threshold afferents that in the absence of tissue injury would, if anything, contribute to the suppression of pain. That is, these afferents would not be considered nociceptors despite the fact that they contribute to the experience of pain. Furthermore, because stimuli adequate for activation of nociceptors differ between tissues (e.g., tissue damage is not always required), defining a noxious stimulus has become a challenge. For example, some nociceptors in skin and joints and most nociceptors in the viscera have low thresholds for mechanical activation that do not conform to the condition that stimulus intensity must be either damaging or threaten damage. Further, so-called “silent” or “sleeping” nociceptors are unresponsive to intense mechanical stimulation (and are better denoted as mechanically insensitive nociceptors) but develop spontaneous activity and mechanosensitivity after exposure to inflammatory and other endogenous mediators. These types of nociceptors—low threshold and sleeping—as well as other subpopulations of sensory neurons that may contribute to the sensation of pain following tissue injury are considered further in the discussion of sensitization in the following section.

Functional Characterization of Nociceptors As suggested earlier, there are many types of nociceptors, our knowledge of which has been advanced by human psychophysical studies while

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recording from afferent fibers (Box 3.1). In human skin, for example, there exist nociceptors that respond only to mechanical, only to cold thermal, or only to hot thermal stimuli as well as those that are insensitive to both mechanical and heat stimuli (mechanically insensitive or sleeping nociceptors).1,2 The most abundant is the polymodal nociceptor, which responds to mechanical, thermal, and chemical stimuli. In general, nociceptors that innervate skin have the broadest range of modality selectivity, whereas nociceptors innervating deeper structures tend to be less modality-selective and more polymodal in character.3 For example, mechanical sensitivity is a prominent feature of visceral and joint nociceptors because stimuli adequate for their activation include hollow organ distension and overrotation, respectively. Many of these nociceptors also respond to chemical and/or thermal stimuli as well, although the functional significance of thermal sensitivity in deep tissues is uncertain. An important characteristic of polymodal nociceptors, whether the modalities of stimulation to which they respond are two or all three, is that when sensitized (e.g., by an inflammatory insult), responses to the other modality or modalities of stimuli to which it responds are all increased.4 That is, it is not only the mechanosensitive modality, for example, that becomes sensitized, but other modalities to which it responds are sensitized as well. BOX 3.1 Microneurography The development of a method to record from human nerve fibers in situ,191,192 termed microneurography, provided an unparalleled opportunity to expand our knowledge about peripheral sensory receptors, including nociceptors. The method involves percutaneous insertion of the tip of a sharp, insulated metal microelectrode into a nerve (e.g., peroneal or radial nerve) and the application of search stimuli to sites distal to the electrode. In earlier work, mechanical search stimuli (e.g., von Frey filaments) were used, and accordingly, only mechanosensitive afferents were studied. An electrical search stimulus (surface electrode), however, has become favored because the electrical stimulus identifies afferent fibers independent of sensitivity to 265

natural stimulation. After an afferent fiber is isolated, the innervation territory can be drawn on the skin and the adequate, natural stimulus/stimuli determined. Because microneurography can be easily coupled with a psychophysical approach, human subjects are able to describe stimulusproduced experiences (e.g., pain) while recording from single afferent fibers. Microneurography also has been expanded to include intraneural electrical stimulation of the fiber through the recording electrode, providing additional insight into the qualities of sensation produced, for example, by low- and high-frequency stimulation in addition to qualities associated with natural stimulation. Microneurography has confirmed in psychophysical experiments sensations associated with activation of rapidly adapting (flutter, vibration) and slowly adapting (pressure) cutaneous mechanoreceptors, Aδ-mechanonociceptors (AM[mechano]; sharp pain), C-polymodal nociceptors (CM[mechano]H[heat]; dull, burning [heat] pain), and group IV muscle nociceptors (cramping pain). Electrical search strategies have revealed a wider range of nociceptors, including190 A-mechanoheat (AMH), which have similar heat thresholds as CMH (C-polymodal) fibers and also typically respond to chemical stimuli; C-mechanonociceptors (CM), C-heat (CH); C-mechano- and heat-insensitive (CMiHi, or sleeping nociceptors); and C-mechanoinsensitive-histamine responsive (CMiHis+, or itch fibers193). Microneurography has also been extended to psychophysical study of pathologic pain states in humans. In a study of patients suffering from erythromelalgia, a condition characterized by painful, red, and hot extremities, a proportion of CMiHi fibers were found to be spontaneously active or sensitized to mechanical stimuli. Because CMiHi fibers also mediate the axon flare reflex, their hyperexcitability was considered to contribute to the patients’ ongoing pain and tenderness as well as the redness and warming in this pain syndrome. In patients with painful peripheral neuropathy, Ochoa et al.194 reported hyperexcitability in CMH and CMiHi fibers. Signs of hyperexcitability included reduced thresholds to mechanical and heat stimuli, spontaneous activity, and increased responses to stimulation. In 266

diabetic neuropathic pain patients, Ørstavik et al.195 found that the ratio of CMH to CMiHi fibers was reduced by about 50%, apparently due to loss of mechanical and heat responsiveness in CMH fibers. These and future studies will help to understand which nociceptors (and non-nociceptors) in which conditions contribute to spontaneous, ongoing pain as well as stimulus-evoked pain and what therapeutic strategies are most effective. With respect to mechanosensitivity, nociceptors at the opposite extremes of sensitivity are most illustrative of the limitations of even a functional definition of a nociceptor. Nociceptors with low mechanical thresholds for response and those with very high mechanical thresholds for response (i.e., sleeping nociceptors) are both clinically important. Mechanosensitive sensory neurons with low thresholds for response have long been classified as non-nociceptors (because it was considered that nociceptors had to have response thresholds in the noxious range). Some mechanosensitive skin, joint, and many visceral sensory neurons have low thresholds for response (i.e., in the nonnoxious range) but possess characteristics that suggest an important role in pain. First, they encode stimulus intensity well into the noxious range and, moreover, typically give greater responses to all intensities of stimulation than do nociceptors with high mechanical thresholds for response. Second, they sensitize after tissue insult. Unlike nociceptors with low mechanical thresholds, mechanically insensitive or sleeping nociceptors normally provide no information to the central nervous system but after tissue insult become spontaneously active and mechanosensitive.5

Identification of Putative Nociceptors As indicated earlier, nociceptors are defined classically in a functional context. However, in experimental situations where function cannot be assessed, other criteria to classify a neuron as a nociceptor have been advanced. These include the presence or absence of axon myelination, cell size, and/or cell content (e.g., peptide or ion channel) as well as central termination pattern. Sensory neurons commonly identified as nociceptors 267

are those with unmyelinated (C-fiber) axons, small cell body diameters (G polymorphism and duration of morphine treatment associated with morphine doses and quality-of-life in palliative cancer pain settings. Int J Mol Sci 2017;18(4):E669. Tegeder I, Costigan M, Griffin RS, et al. GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence. Nat Med 2006;12(11):1269–1277. Campbell CM, Edwards RR, Carmona C, et al. Polymorphisms in the GTP cyclohydrolase gene (GCH1) are associated with ratings of capsaicin pain. Pain 2009;141(1–2):114–118. Tegeder I, Adolph J, Schmidt H, et al. Reduced hyperalgesia in homozygous carriers of a GTP cyclohydrolase 1 haplotype. Eur J Pain 2008;12:1069–1077. Wadley AL, Lombard Z, Cherry CL, et al. Analysis of a previously identified “painprotective” haplotype and individual polymorphisms in the GCH1 gene in Africans with HIVassociated sensory neuropathy: a genetic association study. J Acquir Immune Defic Syndr 2012;60(1):20–23. Kim DH, Dai F, Belfer I, et al. Polymorphic variation of the guanosine triphosphate cyclohydrolase 1 gene predicts outcome in patients undergoing surgical treatment for lumbar degenerative disc disease. Spine 2010;35(21):1909–1914. Fejer R, Hartvigsen J, Kyvik KO. Sex differences in heritability of neck pain. Twin Res Hum Genet 2006;9(2):198–204. Olsen MB, Jacobsen LM, Schistad EI, et al. Pain intensity the first year after lumbar disc herniation is associated with the A118G polymorphism in the opioid receptor mu 1 gene: evidence of a sex and genotype interaction. J Neurosci 2012;32(29):9831–9834. Belfer I, Youngblood V, Darbari DS, et al. A GCH1 haplotype confers sex-specific susceptibility to pain crises and altered endothelial function in adults with sickle cell anemia. Am J Hematol 2014;89(2):187–193. Mountain JL, Risch N. Assessing genetic contributions to phenotypic differences among ‘racial’ and ‘ethnic’ groups. Nat Genet 2004;36(11 suppl):S48–S53. Gower BA, Fernandez JR, Beasley TM, et al. Using genetic admixture to explain racial

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differences in insulin-related phenotypes. Diabetes 2003;52(4):1047–1051. Shriver MD. Ethnic variation as a key to the biology of human disease. Ann Intern Med 1997;127(5):401–403. Shriver MD, Kennedy GC, Parra EJ, et al. The genomic distribution of population substructure in four populations using 8,525 autosomal SNPs. Hum Genomics 2004;1(4):274– 286. Gelernter J, Kranzler H, Cubells J. Genetics of two mu opioid receptor gene (OPRM1) exon I polymorphisms: population studies, and allele frequencies in alcohol- and drug-dependent subjects. Mol Psychiatry 1999;4(5):476–483. Hastie BA, Riley JL III, Kaplan L, et al. Ethnicity interacts with the OPRM1 gene in experimental pain sensitivity. Pain 2012;153:1610–1619. George SZ, Dover GC, Wallace MR, et al. Biopsychosocial influence on exercise-induced delayed onset muscle soreness at the shoulder: pain catastrophizing and catechol-omethyltransferase (COMT) diplotype predict pain ratings. Clin J Pain 2008;24(9):793–801. George SZ, Parr J, Wallace M, et al. Genetic and psychological risk factors are associated with pain and disability in an experimentally induced acute shoulder pain model. J Pain 2012;13(4)(suppl 1):s29. George SZ, Parr JJ, Wallace MR, et al. Inflammatory genes and psychological factors predict induced shoulder pain phenotype. Med Sci Sports Exerc 2014;46:1871–1881. George SZ, Wallace MR, Wu SS, et al. Biopsychosocial influence on shoulder pain: risk subgroups translated across preclinical and clinical prospective cohorts. Pain 2015;156(1):148–156. George SZ, Wallace MR, Wright TW, et al. Evidence for a biopsychosocial influence on shoulder pain: pain catastrophizing and catechol-O-methyltransferase (COMT) diplotype predict clinical pain ratings. Pain 2008;136(1–2):53–61. Slade GD, Sanders AE, Ohrbach R, et al. COMT diplotype amplifies effect of stress on risk of temporomandibular pain. J Dent Res 2015;94(9):1187–1195.

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CHAPTER 9 Functional Neuroanatomy of the Nociceptive System ROBERT GRIFFIN, EZEKIEL FINK, and GARY J. BRENNER From the standpoint of the physician, there are two perspectives from which to view pain. One is as a symptom of a disease process that will inform about the underlying pathophysiology. The other is as the primary cause for suffering that requires treatment in its own right. These two views of pain often coexist when the pain reveals pathology whose treatment will not resolve the pain rapidly enough for the patient to tolerate. For example, in acute myocardial ischemia, the pain is the cardinal symptom of the underlying illness but in itself can provide an ongoing stimulus for a catecholaminergic state that will increase myocardial demand and potentially worsen the ischemic state. Both of these perspectives, either using the pain as a clue or addressing it as the primary aim of treatment,1 are enhanced by considering the patient’s report of their pain in light of the specific anatomic structures that collect information about noxious stimuli and communicate this information to the central nervous system (CNS) where pain is perceived and behavioral responses are generated. Pain may be grouped according to several different parameters including acute versus chronic, physiologic versus pathologic, and somatic versus visceral. Full understanding of the nature of any pain complaint requires knowledge of the anatomic structures involved and the functional status of these structures. Chronicity of pain is determined by the duration of the irritating stimulus and by the plastic response of the peripheral and CNS to injury or ongoing stimulus. Pain may be either nociceptive, induced by high-threshold sensory stimuli required for activation of peripheral nociceptors, or pathologic, induced by low-threshold stimuli 500

due to a heightened state of nervous system excitability brought on by either inflammatory cell–cell signaling (i.e., inflammatory pain) and signal transduction or by the extensive anatomic and physiologic alterations brought on by nerve injury (i.e., neuropathic pain).2 Finally, pain may be somatic, transmitted by the somatosensory nervous system, or visceral, transmitted by splanchnic sympathetic and pelvic nerve afferent fibers (or by specific cranial nerves in the case of the head and neck).3,4 This chapter touches on the specific anatomic structures that are involved in the transduction of physical stimuli into sensory responses, the conduction of sensory information to the CNS, and the processing and relay of this sensory information within the spinal cord and brain and discusses some of the major perturbations in these structures as related to clinical pain phenomena.

Organization of the Peripheral Nociceptive System There are several major anatomic units involved in pain sensation. First, primary sensory neurons whose peripheral terminals respond to physical energy conduct action potentials along long axons bundled into peripheral nerves from the site of sensory stimulus to the CNS.5 Next, nociceptive synaptic relay occurs at the dorsal horn of the spinal cord, where substantial sensory processing occurs.6–8 Ascending fiber tracts carry this information to the brainstem and, from there, diverse brain regions. Descending fiber tracts project from the brainstem and brain to the dorsal horn of the spinal cord and regulate the processing of incoming sensory information.9 The peripheral nerves that carry sensory information from visceral organs, bone, muscle, joint, or skin to the CNS may be either cranial nerves or spinal nerves. Cranial nerves carry sensory information to the brainstem,10 whereas spinal nerves carry sensory information to the spinal cord and may bear axons for neurons that synapse within the spinal cord or brainstem.11,12 Spinal nerves are mixed nerves that carry general somatic afferent fibers, general visceral afferent fibers, general somatic efferent fibers, and general visceral efferent fibers. Somatic afferents primarily carry information from skin, muscle, tendon, and joint, whereas visceral 501

afferents carry information from the other tissues. The cell bodies of both the somatic and the visceral afferent fibers carried by spinal nerves reside in the dorsal root ganglia (DRG) of the spinal cord, whereas those carried by cranial nerves reside in the brainstem cranial nerve nuclei.12 The ability to localize painful stimuli depends on the topographic organization of the nervous system. The somatic afferent system and the visceral afferent system are strikingly different in this regard, with precise stimulus position detected and encoded by the somatic nervous system but only relatively diffuse information coming to conscious awareness from the visceral afferent system.4 In the clinical setting, precise localization of pain is often considered as evidence that the pain is detected by somatic afferents rather than visceral afferents. For example, knifelike welllocalized pain associated with inspiration is likely detected by somatic fibers innervating the parietal pleura.13 In the abdomen, well-localized lower right quadrant pain occurring late in the course of acute appendicitis is likely due to spread of the periappendiceal inflammation that irritates the somatic nerves innervating the abdominal wall overlying the appendix.14 In the somatic system, the spinal cord is segmentally organized, such that each spinal segment receives afferent information about a specific cutaneous band or dermatome (Fig. 9.1).15 This organization arises during embryonic development when the embryonic neural tube and adjacent mesodermal tissues segment into a series of rostrocaudally adjacent somites.16 Each spinal nerve innervates tissue developing from a single somite.17 Spinal nerves from several different spinal segments, such as axons from neurons with cell bodies located in several different DRG, join to give rise to peripheral nerves with cutaneous fields of innervation that span multiple dermatomes (Fig. 9.2).18 The innervation of specific peripheral cutaneous nerves, as compared to the organization of the cutaneous dermatomes, is illustrated (Fig. 9.3).

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FIGURE 9.1 The dermatomes developed by Bonica on basis of personal observation and data published by others. See text for description.

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FIGURE 9.2 Simple diagrams to illustrate the overlap of cutaneous fields of segmental and peripheral nerves. In the upper figure, three intercostal (segmental) nerves extending from the periphery to the spinal cord are represented. The lower figure illustrates a somewhat analogous but less extensive overlap in the peripheral nerves.

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FIGURE 9.3 The cutaneous fields of peripheral nerves (n). A: Anterior view. B: Posterior view. In both figures, the numbers on the trunk refer to the intercostal nerves.

Although there are many anatomic similarities between the somatic and autonomic afferent fibers, there are significant differences in the clinical presentation of visceral pain and somatic pain. Visceral pain is perceived as deep and is typically not well spatially localized. The clinical features of visceral as compared to somatic pain are summarized in Table 9.1. Pain symptoms resulting from visceral afferents are felt in a location different than the organ itself, such as the experience of arm pain with myocardial infarction.19 A possible explanation for the clinical symptoms of referred pain is that peripheral nociceptors from somatic and visceral origin converge on a single projection neuron in the dorsal horn. As a result, higher levels of the CNS cannot distinguish the source of the signal input and attribute the sensation to somatic structures by default because somatic sensory representation predominates in the CNS. Convergence occurs in the dorsal horn neurons in laminae I, IV, and V as well as in the intermediate gray matter in lamina X (Fig. 9.4)20–22 as well as other areas of the CNS including the brainstem, basal forebrain, thalamus, and cerebral cortex.23 Functional neuroimaging studies have shown that regions of the cortex that are activated by noxious stimuli can also be activated by visceral stimuli.24 In the thorax, substernal chest pain may be due to any of the visceral sensory afferents from the T1 to T6 spinal segments and may arise from the heart and great vessels, esophagus, lungs, or chest wall. Visceral pain in the abdomen tends to follow the structure of endodermal embryonic development with pain due to foregut structures (stomach, proximal duodenum, liver, biliary system, and pancreas) perceived in the epigastrium or upper abdomen, pain due to midgut structures (distal duodenum, small bowel, cecum, appendix, ascending colon, and proximal transverse colon) perceived in the periumbilical region, and pain due to hindgut structures (distal transverse colon, descending colon, sigmoid, rectum, and urinary bladder) perceived in the lower abdomen.14

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FIGURE 9.4 Schematic drawing of a cross-section of the cervical spinal cord highlighting the lamina. (Modified from Kiernan JA. Barr’s: The Human Nervous System: an Anatomical Viewpoint. 7th ed. Philadelphia: Lippincott Williams & Wilkins; 1998.)

TABLE 9.1 Comparison of Somatic and Visceral Nociceptive Pain Somatic Nociceptive Pain

Visceral Nociceptive Pain

Localization

More focused

Quality Associated symptoms

Sharp, aching, burning, stabbing Accompanied by motor reflexes

Triggers

Tissue injury

More diffuse and poorly localized; pain felt in distribution innervated by the same spinal segment as organ; referred to other locations Vague discomfort Hyperesthesia, hyperalgesia, allodynia Accompanied by motor and autonomic reflexes: associated muscle contraction/spasm, nausea/vomiting, faint sensation, circulatory changes in the region, decreased pulse/blood pressure, cold sweat Distention, contraction, ischemia, inflammation; pain not evoked from all viscera (organs such as liver and kidneys are not sensitive to pain)

The central processes of the visceral fibers synapse extensively above and below the segment where they entered, thus activating spinothalamic cells at multiple levels. Clinically, noxious stimulation of the viscera elicits an autonomic spinal reflex reaction, with sympathetic activation that causes symptoms such as excessive sweating and pronounced changes in circulatory system resulting in increased blood pressure. This reflex 506

reaction tends to be more pronounced than what is seen with noxious stimulation of the skin. Noxious visceral stimulation can also result in hypotension and bradycardia by either reflex inhibition of sympathetic outflow or activation of the parasympathetic nervous system.25 These reactions may be mediated by the periaqueductal gray matter (PAG) and the nucleus of the solitary tract. There are also protective reflexes that are directed toward reducing pain, such as the inhibition of visceral motility. Deregulation of this reflex as well as aberrant response by vagal afferents in the enteric system is thought to contribute to the pathophysiology of irritable bowel syndrome.26 Coordination centers at higher levels of the CNS, such as the PAG, also mediate nausea and vomiting as well as complex somatic responses in the context of visceral pain.

Peripheral Nervous System Structures of Pain Sensation Among the primary afferent neurons of the peripheral nervous system, there are several neuronal populations classified primarily according to caliber and myelination and secondarily according to the expression of chemical markers.27 Large myelinated fibers comprise the A-beta (Aβ) population, which respond predominantly to low-energy, nonpainful mechanical stimuli and conduct action potentials rapidly. Small, thinly myelinated fibers make up the A-delta (Aδ) population, which respond to high-energy mechanical stimuli and have intermediate conduction velocity. Small, unmyelinated fibers are classified as the C-fiber population and have slow conduction velocity.28 In general, C fibers can respond to chemical, thermal, and high-threshold mechanical stimuli, with several subclasses of C fibers exhibiting responses to various combinations of these stimulus categories.29 Typical of electrically excitable cells, the conduction of action potentials along the axons of primary afferent sensory neurons depends on voltage-gated ion channels. The inward current of the action potential is carried by voltage-gated sodium ion channels. There are six types of these in the DRG neurons of which two, Nav1.8 and Nav1.9, have expression pattern limited to sensory neurons, with Nav1.8 limited to nociceptors.30–32 507

C-fiber neurons are further subdivided into two groups. One group expresses the nerve growth factor (NGF) receptor TrkA, as well as the neuropeptides substance P and calcitonin gene-related peptide (CGRP), whereas the other group of C fibers expresses the glial derived neurotrophic factor receptor c-ret and binds to the isolectin B4 (IB4).33,34 Interestingly, recent data has demonstrated that the free nerve endings in the epidermis are anatomically structured such that the peptidergic fibers terminate in the stratum spinosum, whereas the nonpeptidergic fibers terminate in the more superficial stratum granulosum.35 This topographic separation is maintained at the level of the dorsal horn of the spinal cord, where the peptidergic and nonpeptidergic afferents terminate in distinct Rexed laminae. The peripheral terminals of DRG neurons are specialized to respond to thermal, mechanical, or chemical energy. Briefly, thermosensation depends on thermosensitive ion channels in the transient receptor potential (TRP) family, with TRPV1 and TRPV2 responsive to heat that is usually perceived as painful.36,37 Recently, a specific inhibitor of TRPV1 has been identified that may eventually prove to have a role as a pain-specific local anesthetic agent.38 Mechanosensation likely also depends on a set of mechanosensitive ion channels; however, the receptors responsible for transducing this information have yet to be unequivocally identified.39–41 A wide range of chemical mediators can also act on the peripheral terminals of DRG neurons, acting either directly to activate nociceptors or indirectly by sensitizing the peripheral terminals to be activated at a lower stimulus threshold. Chemical mediators may be either exogenous (e.g., capsaicin, mustard oil, chemical acids, bee venom) or endogenous (e.g., many of the myriad inflammatory mediators). Endogenously released chemical mediators that cause pain directly are typically associated with tissue destruction that alters the chemical microenvironment, for example, H+ ions and adenosine triphosphate, or causes an inflammatory response, such as bradykinin.42,43

Functional Anatomy of the Central Nervous System Pain is defined by not only the physiologic perception of nociception but 508

also the affective and emotional response to that perception. Pain is a highly individual and subjective experience to the extent that the same stimulus can produce different responses in different individuals under the same conditions. The CNS is both the processing center for the perception of noxious stimulation and the primary regulator of adaptive and modulatory mechanisms to produce a pain behavior. Pain is primarily categorized by duration of symptoms (acute vs. chronic) and the origin of the pain signal (visceral vs. somatic and nociceptive vs. neuropathic). Understanding the anatomy and function of the pain structures and pathways in the CNS is essential to understanding and managing the different categories of pain.

DORSAL HORN The dorsal horn represents the termination point of the dorsal root in the CNS. There is a correspondence between the functional and anatomic organization of the dorsal horn. It is arranged into 10 laminae, and distinct sensory modalities from the periphery terminate in distinct laminae (see Fig. 9.4).44 Signals conducting nociceptive signals (Aδ and C fibers) terminate in the superficially located laminae I (also called the marginal layer) and II (also called the substantia gelatinosa). Many neurons from lamina I respond exclusively to noxious stimulation and project to higher levels of the CNS. Some neurons called wide dynamic range neurons respond in a stepwise fashion to peripheral stimulation. The neurons of lamina II are mostly interneurons and modulate nociceptive responses at the level of the dorsal horn. The Aδ fibers also terminate in lamina V which contains wide dynamic range neurons that project to higher levels of the CNS including the thalamus.45 There is some convergence of somatic and visceral nociceptive input into lamina V, which may explain referred pain from visceral structures.46 Single axons of all receptors give off ascending and descending branches after entering the spinal cord. In addition to synapsing at the level they enter, these branches give off multiple collaterals that end in the gray matter of the dorsal horns at one to two levels above and below where the axon entered the spinal cord.47 Integration of signals from the periphery and higher levels of the CNS occur at the level of the dorsal horn through the dense network of dendrites 509

and interneurons. Synaptic transmission by nociceptive afferent neurons at the level of the dorsal horn is mediated primarily by the excitatory neurotransmitter glutamate. Both ionotropic and metabotropic glutamate receptors are located in high concentration in the substantia gelatinosa.48 Many neuropeptides (e.g., substance P, vasoactive intestinal polypeptide, cholecystokinin, and CGRP), which are theorized to modulate synaptic action, are present in the neurons in the dorsal horn. The receptors for most of these neuropeptides are concentrated in the substantia gelatinosa, which suggests that they are involved in the transmission of pain. Among the neuropeptides, substance P and its receptor, neurokinin 1, are likely to be involved in the processing and modulating of pain signals in the dorsal horn. Substance P may increase the excitation from incoming sensory fibers by enhancing and prolonging the actions of glutamate. This has been demonstrated experimentally: Substance P and CGRP have been found to increase the release of glutamate; substance P induces the N-methyl-Daspartate (NMDA) receptors to become more sensitive to glutamate. This unmasks normally silent interneurons and sensitizes second-order spinal neurons.49 Blocking the neurokinin 1 receptors can prevent many of these effects. Substance P can also extend long distances within the spinal cord and sensitize dorsal horn neurons several segments away from the initial nociceptive signal. This results in an expansion of receptive fields and the activation of wide dynamic neurons by nonnociceptive afferent impulses.50 Sustained noxious stimulation or high-intensity nociceptive signals to the dorsal horn neurons may lead to increased neuronal responsiveness or central sensitization.51 Hyperalgesia, which is an exaggerated perception of painful stimuli, is at least partially mediated through low-threshold mechanoreceptors (Aβ afferents) in the dorsal horn. Allodynia, which is a perception of innocuous stimuli as painful, is mediated through highthreshold nociceptors (Aδ or C fibers) in the dorsal horn. The factors that contribute to these hyperexcitable states include altered function of neurochemical and electrophysiologic systems as well as changes in the anatomy in the dorsal horn.52 “Wind-up” refers to a central spinal mechanism in which repetitive noxious stimulation results in a slow summation of these signals that is 510

experienced as increased pain.53 The amplification of the pain signal occurs in the spinal cord when nociceptive C fibers synapse on the dorsal horn nociceptive neurons activating the NMDA receptors.54 A cascade of events ensues with the activation of nitric oxide synthase.55 This ultimately leads to enhance the release of sensory neuropeptides, including substance P, from presynaptic neurons, contributing to the development of hyperalgesia and maintenance of central sensitization.56 Wind-up can be elicited if identical nociceptive stimuli are applied at a frequency of 3 seconds or less.57

SPINOTHALAMIC TRACT Prior to synapsing in the dorsal horn of the spinal cord, C and Aδ fibers may ascend or descend one to two spinal levels, forming a tract dorsal to the dorsal horn called the tract of Lissauer (Fig. 9.5); Lissauer’s tract also contains axons of interneurons that may travel for several spinal segments. Following synapsing of the central projections of C and Aδ afferents, the axons of many of the second-order neurons cross the midline, forming the lateral spinothalamic tract which ascends without interruption from the dorsal horn through the brainstem to the thalamus. This somatotopically organized tract carries information from neurons about the location, intensity, and duration of nociceptive stimuli. This tract is also responsible for relaying the sensation of temperature and, to a lesser extent, it transmits touch and pressure sensation. A large proportion of the neurons that contribute fibers to the lateral spinothalamic tract originate in lamina I. There is also a dorsally located spinothalamic tract arising ipsilaterally from lamina I neurons, although this projection of second-order nociceptive neurons is less well described.

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FIGURE 9.5 Simple diagram of the course and termination of the spinothalamic tract. Most of the fibers cross to the opposite side and ascend to the brainstem and brain, although some ascend ipsilaterally. The neospinothalamic part of the tract has cell bodies located primarily in laminae I and V of the dorsal horn, whereas the paleospinothalamic tract has its cell bodies in deeper laminae. The neospinothalamic fibers ascend in a more superficial part of the tract and project without interruption to the caudal part of the ventroposterolateral thalamic nucleus (VPL), the oral part of this nucleus, and the medial part of the posterior thalamus (PO). In these structures, they synapse with a third relay of neurons, which project to the somatosensory cortex (SI, SII, and retroinsular cortex) (solid lines). Some of the fibers of the paleospinothalamic tract pass directly to the medial/intralaminar thalamic nuclei, and others project to the nuclei and the reticular formation of the brainstem and thence to the periaqueductal gray matter (PAG), hypothalamus (H), nucleus submedius, and medial/intralaminar thalamic (MIT) nuclei. Once there, these axons synapse with neurons that connect with the limbic forebrain structure (LFS) via complex circuits and also send diffuse projections to various parts of the brain (dashed lines).

Lamina V also contributes a large group of neurons to the spinothalamic 512

tract mostly composed of Aδ fibers. The anterior spinothalamic tract, which conveys information about the location of nociception, is largely composed of fibers from laminae VII and VIII. Conversely, lamina II sends very few fibers to the spinothalamic tracts despite being the destination for many C fibers. The fibers from lamina II modulate the spinothalamic cells in laminae I, V, VII, and VIII at the level of the nociceptive input as well as at spinal segments above and below via spinal interneurons that travel in the tract of Lissauer. This complex mesh of interneurons plays a significant role in determining whether signals from nociceptors will be propagated to higher levels of the nervous system or be inhibited. Spinal interneurons modulate the intensity of a stimulus and also establish connections with other spinal neurons to form somatic and autonomic reflex arcs at the level of the spinal cord. Whereas interruption of the spinothalamic tract results in immediate loss of pain and temperature perception in the contralateral side of the body, injuries of the spinothalamic tract can develop into central pain (CP) syndromes. Nociceptive afferents from visceral organs and somatic structures terminate in the same population of spinothalamic cells in the spinal cord, which in turn synapse in the thalamus. The convergence of nociceptive signals in the spinal cord is segmentally arranged and may account for pain from visceral organs being referred to somatic structures; this topic is discussed in more detail later in the chapter. There are several other ascending tracts that supply nociceptive signals to higher levels of the CNS. The spinoreticular tract transmits nociceptive signals on the ipsilateral side of the spinal cord. This tract is clinically important as it may explain the persistence of pain after an anterior cordotomy.

THALAMUS The majority of the second-order lateral spinothalamic tract fibers terminate in the lateral nuclear group of the thalamus which contains both the ventroposterior lateral (VPL) nucleus and the ventroposterior medial (VPM) nucleus. The VPL nucleus of the thalamus receives information from the lateral spinothalamic tract, whereas the VPM nucleus receives sensory information from the spinal trigeminal nucleus, which transmits sensory information from the face (Fig. 9.6). Spinothalamic fibers also 513

terminate in areas of the intralaminar nuclei and in the mediodorsal nucleus. These fibers transmit signals to the limbic system which integrates autonomic and arousal responses and attention to the perception of pain. Many of the fibers originating in lamina I terminate in the ventromedial (VM) nucleus. Most of the neurons in VM are activated by nociceptors. Lesions of the thalamus, such as stroke, can result in severe CP syndromes on the contralateral side of the body.

FIGURE 9.6 Schematic diagram of the human thalamus. A: Superior view. B: Lateral view shows the locations of the most important nuclei. C: Frontal section of the anterior part of the thalamus depicts the relationships of various nuclei. D: Frontal section of the middle part of the thalamus. Note that the spinothalamic tract and medial lemniscus terminate in nucleus (N.) ventralis posterolateralis, whereas the trigeminothalamic tract terminates in N. ventralis posteromedialis.

With the exception of olfaction, all sensory pathways traveling from the periphery to the cerebral cortex synapse in the thalamus. The spinothalamic fibers terminate in multiple areas of the thalamus and subsequently are relayed to different areas of the cortex. VPL/VPM supplies the primary and secondary somatosensory cortex (S1, S2) with nociceptive signals. Spinothalamic fibers terminating in other areas of the thalamus influence other cortical areas, such as the insular cortex.

SENSORY CORTEX Nociceptive signals from the thalamus terminate in multiple areas of the 514

cerebral cortex and subcortical regions. The thalamic fibers project primarily to layer IV of the primary somatosensory cortex (S1) to transmit information about limb position, sense of touch, and discriminative aspects of sensation. This area of the cortex makes a limited contribution to the perception of nociception. The cortical association areas and secondary somatic sensory cortex are connected with S1 and help further process tactile information necessary for object recognition and spatial relationships. Functional imaging has demonstrated that the insula and anterior cingulate gyrus are the areas most consistently linked with nociceptive stimulation.58 The insular cortex receives direct projections from the medial thalamic nuclei as well as from the lateral nuclear group. This area of the cortex processes nociceptive information on the internal state of the body and regulates the autonomic component of the pain response. Patients with lesions of the insular cortex do not display appropriate emotional responses to pain as part of a syndrome termed pain asymbolia.59 The anterior cingulate gyrus integrates the affective component of pain. To a lesser extent, S1, the premotor cortex, the prefrontal cortex, and posterior parietal cortex are activated with nociception. In the subcortical region, the amygdala, hypothalamus, PAG, basal ganglia, and cerebellum are all activated with nociception. Although there are multiple cortical regions that play significant roles in the perception of nociception, there is enough variability in the patterns of activation that, as of yet, there is not a defined area considered to be specific for nociceptive perception.

DESCENDING PATHWAYS OF THE CENTRAL NERVOUS SYSTEM There are descending pathways from the cortex that modulate sensory impulses. For example, somatotopically organized fibers from the primary somatosensory cortex terminate in the thalamus, brainstem, and spinal cord. Descending pathways may modulate sensory signals from specific receptors and/or areas of the body. The inhibitory effects are most common and are usually transmitted through inhibitory interneurons. The sensory system is designed to react to the dynamic nature of the 515

environment. As a result, sensory signals are regulated at multiple levels of the nervous system.60 Collateral fibers from the periaqueductal gray, matter modulate both descending and ascending pain pathways. The PAG has been experimentally demonstrated to produce analgesia when stimulated and is felt to play a major role in modulating nociception at the level of the dorsal horn as well as at higher levels of the CNS.61 The PAG receives signals from limbic and cortical centers involved in the affective component of pain. The descending signal from the PAG travels through the nucleus raphe magnus (NRM) in the medulla as well as the medullary reticular formation. The serotonergic NRM fibers descend to inhibit peripheral nociceptors in the dorsal horn in laminae I and II. Clinically, this descending system blocks the spinal withdrawal reflex at the level of the dorsal horn. The PAG has ascending connections which may modulate sensory signals at the level of the thalamus. The PAG also supplies the reticular activating system responsible for arousal to painful stimuli.

CENTRAL PAIN CP is a term that includes dysesthesias, paresthesias, and even pruritus62 initiated by a lesion that interferes with the pathway of nociceptive signals within the CNS from the spinothalamic tract to the parietal somatosensory areas. CP remains an underdiagnosed condition that occurs with damage to the CNS. Studies suggest that up to 10% of all individuals who experience strokes (more correctly, cerebrovascular accidents),63 up to two-thirds of spinal cord injury (SCI) patients,64 18% of patients with multiple sclerosis, and an undefined number of patients with other neurologic conditions suffer CP.65 CP is a complex complaint with several subtypes of pain that can be moderate to severe in intensity. Patients may complain of a constant pain often described as aching, burning, pricking, dysesthesias, paresthesias, or pruritus in isolation or in combination. Most of these patients also complain of stimulus-evoked pain. Patients may complain of spontaneous episodic pain superimposed on their chronic symptoms that is most commonly characterized as lancinating.61 These uncomfortable sensations are difficult to treat and are often poorly tolerated, which leads to a 516

decrease in quality of life. Central poststroke pain was first described by Dejerine and Roussy66 in 1906 who found that thalamic stroke on one side of the brain can cause a pain syndrome affecting the contralateral half of the body. This syndrome may occur after a stroke in any location in the CNS. There are several theories as to the mechanism of central poststroke pain. Interruption of the descending inhibitory pathway, hyperexcitability of the affected afferent sensory pathways, denervation hypersensitivity, as well as loss of balance between excitatory (glutamatergic) and inhibitory (GABAergic) neurotransmitters are all possible contributors.

CENTRAL PAIN AFTER SPINAL CORD INJURY Chronic pain is a major complication of SCI, with approximately twothirds of all SCI patients experiencing some type of chronic pain and up to one-third complaining of that their pain is severe.67 The prevalence of pain after SCI often increases with time after injury.67 There are an estimated 40 cases per million population in the United States, or approximately 11,000 new individuals with SCI pain each year.68 Research suggests that chronic pain in SCI patients significantly interferes with their rehabilitation and activities of daily living and therefore reduces quality of life. Attempts to manage these pain symptoms are costly, and success is often limited.69 In addition to CP, there are multiple types of pain that develop after SCI including musculoskeletal, visceral, and peripheral neuropathic pain. The etiology of pain in SCI is multifaceted and the various types of SCI pain differ with regard to clinical findings, pathophysiology, and therapy. The mechanisms involved in the development of CP after SCI are not fully elucidated, but continuing research has identified possible mechanisms for pain generation. CP has been reported with injury to all levels of the spinal cord.70 CP is a common sequelae of SCI. It has many descriptors; it is often characterized by patients as a continuous burning, shooting, aching, and tingling. The distribution of pain is usually bilateral and can involve multiple adjacent dermatomes or be regional in nature. In addition, many patients with SCI report feeling the phantom phenomenon of their body 517

below the lesion, and it is described in a distorted fashion. This occurs despite most patients having no conscious appreciation of sensory input below the spinal cord lesion.71 Central neuropathic pain after SCI has been categorized based on the location of the complaint as either at the level of the injury or below the level of the injury. Although it may be difficult to distinguish the two clinically (and both may be present in the same patient), CP that occurs at the level of injury is due to segmental spinal cord damage, not nerve root damage. CP that occurs at the level of injury can be within two dermatomal levels either above or below the level of injury.72 CP associated with SCI may also be caused by syringomyelia.71 Physiologic changes occur to the nociceptive neurons in the dorsal horn following SCI, including an increase in abnormal spontaneous and evoked discharges from dorsal horn cells.73,74 Noxious stimulation causes primary afferent C fibers to release excitatory amino acid neurotransmitters in the dorsal horn. Prolonged high-intensity noxious stimulation activates the NMDA receptors, which induces a cascade that may result in central sensitization.75 The cascade includes upregulation of neurokinin receptors and activation of the intracellular cyclo-oxygenase-2, nitric oxide synthase, and protein kinase C enzymes.76 Other neuroanatomic and neurochemical changes thought to impact CP in SCI include alteration in the activity of the neurotransmitter glutamate,77 interruption of descending inhibitory pathways,78 and dysfunction of the inhibitory GABAergic interneurons,79 all at the level of the dorsal horn. On a molecular level, abnormal sodium channel expression within the dorsal horn (laminae I to VI) bilaterally has been implicated as a major contributor to hyperexcitability. Thalamic neurons appear to undergo changes after SCI in both human and animal models. In the animal model, enhanced neuronal excitability in the VPL has been demonstrated directly80 as well as indirectly; enhanced regional blood flow has been found in the rat VPL after SCI, suggesting increased neuronal activity.81 Magnetic resonance spectroscopy studies have demonstrated changes in metabolism of the neurons in human thalamus associated with pain in SCI.82 Much like the neurons in the dorsal horn, the thalamic neurons after SCI show increased activity with noxious and nonnoxious stimuli. VPL neurons are spontaneously hyperexcitable following SCI without receiving input from the spinal cord 518

neurons suggesting that the thalamus may act as a pain signal generator in CP accompanying SCI.71 There is emerging evidence that cortical reorganization may play a role in the development of phantom symptoms after loss of limbs, but little evidence of the cortical mechanisms at work with the development of phantom phenomena after SCI.83 The full spectrum of anatomic, chemical, and physiologic changes contributing to central neuropathic pain after SCI is still being elucidated.

Autonomic Nervous System At the turn of the 20th century, the Cambridge physiologist John Newport Langley84 coined the term “autonomic nervous system” (ANS) to describe the portion of the nervous system that mediated the unconscious function of the internal organs. Soon afterward, the concept of two distinct components of the ANS, the sympathetic and parasympathetic systems, which antagonize each other to maintain homeostasis, was developed. The enteric system is also recognized as being a distinct part of the ANS. In addition to regulating the activity of visceral organs, vessels, and glands, the ANS has been found to play an active role in many pain states. Understanding the complexity of the pain–ANS interaction is essential to physicians managing all types of pain. The anatomy of the ANS with the current understanding of the interrelationship between these structures is shown in Figure 9.7. The ANS is composed of peripheral and central portions.

FIGURE 9.7 Ganglia of the peripheral autonomic nervous system.

PERIPHERAL AUTONOMIC NERVOUS SYSTEM The peripheral efferent pathways of both the sympathetic and 519

parasympathetic nervous system have two components: a primary presynaptic or preganglionic neuron and a secondary postsynaptic or postganglionic neuron. Unlike the somatic motor system which has its motor neurons in the CNS, the motor neurons of the ANS are located in the periphery. As such, the transmission of autonomic signals from the CNS synapses at ganglia in the periphery prior to reaching the target organ (Fig. 9.8). The different locations of the cell bodies of the primary preganglionic neurons of the different divisions of the ANS are discussed later.

FIGURE 9.8 Transmitter substances in the peripheral autonomic nervous system. (Modified by permission from Springer: Jänig W. The autonomic nervous system. In: Schmidt RF, Thews G, eds. Human Physiology 1st ed. Berlin: Springer-Verlag; 1983:111–144. Copyright © 1983 SpringerVerlag Berlin · Heidelberg.)

The cell bodies of the postganglionic neurons are arranged in aggregates known as ganglia, wherein the synapses between pre- and postganglionic neurons are located. As shown in Figure 9.7, there are four general groups of these ganglia, two within the sympathetic division and two within the parasympathetic division. A typical feature of the ANS is that postganglionic fibers form nerve plexuses around their target organs composed of both sympathetic and parasympathetic fibers. Unlike their somatic efferent counterparts, the postganglionic fibers branch extensively, forming a network in the vicinity of their effector cells allowing one fiber to act on several effector cells.

PARASYMPATHETIC DIVISION 520

The parasympathetic preganglionic fibers travel from the CNS to synapse in ganglia located close to their target organs. In most areas, parasympathetic innervation tends to be more precise than sympathetic innervation. Parasympathetic fibers generally innervate visceral organs. Table 9.2 summarizes parasympathetic nerve supply to essential body structures. TABLE 9.2 Summary of Parasympathetic Nerve Supply to Essential Body Structures Parasympathetic Nerve Supply

Region/Structure/Organ Head and Neck Eye

Lacrimal gland Parotid gland Submandibular and sublingual glands Thoracic Viscera Heart Trachea, bronchi, and lungs

Abdominal Viscera Stomach

Pancreas

Location of Cell Body/Preganglionic Neurons in the Central Nervous System

Site of Synapse of the Preganglionic with Postganglionic Neurons

Action

Parasympathetic oculomotor nucleus/EdingerWestphal nucleus Superior salvatory nucleus Inferior salvatory nucleus Superior salvatory nucleus

Ciliary ganglion

Submandibular ganglion

Secretion

Dorsal motor vagus nucleus Dorsal motor vagus nucleus

Cardiac plexus

Decreased heart rate and cardiac output Constriction of bronchial muscles and increased glandular secretion

Dorsal motor vagus nucleus

Gastric plexus

Dorsal motor vagus nucleus

Periarterial plexus

Pelvic Viscera

521

Pterygopalatine nucleus Otic ganglion

Pulmonary plexus

Pupillary constriction, accommodation for near vision Secretion Secretion

Increased motility and secretion, relaxed sphincter Dilation of blood vessels and increased secretion

Ureter

Sacral cord S3–S4

Pelvic plexus

Bladder

Sacral cord S3–S4

Pelvic plexus

Increased tone and motility Contracted detrusor muscle

CRANIAL PARASYMPATHETICS The preganglionic parasympathetic neurons have their cell bodies in the gray matter of the brainstem, and their fibers travel with the oculomotor, facial, glossopharyngeal, and vagus nerves (Fig. 9.9). The preganglionic fibers from the oculomotor, facial, and glossopharyngeal nerves synapse in the ciliary, sphenopalatine, otic, and submaxillary ganglia, all of which are located in the head. From these ganglia, the postganglionic fibers travel to the target organs (e.g., the lacrimal and salivary glands).

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FIGURE 9.9 Schematic representation of autonomic pathways in the neuraxis and the efferent peripheral pathways. Note the connection among the various hypothalamic nuclei and between these structures and the nuclei and important autonomic centers in the brainstem and spinal cord. The dorsal longitudinal fasciculus (DLF) passes from the hypothalamus caudad through the central and tegmental portion of the mesencephalon and the tegmental portion of the pons to terminate in the reticular formation, the autonomic centers and cranial nerve nuclei in the brainstem, and in the intermediolateral cell column of the spinal cord. The DLF is composed of both crossed and uncrossed fibers, including some long ones and an extensive system of short fibers, which are arranged in the gray matter in frequent relays. Note also that the cell bodies of preganglionic sympathetic neurons are located only in spinal cord segments T1–L2, whereas the parasympathetic neurons are located in cranial nerves and in S2, S3, and S4. The solid lines represent preganglionic fibers, the dashed lines represent postganglionic fibers, and the dotted lines are afferent (sensory) fibers. Not shown are the sensory fibers contained in the facial, glossopharyngeal, and vagus nerves, which transmit nociceptive and other somatosensory information from the head.

The preganglionic parasympathetic fibers in the vagus nerve descend 523

from the brainstem to terminate in visceral organs. In the abdomen, many of these fibers synapse in a diffuse network of postganglionic neurons to form a plexus within the wall of the gastrointestinal tract. The postganglionic neurons within this plexus send short processes to innervate the smooth muscles and glands in the gastrointestinal tract. In the thorax, the vagus nerve supplies parasympathetic innervation to the heart (via the cardiac plexus) and airways. In the heart, the sinus node and atrioventricular node have significant parasympathetic innervation. This is in contrast to the ventricles, which are supplied with dense sympathetic innervation.85

SACRAL PARASYMPATHETICS The sacral portion of the parasympathetic system consists of preganglionic neurons which have their cell bodies in the intermediolateral column of the gray matter of the S2–S4 spinal segments (see Figs. 9.9 and 9.10). The preganglionic fibers travel via the ventral roots to the corresponding spinal nerves for a short distance and then form the pelvic splanchnic nerves. These nerves form the pelvic plexuses which are in close proximity to the target organs (rectum, bladder, prostate gland in the male, cervix in the female). Many of these preganglionic fibers synapse in the plexus, whereas other fibers pass through the plexus without interruption and terminate in intramural ganglia of their target organs (e.g., urinary bladder, descending colon, sigmoid colon and rectum, and genital organs). All of the pelvic organs are innervated by postganglionic parasympathetic fibers. These fibers play an essential role in eliminating waste products from the bladder and rectum.86

524

FIGURE 9.10 Distribution of peripheral autonomic nervous system to various structures of the body. On the reader’s right are shown (from above downward) the four cranial nerves which contain preganglionic parasympathetic fibers, the axons of preganglionic sympathetic fibers (which pass from the anterior root to the paravertebral sympathetic chain), and the parasympathetic preganglionic axons in S2, S3, and S4. Note that the axons of all of the preganglionic sympathetic neurons pass via the white rami communicantes into the paravertebral chain, in which some synapse with postganglionic neurons, whereas others pass to the prevertebral sympathetic ganglia, in which they synapse with postganglionic fibers. On the reader’s left are depicted the gray rami communicantes, containing postganglionic sympathetic fibers, which originate in the paravertebral chain and then pass to each of the spinal nerves to innervate blood vessels, hair follicles, and sweat glands in various parts of the body.

SYMPATHETIC (THORACOLUMBAR) DIVISION The peripheral sympathetic nervous system is composed of efferent and afferent fibers. The efferent portion of the sympathetic division of the ANS 525

consists of preganglionic neurons, the two paravertebral (lateral) sympathetic chains, prevertebral and terminal ganglia, and postganglionic neurons (see Figs. 9.9 and 9.10).87,88

Sympathetic Preganglionic Neurons The cell bodies of the efferent preganglionic neurons are located in the intermediolateral column in the spinal cord from T1 to L2. The efferent fibers of these preganglionic neurons travel from the spinal cord into the periphery through the ventral roots accompanying the somatic fibers at these levels at the thoracolumbar spine. From this point, the preganglionic neurons diverge to provide inputs to ganglia in multiple locations. Each preganglionic fiber synapses on multiple postganglionic cells, thus serving to amplify the sympathetic outflow from the CNS.89 Some of the sympathetic fibers leave the spinal nerve immediately after the ventral and dorsal roots fuse to form the white communicating ramus which synapses with postganglionic neurons in the sympathetic ganglia outside the neuraxis (see Fig. 9.10). The white rami are usually present only in the thoracic and upper two or three lumbar segments corresponding to the location of the intermediolateral column in the spinal cord (see Fig. 9.10). The white color of the rami is a result of the sympathetic fibers being myelinated. The peripheral ganglia of the sympathetic nervous system are located close to the CNS. These paravertebral ganglia are segmentally arranged in two sympathetic trunks, each of which is a vertical row along the anterior margin of the vertebral column. Each trunk is composed of a longitudinal network of ganglia connected to each other by ascending and descending nerve fibers that extend the entire length of the spinal column. As each spinal segment develops in the embryo, one sympathetic ganglion is formed for every level on each side. Some of these ganglia fuse, so the final number of ganglia is usually less than the number of spinal segments.90 This is most prominent in the cervical region where only the superior, middle, intermediate, and inferior cervical ganglia are present for seven cervical vertebrae. The middle cervical ganglion is often not present, and the inferior cervical ganglion commonly fuses with the upper thoracic ganglion forming the stellate ganglion. The cephalic end of the 526

paravertebral ganglia continues beyond the cervical spine, traveling along the carotid nerve to eventually distribute sympathetic fibers within the head. The caudal end of the two trunks converges and terminates in front of the coccyx as the ganglion impar.87 The paravertebral sympathetic ganglia are connected by interganglionic fibers forming the lateral sympathetic chain, which extends from the skull to the coccyx. On entering the sympathetic chain, some preganglionic axons synapse in the ganglia at the spinal level they exited the neuraxis. Other preganglionic fibers pass uninterrupted cephalad or caudad within the sympathetic trunk before they synapse to ensure that preganglionic fibers synapse at all levels of the sympathetic trunk. Some preganglionic sympathetic fibers pass uninterrupted through the sympathetic chain to form splanchnic nerves that synapse within one of the prevertebral ganglia that are found at the junction of the celiac and mesenteric arteries and the abdominal aorta. The postganglionic fibers that travel from the prevertebral ganglion tend to follow arteries within the abdomen to their target organs. The greater and lesser splanchnic nerves are formed from preganglionic fibers from the T6 to T10 levels, pass through the sympathetic chain without synapsing, and terminate in ganglia that innervate the abdominal viscera in the upper and middle part of the abdomen. Splanchnic nerves also contribute preganglionic fibers to the adrenal medulla. These fibers synapse within chromaffin cells, which are homologous to postganglionic neurons but release epinephrine into the bloodstream with sympathetic stimulation.91

Sympathetic Postganglionic Neurons The axons of the postganglionic neurons travel via multiple pathways into the periphery. Some of the postganglionic neurons which have their cell bodies in the paravertebral chain reenter the spinal nerves via the gray communicating ramus, which, in distinction to the white rami, has a gray color because most of these postganglionic fibers are unmyelinated. Postganglionic sympathetic neurons from gray rami communicans travel in all spinal nerves. These postganglionic sympathetic fibers follow the spinal nerves into somatic areas innervating various somatic, sudomotor, and pilomotor structures, such as the sweat glands and smooth muscle fibers in 527

hair follicles in the skin. The axons of other postganglionic neurons, which have their cell bodies in the paravertebral chain, travel largely along arteries to pass to the thoracic and pelvic viscera. This is in contrast to the preganglionic neurons that pass uninterrupted to the prevertebral ganglia via the greater and lesser splanchnic nerves and are distributed to the viscera in the upper and middle part of the abdomen. The visceral organs in the lower abdomen receive their sympathetic innervation from the lumbar splanchnic nerve which also synapses in prevertebral ganglia. The celiac ganglia is usually the largest of the prevertebral ganglia, and it surrounds the celiac artery at its juncture with the aorta. The sympathetic innervation of the heart originates in the cervical and thoracic ganglia and travels via the cardiac nerves to the heart. Table 9.3 summarizes the autonomic and nociceptive pathways to various body structures. TABLE 9.3 Summary of Sympathetic and Nociceptive Nerve Supply to More Important Body Structures Sympathetic Nerve Supply

Region, Structure Head and Neck Meninges and arteries of brain

Eyeb

Lacrimal glandb

Parotid glandb

Location of Cell Body in Spinal Cord and Course of Preganglionic Neurons

Site of Synapse of Preganglionic with Postganglionic Neurons

Course of Postganglionic Axons

All cervical Plexuses around T1, T2, (T3)a sympathetic internal carotid and To and through ganglia vertebral arteries cervical sympathetic chain T1, T2, T3, (T4) Superior Internal carotid and To and through cervical cavernosus plexuses cervical ganglion and → ciliary ganglion sympathetic ganglia in or nasociliary nerve chain internal → ciliary nerves or carotid plexus along ophthalmic artery T1, T2 Superior Internal carotid plexus To and through cervical → vidian nerve → cervical sympathetic sphenopalatine sympathetic ganglion ganglion → ganglia maxillary nerve → zygomatic/lacrimal nerves As above All cervical External carotid plexus sympathetic → internal ganglia maxillary and middle meningeal plexus → to

528

Nociceptive Pathways

Location of Primary Afferent Pathway

Entrance into Central Nervous System

Cranial nerves (CN) V, IX, X C1–C3

Trigeminal subnucleus caudalis C1– C3 spinal segments Ophthalmic branch Trigeminal of CN V subnucleus caudalis

Lacrimal nerve → ophthalmic branch of CN V

As above

Parotid nerve → As above auriculotemporal nerve of mandibular division of CN

Submandibular As above and sublingual glandsb

As above

Thyroid gland

As above

Middle and inferior cervical sympathetic ganglia

Blood vessels of skin and somatic structures Sweat glands Hair follicles

T1–T4 To and through cervical sympathetic chain

All cervical sympathetic ganglia

Thoracic Viscera Heart T1–T4, (T5) To upper thoracic and cervical sympathetic chain Larynx

T1, T2 To and through cervical sympathetic chain Trachea, bronchi, T2–T6, (T7) and lungs To upper thoracic sympathetic chain Esophagus T2–T4 Cervical To and through upper thoracic sympathetic chain Thoracic T3–T6 To and through upper thoracic sympathetic chain Abdominal T5–T8 To thoracic sympathetic chain— superior thoracic

auriculotemporal nerve and plexus and to the parotid arterial plexuses External carotid plexus → facial plexus → submandibular ganglion → direct glandular filaments or via lingual nerves or directly to glands along vessels Perivascular sympathetic plexuses accompanying superior and inferior thyroid arteries In perivascular plexuses accompanying various branches of external and internal carotid arteries

V

Submandibular As above branch of lingual nerve → mandibular division of CN V

Afferents accompanying sympathetic pathways

T1 and T2 spinal cord segments

Afferents accompanying sympathetic nerves CN V, IX, X C2–C4

T1–T4 spinal cord Subnucleus caudalis C2–C4 spinal cord segments

All cervical and Superior, middle, and upper four inferior cervical (five) thoracic cardiac nerves and ganglia the four (five) thoracic cardiac nerves → cardiac plexuses Superior Laryngeal branch of cervical superior cervical ganglion ganglion → superior laryngeal nerve

Afferents in middle T1–T4 (T5) and inferior cervical cardiac and the thoracic cardiac nerves

Superior laryngeal nerve

Trigeminal subnucleus caudalis

T2–T6, (T7) Sympathetic ganglia

Pulmonary branches from sympathetic trunk → pulmonary plexuses

Afferents with sympathetics Afferents with vagus

T2–T6, (T7) Nucleus tractus solitarius (medulla)

All cervical sympathetic ganglia and pharyngeal plexus

From cervical ganglia to recurrent laryngeal nerve

Afferents in vagus Afferents with sympathetics

Nucleus tractus solitarius T2–T4 (?)

Stellate and Direct esophageal upper thoracic branches and ganglia through cardiac sympathetic nerves

Afferents with vagus Afferents with sympathetics

Nucleus tractus solitarius T3–T6 (?)

Celiac ganglia

Afferents with sympathetics Afferents with vagus

T5–T8 Nucleus tractus solitarius

Via plexuses around left gastric and inferior phrenic arteries

529

Thoracic aorta

splanchnic nerve T1–T5, (T6) To thoracic sympathetic chain

Abdominal Viscera Abdominal aorta T5–L2 Some through splanchnic nerves and direct branches Stomach and (T5), T6–T9, duodenum (T10), (T11) Superior (greater) and middle (lesser) thoracic splanchnic nerves and celiac plexus Gallbladder and (T5), T6–T9, bile ducts (T10) Superior thoracic (greater) splanchnic nerves and celiac plexus Liver (T5), T6–T9, (T10) Superior thoracic (greater) splanchnic nerves and celiac plexus Pancreas (T5), T6–T10, (T11) Superior thoracic (greater) splanchnic nerves and celiac plexus Small intestines T8–T12 (right side) T8–T11 (left side) To superior (greater) and middle (lesser) thoracic splanchnic nerves to celiac plexus

Synapse upper five (six) thoracic sympathetic ganglia

Branches from cardiac sympathetic nerves and direct fibers from thoracic sympathetic chain

Afferents with sympathetic pathways

T1–T5, (T6)

Celiac ganglia and paravertebral sympathetic chain

Fibers that contribute to the aortic plexus

Afferents associated with sympathetics

T5–L2

Celiac ganglia

Right and left gastric and gastroepiploic plexuses

Afferents with sympathetics

(T5), T6–T9, (T10), (T11)

Celiac ganglia

Hepatic and gastroduodenal plexuses

Afferents associated with sympathetics

(T5), T6–T9, (T10)

Celiac ganglia

Hepatic plexus

Afferents associated with sympathetics

(T5), T6–T9, (T10)

Celiac ganglia

Direct branches from celiac plexus and offshoots from splenic, gastroduodenal, and pancreaticoduodenal plexuses

Afferents associated with sympathetics

T5–T10, (T11)

Celiac and superior mesenteric ganglia

Superior mesenteric plexus → nerves alongside jejunal and ileal arteries

Follow sympathetic pathways through celiac and inferior mesenteric plexuses

(T8), T9, T10 T10, T11

530

Cecum and appendixb

Colon to splenic flexureb

Splenic flexure to rectumb

Suprarenal (adrenal) glandsb

Kidneysb

T10–T12 Superior (greater) and middle (lesser) thoracic splanchnic nerves → celiac and superior mesenteric plexuses T10–L1 Middle (lesser) and inferior (least) thoracic and first lumbar splanchnic nerves

Celiac and superior mesenteric ganglia

Nerves alongside ileocolic artery

Accompanying sympathetic pathways

T10–T12

Superior and inferior mesenteric ganglia

Mesenteric plexus → nerves alongside right, middle, and superior left colic arteries

L1, L2 (left side) S2–S4 Lumbar and sacral splanchnic nerves → inferior mesenteric and inferior hypogastric pelvic plexuses (T7), T8–L1, (L2) Superior (greater), middle (lesser), and inferior (least) thoracic splanchnic nerves and first (second) lumbar splanchnic nerves T10–T12, L1, (L2) Middle (lesser) and inferior (least) thoracic splanchnic nerves and first (second) lumbar splanchnic

Inferior mesenteric ganglion and ganglia in superior and inferior hypogastric plexuses

Nerves alongside inferior left colic and rectal arteries

Associated with T10–L1 sympathetics, pass through superior and inferior mesenteric plexuses and splanchnic nerves and to spinal cord Afferents with S2–S4 parasympathetic nerves and pudendal nerves

Chromaffin cells Within the gland of adrenal medulla

Celiac and aorticorenal ganglia

Along renal plexus

531

Accompanies sympathetic pathways

T10–L12, (L1, L2)

nerves → celiac and renal plexuses b T(10), T11, Celiac and Ureters T12, L1, L2 aorticorenal Upper two-thirds Middle and ganglia inferior thoracic splanchnic and upper two lumbar splanchnic nerves Ureters T11–L1, S2–S4 Aorticorenal Lower one-third ganglion and sacral sympathetic ganglia Pelvic Viscera Bladder

Uterus

Testes, ductus deferens, epididymis, seminal vesicles, prostate

(T11), T12, L1, Inferior L2 mesenteric Middle and ganglion and inferior sacral thoracic paravertebral splanchnic ganglia nerves (T6–T9), T10– Celiac ganglion T12, L1, (L2) and various Splanchnic paravertebral nerves to ganglia aortic and ovarian plexuses and superior and inferior hypogastric plexuses T10–L1 Prevertebral inclusive ganglia and Splanchnic inferior nerves → mesenteric aortic and ganglion superior hypogastric plexus

Superior mesenteric and renal plexuses → superior and middle ureteric nerves

Associated with sympathetics

Aortic, superior hypogastric, and inferior hypogastric (pelvic) plexuses and sacral splanchnic nerves

Accompany T10–T12 sympathetic and parasympathetic nerves

Superior and inferior hypogastric plexuses and sacral splanchnic nerves to vesical plexus

Predominantly S2–S4 afferents of parasympathetic nerves; also some sympathetic afferents Accompanying T11–L2 sympathetic pathways

Lumbar and sacral splanchnic nerves; superior, middle, and inferior hypogastric plexuses → uterine plexus

Follow various vascular plexuses in sacral splanchnic nerves

Trunks and Limbs (Innervation of Vessels, Sweat Glands, and Hair Follicles) Trunk T1–T12 T1–T12 Gray rami paravertebral communicantes → sympathetic thoracic spinal ganglia nerves Upper T2–T8, (T9) Middle and Gray rami extremities To and through stellate communicantes to upper ganglia; T2 roots of brachial thoracic and and T3 plexus → brachial lower cervical ganglia plexus and its major sympathetic nerves; some chain directly to plexuses around subclavian, axillary, and upper

532

T10–T12, (L1, L12)

Testes (ovaries) Prostate Parasympathetic afferents

T10 S2–S4

Primary afferents in spinal nerves

T2–L1

Brachial plexus and its branches

C5–T1

Lower extremities

aSegments bUnilateral

T10–T12, L1, L2 To and through lumbar and upper sacral sympathetic chain

L1–L5, S1–S3 paravertebral ganglia

brachial arteries Gray rami communicantes → lumbosacral plexus and its major nerves; direct branches to perivascular plexuses as far as upper femoral artery

Lumbosacral plexus

L1–S3

in parentheses are inconstant. innervation.

In addition to the gray rami, the sympathetic trunks give off postganglionic rami that supply the viscera of the head, chest, and abdomen. These rami include the carotid nerve; the superior, middle, and inferior cardiac nerves; the superior, middle, and inferior thoracic splanchnic nerves; and the lumbar and sacral splanchnic nerves. Some preganglionic fibers synapse in the intermediary ganglia in the white communicating rami, ventral nerve roots, or the spinal nerves outside of the sympathetic chain.87,88 These anomalous sympathetic pathways are most commonly found in the sympathetic trunk at the cervicothoracic juncture and the thoracolumbar juncture.92–94 These pathways explain why surgical interruption of the sympathetic chain may not completely block sympathetic outflow. Conversely, these anatomic variations often respond to sympathetic blockade with a local anesthetic solution because it diffuses locally to affect these pathways.92 A sympathetic block can therefore be a poor predictor of the efficacy of surgical sympathectomy. In cases of incomplete sympathectomy, a postsurgical sympathetic block that produces complete interruption of sympathetic outflow and pain relief in sympathetically dependent pain syndromes may suggest the presence of anomalous sympathetic ganglia.92,93 Sympathetic postganglionic neurons may be involved in the generation of pain, hyperalgesia, and inflammation in disease. Depending on the extent of the peripheral nerve lesion, plastic changes can occur at multiple levels of the ANS. Release of mediators (e.g., epinephrine, norepinephrine) from efferent sympathetic nerves both locally and systemically and upregulation of adrenoreceptors in nociceptive afferents contribute to the increased excitability of nociceptors and changes in local 533

vasomotor and sudomotor activity.95 This reorganization of the peripheral neurons may lead to chemical coupling between sympathetic and afferent neurons. This may be responsible for sensitization and/or activation of primary afferent neurons by the sympathetic neurons.96

SENSATION IN VISCERAL ORGANS Visceral afferent fibers convey sensory information from the internal organs to the CNS. Sensory fibers from viscera follow autonomic nerves as they travel centrally; the majority of the fibers conducting nociceptive information travel along sympathetic nerves. The neurons of visceral afferent fibers are structurally similar to somatic afferent fibers and, like their somatic counterparts, have cell bodies in the DRG of spinal nerves. Their central processes pass to the spinal dorsal horn, primarily in laminae I and V, and from there, visceral information travel centrally via dorsal column pathways as well as by the spinothalamic and spinoreticular tracts. At the level of the dorsal horn, some primary afferents make synaptic connections with somatic motor neurons, whereas others synapse with preganglionic neurons in the intermediolateral cell column, thus mediating complex visceral reflexes. These reflexes usually involve alteration of the function of the viscera, increase in skeletal muscle tension, and increase in sympathetic activity. Visceral afferent fibers mediate reflexes such as coughing, cardiopulmonary reflexes, and emptying of the bladder. Most of the visceral receptors are free nerve endings with large receptive fields that are able to respond to varied stimuli. The receptors responsible for transmitting nociceptive signals are largely chemoreceptors that are sensitive to changes that disrupt the internal milieu such as ischemia, inflammation, or the presence of an irritant (e.g., bile, blood). Indeed, in inflammatory diseases of the viscera, such as Crohn’s disease or ulcerative colitis, the peripheral nerve endings may become essentially engulfed in the inflammatory infiltrate that invades the mucosa. The visceral afferent fibers are sensitive to distension and contraction, not cutting or tearing of tissue like the somatic afferents. Although visceral sensations are for the most part not consciously perceived, nociceptive information is transmitted. These fibers also transmit information about the immune 534

system and contribute to the development of fever in the presence of infection.89,97 Cervical spinothalamic cells receive input from cardiothoracic afferent fibers and transmit the information to autonomic and nociceptive centers higher in the CNS; these afferent fibers also activate propriospinal pathways in the cervical spine that modulate visceral input from lower levels of the spine.98

AUTONOMIC CENTERS IN THE CENTRAL NERVOUS SYSTEM Unlike the peripheral ANS, distinctions between the somatic and autonomic structures and pathways are often difficult in the CNS. The cortex is the central integration center for both somatic and vegetative functions. Multiple cortical structures have been identified as playing a role in the pain–ANS interaction. The insula, in addition to being associated with the limbic system, is the primary cortex for the viscerosensory system and is involved in the discriminative aspect of pain sensation. It plays a role in the subjective experience of pain and has connections with multiple centers (amygdala, lateral hypothalamus, etc.) involved with autonomic outflow.99,100 The anterior cingulate cortex receives nociceptive inputs and maintains broad connections with multiple areas of the central autonomic network. In addition to being included as part of the limbic system and being involved in goal related behavior, it plays an essential role in affective and motivational components of pain.101 Surgical stimulation of this region elicits a range of autonomic responses.102 The amygdala is composed of several nuclei with distinct functional properties. It plays an essential role in modulating the ANS and is closely linked to the hypothalamus. The amygdala plays a role in the subjective perception of pain as well as expression of emotional response to pain.103 The PAG is a complex region of the CNS that has distinct anatomic and functional regions. Different areas of the PAG receive sensory information and help integrate and regulate autonomic responses to these signals and modulate the sympathetic nervous system in analgesia.104 The PAG receives sensory signals from laminae I and V of the dorsal horn and helps regulate responses to cardiovascular and 535

nociceptive input. There are several autonomic centers in the brainstem that have been physiologically delineated. In addition to regulating vital functions such as breathing and circulation, aggregates of neurons in the medullary and pontine reticular formation regulate the ANS through ascending and descending tracts. In the medulla, the nucleus of the solitary tract is a control center of vegetative functions and also appears to contribute antinociceptive input to the dorsal horn.24 The parabrachial nucleus integrates nociceptive and visceral information through its extensive connections with the medulla, hypothalamus, and amygdala to maintain homeostasis. The autonomic centers in the brainstem give rise to the parasympathetic visceral efferent fibers of the cranial nerves.105 The spinal cord is a central area of integrating the somatic and autonomic functions. Through spinal reflexes, somatic nociception can exert a major impact on the autonomic system. Noxious stimulation to the skin induces a cascade of sympathetic responses, including increased sweat production and skin vasomotor responses.106 The location of the preganglionic neurons for the sympathetic and parasympathetic nervous systems in the CNS differ. The sympathetic preganglionic neurons are located in the T1–L2 spinal segments of the spinal cord. The parasympathetic preganglionic neurons are located in the brainstem and the S2–S4 spinal segments (see Figs. 9.9 and 9.10). The locations of the cell bodies of preganglionic sympathetic and parasympathetic neurons, which mediate their function in various parts of the body, are listed in Table 9.4. There are essential differences between the ganglia these neurons form. The sympathetic ganglia are distributed widely throughout the body, are located close to the CNS, and use epinephrine as the primary neurotransmitter. In contrast, the parasympathetic ganglia largely innervate visceral organs, which they are in close proximity to, and use acetylcholine as a neurotransmitter. Figure 9.9 depicts the autonomic pathways that connect the preganglionic neurons in the intermediolateral horn of the spinal cord with the hypothalamus and other brainstem structures. TABLE 9.4 Autonomic Centers (AC) in Spinal Cord 536

Structure

Location of AC in Spinal Cord

Head and neck Upper limb Upper trunk Lower trunk Lower limb Viscera Thoracic (sympathetic) Abdominal (sympathetic) Pelvic (parasympathetic)

T1–T4 T2–T8/T9 T2–T8 T9–L2 T10–L2 T1–T5 T5–L2 S2–T4

TRANSMISSION IN THE PERIPHERAL AUTONOMIC NERVOUS SYSTEM The majority of preganglionic neurons in the ANS are cholinergic, as are some sympathetic postganglionic neurons, such as sweat glands. Acetylcholine binds nicotinic receptors in the membrane of postganglionic neurons. Postganglionic parasympathetic neurons also release acetylcholine, which binds to muscarinic receptors in effector organs (e.g., cardiac and smooth muscle, glandular cells). There are drugs that selectively block each of these receptors (see Fig. 9.8). Norepinephrine is the transmitter substance in the majority of sympathetic postganglionic nerve endings. The response of the effector cells is mediated by two types of receptors: the α- and β-adrenergic receptors. These receptors have different effects at different organs. For example, in the heart, norepinephrine binding to a β receptor causes an increase in heart rate, whereas in the bladder and airways, this same process causes a relaxation of smooth muscle cells. A variety of pharmacologic agents can either enhance or block the action of these receptor subtypes. The cells in the adrenal medulla, which are homologues of the postganglionic neurons, mainly release epinephrine into the bloodstream with sympathetic stimulation. Although it has many of the same effects as norepinephrine, epinephrine stimulates the β receptors in the fat and liver cells accelerating metabolism of fat and glucose. There are other neurotransmitters in the ANS. Most preganglionic neurons contain neuropeptides (enkephalin, somatostatin) of unclear functional purpose in addition to acetylcholine. Some autonomic neurons 537

do not contain either acetylcholine or norepinephrine. These are primarily located in the gastrointestinal tract.

PHYSIOLOGY OF THE AUTONOMIC NERVOUS SYSTEM The ANS regulates activities that are required for maintenance of the internal environment of an organism but which are not normally under voluntary or conscious control. This includes modulating functions such as metabolism, circulation, respiration, body temperature, digestion, sweating, circadian rhythm, and endocrine secretion. The ANS coordinates these physiologic processes to maintain homeostasis,107 such as the constancy of the internal environment. The effects of stimulating either portion of the ANS and its impact on various organs, visceral structures, and effector cells are summarized in Table 9.5. The sympathetic nervous system is focused on catabolic function and mobilizing the body’s resources. In contrast to the sympathetic nervous system, the parasympathetic function is anabolic and dedicated to regulating functions that maintain an organism over the long term. Through regulation of the enteric system, it conserves and stores energy, it plays a central role in coordinating the muscular contraction of the bladder and rectum to eliminate waste products, and it maintains the basal heart rate and respiration under normal conditions.90 TABLE 9.5 Physiologic Responses to Autonomic Stimulation Structures/Organs Eye Ciliary muscle

Pupillary muscles Dilator Sphincter Lacrimal gland Salivary glands Parotid

Sympathetic Stimulation

Adrenergic Receptors

Parasympathetic Stimulation

Relaxed for far vision

β

Contraction (accommodation for near vision)

Dilated (mydriasis) — —

α

— Contraction (miosis) Secretion

Sparse, thick secretion

α

Profuse serous secretion

Sublingual

538

Submaxillary Thyroid gland Tracheobronchial tree Bronchial muscles Bronchial glands Heart Rate Output Esophagus Motility Sphincters Stomach Motility Sphincters Secretion Liver Gallbladder and biliary ducts Pancreas Blood vessels Insulin secretion Spleen Intestines Motility Sphincters Secretion Adrenal gland

Kidneys Arterioles Ureter Tone and motility Urinary bladder Detrusor muscles Trigone and sphincter Genital organs Seminal vesicles Vas deferens Uterus

Stimulated

—

Relaxed —(?)

β

Contracted Secretion

Increased Increased

β β

Decreased Decreased

Decreased Contracted

α and β α

Increased Relaxed

Decreased Contracted Inhibited Glycogenolysis, gluconeogenesis Relaxed

α and β α α β

Increased Relaxed Increased —

β

Contracted

α α

Dilation Increased —

α and β β α α

Increased Contracted Increased —

Constriction Reduced Contraction of capsule Decreased Relaxed Decreased Secretion of 80% epinephrine/20% norepinephrine Constriction

α

Dilation

Decreased

α

Increased

Relaxed Contracted

β α

Contracted Relaxed

Contraction Contraction Contraction

α α α

—(?) —(?) Depends on species and hormonal status

539

Blood vessels Coronary arteries Arteries in skeletal muscles Arteries in penis or clitoris All other arteries Veins

Relaxation

β

Constriction Dilation(?) Constriction

α β αa

Dilation —(?)

β

Constriction Constriction

α α

— — —

Dilation Dilation —

a

By circulating epinephrine only.

The functional balance that is normally maintained by the two divisions of the ANS can be disturbed in disease. Linkages exist between the autonomic and immune systems that may be important in the production of disease states and the response to neoplasia and other chronic disease that may lead to pain.108 Pain itself may alter the immune response and thereby alter the progression of a disease.109 Animal and human physiologic and pharmacologic studies of visceral as well as somatic pain have demonstrated both plasticity and functional characteristics that are far more complex than the basic anatomy described in this chapter; entire books have been written, for example, on visceral pain.110

ENTERIC NERVOUS SYSTEM The enteric nervous system (ENS) is a highly dynamic division of the ANS often referred to as the “little brain” of the gut and contains as many neurons as the spinal cord. It controls gastrointestinal motility and secretion and is involved in visceral sensation. The digestive tract consists of two plexuses, the myenteric and submucous plexuses, formed from sympathetic and parasympathetic postganglionic neurons and a significant number of enteric neurons (Fig. 9.11).111 Although these plexuses interact with the ANS ganglia in the periphery as well as the spinal cord, brainstem, and cortex, the ENS can function autonomously without input from the sympathetic and parasympathetic systems or the CNS.112 Enteric neurons were once felt to be postganglionic parasympathetic fibers but are now felt to comprise an independent system in the ANS. The ENS regulates the gastrointestinal system to maintain homeostasis through 540

control of peristalsis, blood vessels, and glandular activity. The ENS also has extensive interaction with the immune system. Disruption of this delicate relationship may be the cause of functional bowel disorders such as irritable bowel syndrome.26 Enteric neurons appear able to change their function and phenotype, a phenomenon called neuronal plasticity, which contributes to the pathogenesis of visceral hypersensitivity.111

FIGURE 9.11 Arrangement of nerve cells and nerve fibers in the intramural plexuses in the intestine. The axonal endings of the parasympathetic preganglionic neurons synapse in the wall of the intestine, whereas the axonal endings of postganglionic sympathetic neurons are largely distributed to the intramural ganglia and the blood vessels. (Modified from Kuntz A. Autonomic Nervous System. 4th ed. Philadelphia: Lea & Febiger; 1953:215.)

Conclusion Complete evaluation of individuals with persistent pain includes anatomic localization of the lesion or lesions responsible for both the initiation and maintenance of pain. It is necessary to distinguish between pain that is of peripheral, central, and mixed origin; it is necessary to determine whether pain is somatic or visceral. Thus, optimal evaluation and care of patients with persistent pain is dependent on a thorough knowledge of the anatomy of nociceptive systems. Future advances in our understanding of the 541

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CHAPTER 10 Clinical Trials ROGER CHOU and RICHARD A. DEYO Controversies abound in the clinical management of pain, and there are enormous geographic variations in care. Lumbar spine surgery rates historically vary fivefold among developed countries, with rates in the United States being highest and rates in the United Kingdom being among the lowest1—yet, patient outcomes appear to be broadly similar across countries. In smaller geographic areas, variations are also striking. Within the United States, rates of lumbar fusion surgery among Medicare enrollees vary more than 20-fold between regions, from 4.6 per 1,000 enrollees in Idaho Falls, Idaho, to 0.2 per 1,000 in Bangor, Maine.2 Within Washington State, county back surgery rates vary more than sevenfold, even after excluding the smallest counties.3 Another problem in pain management is the successive uptake of a series of fads in treatment. Research has eventually discredited many of these, but they enjoyed widespread use, with substantial costs and side effects, before they were found to be ineffective. Examples include sacroiliac joint fusion for the treatment of low back pain, coccygectomy for coccydynia, bed rest and traction for back pain, and many others.4 This phenomenon is prominent in the field of pain medicine but not unique to it. Examples of abandoned therapies from other areas of medicine include internal mammary artery ligation for treating angina pectoris, gastric freezing for duodenal ulcers, and vitamin E and hormone therapy for prevention of cardiovascular events.5–7 Promoting such ineffective treatments drains resources from more useful interventions, produces side effects, and eventually damages professional credibility. Despite welcome breakthroughs in basic science research on pain, increases in knowledge regarding optimal ergonomics of work tasks, and the development and use of more technologically advanced medical therapies, evidence indicates an increasing prevalence of chronic back pain and disability. In the state of North Carolina, the prevalence of chronic, 547

impairing back pain more than doubled from 3.9% in 1992 to 10.2% in 2006.8 A large and steady rise in use of opioids, surgery, and interventional therapies for low back pain has not been associated with improved health status but appears to be an important factor contributing to increases in health care expenditures associated with back pain.9–11 Thus, despite impressive gains in our understanding of the molecular and cellular origins of pain, there is an important gap in translating this knowledge into effective clinical management. One reason may be the widespread reliance on inadequate research designs that lead to conflicting, confusing, or misinterpreted results. Biostatistical and epidemiologic methods make it possible to substantially improve this situation, but many key principles are not widely appreciated.

Uncontrolled Studies Paradigm Historically, much of pain treatment research consisted simply of uncontrolled studies in which clinicians treated a group of patients and then reported mean pain scores or the proportion who improved. Such studies are often referred to as case series, although the alternative term before-after study or treatment series may help distinguish them from studies that identify “cases” based on an outcome (such as an adverse event) rather than an exposure (such as a medical intervention) and only assesses patients at one point in time.12 The before-after study design remains popular in part because it usually does not require extensive resources but is vulnerable to many pitfalls.13 First, many uncontrolled studies are retrospectively reported. After treating a certain number of patients, the clinician looks back at his or her experience and tries to summarize the characteristics, treatments, and outcomes of the patients studied. Unfortunately, in this retrospective approach, there is often incomplete baseline information on patient characteristics. For example, factors such as age, sex, previous surgery, disability compensation, neurologic deficits, psychological comorbidities, and pain duration often have a major influence on the outcomes of back surgery. Yet, in a systematic review of outcome studies on surgery for spinal stenosis, 74 relevant articles were found, but less than 10% 548

mentioned all these patient characteristics.7 Another problem with the retrospective approach is that it can be difficult to identify an “inception cohort” of all patients (or a random sample) who met specified criteria and received the intervention. A systematic review of 72 uncontrolled studies of spinal cord stimulation for chronic low back pain or failed back surgery syndrome found that less than one-quarter clearly described evaluation of a consecutive or representative sample of patients.14 In such studies, it is impossible to know if patients with poorer results were excluded for arbitrary reasons, or how many patients received the treatment but were lost to follow-up. If patients excluded from analysis or lost to follow-up were more likely to experience poor outcomes than those who were followed, this could result in serious overestimates of benefits. A third problem with uncontrolled studies is that even if the researcher collects data prospectively, there is typically no blinding of patient, therapist, or outcome assessor to the nature of the treatment provided. This allows important unconscious—or conscious—biases to affect assessments. This is particularly important for outcomes related to pain, which by nature are subjective. Most of us would question the reliability of outcomes rated by a surgeon evaluating his or her own patients, and yet, this is the norm in much of the literature. By definition, uncontrolled studies do not include control groups for comparison. The assumption seems to be that patients with painful conditions, especially chronic pain, will not improve unless effective treatment is given. However, there are many reasons why patients improve in the face of ineffective therapy, some of which are listed in Table 10.1. First, the natural history of many painful conditions is to improve spontaneously. This may be true even for patients with long-standing pain, who sometimes improve for unclear reasons. For acute conditions such as acute low back pain, rapid early improvement is the norm.15 Second are placebo effects, which are not well understood but are consistently underestimated and may be particularly important when assessing pain.7 Several factors may mediate placebo effects, including patient expectations,16 learning and conditioning from previous treatments, reduction of anxiety, and endorphin effects. Placebo effects for pain 549

treatments may be getting larger. In 1996, patients in US clinical trials reported that drugs relieved neuropathic pain 27% more than placebo, but by 2013, the difference had decreased to 9%,17 a trend that appeared due to a stronger placebo response in the setting of stable drug effects. TABLE 10.1 Why Patients May Improve with Ineffective Therapy Natural history of a condition to improve Placebo effects Regression to the mean Nonspecific effects: concern, conviction, enthusiasm, attention

Another poorly appreciated factor is regression to the mean.18 This term was coined by statisticians who observed that in a group of patients who are assembled because of the extreme nature of some clinical condition, there is a tendency for the condition to return to some average level that is less severe over time. Figure 10.1 shows what we often assume to be the course of chronic pain problems, with a steady level of severity that falls after successful intervention. However, the second panel is more likely to represent the true natural history, with good days and bad days, and fluctuations being the norm.19 Patients seek health care when their symptoms are most extreme. We might easily be misled into believing that improved outcomes are due to the intervention, when in fact, random fluctuations are why their symptoms have returned toward a more average level. As Sartwell and Merrell20 pointed out, “the term chronic has a tendency to conjure up ideas of stability and unchangeability . . . it is changeability and variation, not stability, that is in fact the dominant characteristic of most long-lived conditions.”

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FIGURE 10.1 Hypothetical course of chronic low back pain (LBP). (Reprinted with permission from Deyo RA. Practice variations, treatment fads, rising disability. Do we need a new clinical research paradigm? Spine 1993;18[15]:2153–2162)

A host of other nonspecific effects also can affect assessments of patient improvement. Increased concern, conviction, enthusiasm, and attention of a therapist, a researcher, and a clinical staff may all have positive but nonspecific effects on patient outcomes. Table 10.2 shows a potential consequence of all these factors, using data from a clinical trial of patients with chronic low back pain.19 The 31 patients in Table 10.2 have had back pain an average of 4 years. They received a clinical intervention that resulted in 20% to 44% improvements in pain frequency, severity, and function, all of which were highly statistically significant. However, this seemingly effective treatment for chronic pain was a sham transcutaneous electrical nerve stimulation (TENS) unit, along with hot packs twice a week. This was the control arm of a randomized trial and illustrates the substantial improvements that may occur among those with long-standing 551

pain who receive ineffective treatments. TABLE 10.2 Therapeutic Trial for Patients with Chronic Low Back Pain: Mean Duration of 4 Years, n = 31 Score Improvement Outcome Measure

Baseline to 1-Month FollowUp

p Value

32% 44% 33% 20%

.002 .001 .006 .000

Overall function (SIP) Physical function Pain severity (VAS) Pain frequency (5-point scale)

SIP, Sickness Impact Profile; VAS, visual analog scale. Reprinted with permission from Deyo RA. Practice variations, treatment fads, rising disability. Do we need a new clinical research paradigm? Spine 1993;18(15):2153–2162.

Finally, an issue that has begun to receive more attention is that uncontrolled studies are highly susceptible to publication bias.21 There is little incentive for clinicians to publicize poor or even average results. Estimates of efficacy from uncontrolled studies that get published will therefore often overrepresent the most positive results. There is considerable room for improvement in the design and conduct of uncontrolled studies of pain interventions.14,22 However, even when conducted well, the ability of uncontrolled studies to provide reliable information about treatment efficacy will always be limited. Exceptions can occur when the relationship between an intervention and outcomes is obvious, the effects are immediate, and the effects are so dramatic that they cannot be explained by other factors.23 Examples include surgery for appendicitis, eyeglasses for correction of refractive error, and cataract surgery. For nearly all pain conditions, however, there are many plausible alternative explanations for the observed changes in outcomes, and reliable conclusions about treatment efficacy require the use of more rigorous study designs. There is simply too much “noise” to sort out whether outcomes are due to the treatment or to other factors.24

CONTROL GROUPS: AN IMPROVEMENT OVER THE CASE SERIES Given the variety of factors that may produce improvement with 552

ineffective therapy, it is incumbent on investigators to have a comparison group of subjects with the same likelihood for improvement as a treatment group but who do not receive the active therapy. The goal should be to minimize the potential differences across groups in the effects of the various nonspecific causes for improvement that are listed in Table 10.1. With this goal in mind, the appropriate comparison group is unlikely to be one that receives no care at all. Patients in such a group would not experience placebo effects or the nonspecific effects of clinical concern and enthusiasm. The importance of having an adequate placebo is illustrated by a trial that found acupuncture more effective than no treatment for chronic low back pain but no more effective than sham acupuncture.25 Similarly, using a “waiting list” control group is often suboptimal because these patients experience none of the placebo or nonspecific effects of the intervention group. A preferable control group would be one that receives other credible, appropriate care that does not include the specific treatment under study. This might consist of “usual care” supplemented by a placebo of some sort. The placebo should be difficult to distinguish from the intervention under study so that it is perceived as being as likely to help as the active therapy. This is the reason for providing inactive pills in the control groups of drug trials, but even for nondrug treatments, credible placebos should be provided when possible. Examples include the use of sham TENS units in trials of TENS, the use of sham injections in trials of interventional therapies, the use of subtherapeutic weight in trials of traction, or “misplaced needling” as a control for acupuncture. In some cases, it may be unethical or impossible to provide a true placebo. Examples include many surgical interventions, psychological therapies, and rehabilitation interventions. In such situations, a reasonable alternative is to provide a control treatment that creates some sense that patients are receiving an additional intervention and attention but is not likely to have a strong effect on outcomes. One example might be a brief educational brochure.26 In addition to choosing an appropriate control intervention, it is also important to make the treatment and control groups as similar to each other as possible in other ways. Confounding is a critical concept that refers to 553

variables associated with both the intervention being evaluated and observed outcomes. A classic example of confounding is the association between alcohol consumption and lung cancer. This association is confounded by smoking, which is associated with alcohol consumption and is also an independent risk factor for lung cancer. Examples of common confounders in pain research include severity of baseline pain or functional deficits, psychological and medical comorbidities, age, and use of other therapies. The consequence of confounding is that the observed treatment effect is a poor estimate of the true effect. The modifying effect of the confounding variables result in either an overestimate or underestimate of treatment benefits and can sometimes even result in a positive effect when the true effect is negative (or vice versa). Selection of controls to minimize the potential for confounding is often a challenge. Control groups that are convenient to assemble are also unfortunately frequently associated with important pitfalls. For example, it would be unwise to choose patients who did not have adequate insurance coverage for the treatment being provided as a control group because insurance coverage is related to important sociodemographic characteristics. Patients with the best insurance are typically those with the highest salaries and the most satisfying jobs, are happier with their insurance, and are more likely to practice healthy behaviors. Failure to adjust for socioeconomic status in observational studies could have resulted in the subsequently disproven belief in the positive cardiovascular benefits of hormone replacement therapy.27 Similarly, selecting patients nonadherent with intended therapy as a control group is a flawed strategy. In a large-scale study of cholesterol-lowering therapy, control patients were divided among those who took more than 80% of their placebo tablets and those who took less than 80%.28 Even after adjusting for 40 coronary risk factors, there were enormous differences in mortality between the adherent and nonadherent groups. Patients who were adherent with their placebos had a 5-year mortality of only 16%, whereas those who were not adherent had a 5-year mortality rate of 26% (P < .0001). These findings were probably related to important differences between the groups that were not reflected in their coronary risk factors. These may have included other health habits, behaviors, attitudes toward risk, and 554

occupations. Thus, nonadherent patients are often strikingly different from adherent patients, and we cannot assume that any differences in outcome are related only to treatment effects. Sometimes, the issues of proper selection of control patients and treatments are intertwined. A study that assigned patients with presumed discogenic low back pain to intradiscal electrothermal therapy (IDET) or rehabilitation therapy based on their insurance coverage for IDET reported an average 4.5-point improvement in pain scores.29 Subsequent randomized trials found either no advantage of IDET or only a 1-point difference between IDET and sham treatment.30,31 In addition to potential socioeconomic differences related to differential insurance coverage, patients who were denied IDET probably had lower expectations about the likely benefits of rehabilitation therapy, particularly because some had previously received this treatment but had not responded. Confounding by indication is particularly important in studies that assess treatment efficacy. It refers to the strong, natural (and appropriate) tendency for clinicians to selectively use therapies in patients most likely to benefit. A striking example of confounding by indication is a study of new users of nonsteroidal anti-inflammatory drugs that found use of ulcerhealing drugs associated with a 10-fold increase in risk of gastrointestinal bleeding or perforations.32 Obviously, ulcer-healing drugs do not cause ulcers. Rather, the increased risk of gastrointestinal complications in patients deemed appropriate for ulcer-healing drugs dwarfed any protective effect of the drugs. There are ways to minimize or adjust for the effects of confounding. These include matching patient selection on the variables thought to be most important potential confounders, restricting enrollment to patients defined by a narrow set of inclusion criteria, and statistically adjusting and analyzing known confounders.33 Nonetheless, the effects of confounding can be dramatic even when one or more of these strategies are employed. For example, confounding by indication was strong in the study on ulcerhealing drugs, even though it attempted to restrict enrollment to lower risk patients without a previous ulcer or who had even been previously prescribed an ulcer-healing drug.32 Matching also may not be enough to overcome effects of confounding. 555

Table 10.3 shows how one might assemble two groups of objects that are well matched on five different characteristics and yet literally be comparing apples and oranges.19 Table 10.4 shows real data from a comparison of outcomes of two groups of Medicare patients who underwent low back surgery. They were matched on diagnosis (all had spinal stenosis), gender, age, insurance (all Medicare), and surgical procedure (all had a laminectomy without fusion). Despite being well matched on these five characteristics, the likelihood of reoperations differed almost fourfold between the two groups. Differences of this magnitude might easily be attributed to some dramatic advantage of the treatment used in group A. However, these groups were intentionally assembled in such a way that group A was composed of African American patients who had not had prior surgery and group B was composed of white patients with prior surgery.19 These two characteristics, which might have easily been overlooked, accounted entirely for the difference in reoperation rates. Unfortunately, it usually is not as simple as matching on a few critical and easily measured variables. The cholesterol-lowering placebo study described earlier shows how even matching (or adjusting) for 40 different risk factors may not capture important differences between two groups of patients.28 TABLE 10.3 Why Not Find “Matching” Controls? Shape Source Edible? Size Weight

Apples

Oranges

Round Tree Yes Handheld ½ lb.

Round Tree Yes Handheld ½ lb.

Reprinted with permission from Deyo RA. Practice variations, treatment fads, rising disability. Do we need a new clinical research paradigm? Spine 1993;18(15):2153–2162.

TABLE 10.4 Two Cohorts of Medicare Patients with Laminectomy for Stenosis (1985) % Women Mean age % Fusion

Group A (n = 252)

Group B (n = 141)

Significance

57% 71 0

55% 72 0

NS NS NS

556

4-Year reoperations

4%

15%

20% in all included trials, even though duration of follow-up was relatively brief.57 Attrition tends to increase as the duration of follow-up increases. One way to ensure that the results are 563

robust in the face of dropouts is to do a “worst-case analysis,” in which one assumes that all dropouts from the treatment group failed to improve, whereas all dropouts from the comparison group improved substantially. If this worst-case analysis does not change the conclusion, one can be confident in the findings.42 In one analysis, over half of trials that reported statistically significant results no longer reported statistically significant effects under a worst-case scenario.58 However, it is implausible that all persons lost to follow-up will experience the worse outcome. Under more plausible assumptions regarding outcomes of persons lost to follow-up, results of 0% to 33% of trials were no longer significant. An alternative approach for handling missing data is “baseline observation carried forward.” This technique utilizes the baseline value for the outcome of interest for patients who are lost to follow-up.59 Although it has the advantage over “worst-case analysis” of being based on “real” data, it is based on the flawed assumption that the baseline values will not change during the course of follow-up or as a result of treatment. “Last observation carried forward” has an advantage over using baseline values in that it takes into account any recorded changes in outcomes. More sophisticated methods such as multiple imputation create several different plausible data sets for missing data based on the observed data and appropriately combine the results obtained from each of them.60 It is also important that patients be analyzed in the groups to which they were randomized (“intention-to-treat analysis”) regardless of whether they received the intended treatment, how well they adhered to the assigned therapy, and whether they completed the trial.61 We have seen the hazards of assuming that patients who are noncompliant are otherwise the same as compliant patients. Indeed, patients who do not receive the intended therapy may be systematically different from those who do. The only way to maintain the benefits of randomization and to avoid a biased comparison is to keep patients for analytic purposes in the group to which they were assigned. Intention-to-treat analyses take into account the fact that patients in clinical practice are autonomous and do not always follow the trial protocol to the letter—or at all. In some cases, intention-to-treat analyses can be difficult to interpret. In the Spine Patient Outcomes Research Trial of surgery, nearly 40% of patients crossed over from 564

surgery to nonsurgical therapy and vice versa.62 The intention-to-treat analysis still provides information about patient outcomes when they are advised to undergo surgery or nonsurgical therapy, even though many patients decided not to proceed with the recommended therapy. An astreated analysis provides additional information based on which therapy the patients actually received. This can also be informative, so long as potential confounders are adjusted for and the high probability of some residual confounding is recognized.63

Other Issues in Clinical Trials MEASUREMENT OF OUTCOMES What outcomes should be measured in a clinical trial? In traditional clinical trials, investigators often seek the most objective possible outcomes for evaluation, such as joint range of motion, spinal fluid endorphins, or dynamometer measures of muscle strength. Although the search for objective outcome measures is appropriate for many medical conditions, pain is inherently a subjective phenomenon and one that often correlates only modestly with these physiologic measures. Table 10.7 illustrates several examples of dissociations between physiologic measures and pain or functioning.64 Some researchers have argued that the essence of “hard” data is their reproducibility under the same circumstances.65 Happily, many subjective phenomena can be measured in reproducible fashion. A good example is the use of visual analog pain scales and other ordinal rating scales for quantifying pain. TABLE 10.7 Examples of Dissociations between Various Outcome Measures Biofeedback reduces paraspinal electromyography activity but not pain. Tricyclic antidepressants relieve pain and depression but do not alter cerebrospinal fluid betaendorphin levels or paraspinous electromyography activity. Statements of pain severity correlate poorly with medication use, health care use, and activity level. Reduced spinal mobility may be associated with improvement in pain and disability or lower risk of pain. Muscle function does not predict 10-year incidence of back symptoms. Correlations between lumbar spine mobility and modified Oswestry questionnaire are only

565

.04–.17 (absolute value). In a clinical trial of rigid corset, improvements in symptoms with activity were observed but not in spine mobility or straight-leg raising. Reprinted from Deyo RA. Measuring the functional status of patients with low back pain. Arch Phys Med Rehabil 1988;69(12):1044–1053Copyright © 1988 Elsevier. With permission.

For evaluation of therapies for chronic pain, trials should go beyond the self-report of pain to routinely examine patients’ behavior and function in their daily lives.66 Function should be considered a separate domain from pain and measured separately because improvements in pain and function often correlate only loosely with one another.67 For example, trials of opioids for chronic noncancer pain and exercise therapy for low back pain both found considerably smaller benefits according to measures of function compared to measures of pain.68,69 So how should function be assessed? Performance measures such as a series of timed tasks or an “obstacle course” may have the attraction of seeming objectivity, but performance can be highly influenced by motivation, mood, setting, financial incentives, and other nonphysical attributes of the patient and his or her environment. Such measures often do not correlate well with how a patient actually functions on a day-to-day basis. By contrast, a number of self-report measures of health status or functional status have been validated and are quite reproducible. Examples include the Sickness Impact Profile70,71 the Brief Pain Inventory,72 and the Medical Outcomes Study Short-Form-3673 as well as condition-specific scales such as the Roland-Morris Disability Questionnaire and Oswestry Disability Index for patients with back pain,74 the Arthritis Impact Measurement Scale,75 the Western Ontario and McMaster Universities Osteoarthritis Index physical function subscale,76 and many others. A simple three-item measure of pain and function adapted from the Brief Pain Inventory is the Pain, Enjoyment of Life, and General Activity (PEG) scale.77 To provide a full picture of the effects of pain interventions, the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) recommends that clinical trials routinely measure outcomes in multiple “core” domains. In addition to pain, physical functioning, and emotional functioning, IMMPACT recommends assessment of participant ratings of global improvement and satisfaction 566

with treatment, symptoms and adverse events, and participant disposition.66 A task force convened by the National Institutes of Health (NIH) Pain Consortium developed research standards for studies of chronic low back pain including reporting of outcomes addressing pain intensity, pain interference, physical function, depression, sleep disturbance, and catastrophizing.78 Work status is often used as an outcome measure for chronic pain treatment because of its clear relevance to both patients and to society. However, it has a number of drawbacks as an outcome measure, most important of which is that it is influenced by many nonmedical factors. For example, studies have demonstrated that the likelihood of return to work in the face of a painful medical condition varies depending on job satisfaction, relationships with fellow employees and supervisors, regional unemployment rates, the presence of another breadwinner in the family, proximity to retirement age, and physical job demands. Similarly, the duration of pain-related disability is strongly associated with the patient’s educational status, income,79 and the generosity of disability benefits. For many members of our society, including students, homemakers, and retired persons, return to employment is simply not available as an indicator of outcome. Thus, although this measure of outcome is important in many settings and is recommended by the NIH Task Force on Research Standards for Chronic Low Back Pain as part of the minimum data set,78 it should be interpreted in light of these potentially confounding factors.

REPORTING THE RESULTS Many clinical trials report mean outcome scores or mean differences in scores compared to baseline values. This can be difficult to interpret clinically, as a 10-point mean improvement on a 100-point scale could indicate that nearly all patients experienced only very mild improvement or that some proportion of patients experienced a clinically significant improvement, whereas others did not. The minimal important change, or the smallest change in outcome scores perceived by patients to be meaningful, is a key concept.80 It refers to the smallest amount of improvement perceived by patients as being important. For low back pain, a consensus group recently proposed a 30% improvement from baseline in 567

pain or function as the minimum important change.81 A randomized trial found that the average difference between mindfulness-based stress reduction versus usual care was less than 1 point on a 0-to-10 pain bothersomeness scale at 1 year, indicating a relatively small average effect well below the threshold for clinical significance.82 However, the proportion of patients who experienced ≥30% improvement was greater in the mindfulness group (48% vs. 31%; relative risk [RR], 1.56; 95% confidence interval [CI], 1.1 to 2.1), indicating that persons who respond to mindfulness therapy often experience clinically meaningful improvements. Therefore, reporting the proportion of patients that meet a certain threshold for improvement can be very helpful for interpreting the clinical significance of results. This is sometimes referred to as a responder analysis and is recommended by the NIH Task Force on Research Standards for Chronic Low Back Pain in addition to reporting mean outcome scores.78 In some studies, actual outcome measurements are not reported. Rather, only the P values for the significance of results are provided. A P value tells us the probability of obtaining a result that is at least as extreme as the one actually observed, assuming that the null hypothesis of no difference between treatments is true. However, this gives a reader no idea what the magnitude of treatment effects may have been.83 In a very large trial, a difference between groups may achieve statistical significance even though the difference is too trivial to be clinically relevant. On the other hand, in a very small trial, a large treatment effect might fail to achieve statistical significance. Thus, the magnitude of treatment effect is somewhat independent of statistical significance and should be reported. An ideal way to present the results is to give the actual estimate of success rates or mean scores along with 95% confidence limits, which allows the reader to see the range of results that would be consistent with the study findings. The 95% confidence limits are closely related to P values but give readers a better understanding of the potential range of effects compatible with the data.

STATISTICAL POWER When a trial shows “no statistically significant difference,” it is often 568

interpreted as meaning that it has proven that there is no difference between the intervention and control groups. However, this interpretation is often incorrect. In fact, most trials are too small to prove that there is no difference between groups—rather, they only show an absence of evidence of a difference.84 This is a critical distinction. The likelihood that a true difference may not have been detected is referred to as type II (or β) error, in contrast to type I (or α) error (which is reflected in the P value).85 Statistical power (calculated as 1 − β) refers to the likelihood that a clinically relevant difference between groups will be identified. Larger sample sizes increase statistical power. On the other hand, statistical power decreases as the size of the clinical effect to be detected (typically the minimal important change) goes down. Nonstatistically significant results should always be interpreted in the context of the statistical power of the study.

GENERALIZABILITY OF RESULTS AND EFFICACY VERSUS EFFECTIVENESS Even if a clinical trial is internally valid, its results may not be applicable (generalizable) to other patients and settings. Patients who enroll in low back pain clinical trials, for example, tend to be better educated, more frequently employed, and different in other prognostically important ways from patients in everyday practice.86 Clinical trials often exclude patients with medical or psychological comorbidities or use run-in periods to identify and exclude patients who experience adverse events before randomizing them. For example, older patients have often been excluded from trials of arthritis drugs, even though they are the most likely to receive such drugs in actual practice. Patients enrolled in clinical trials are usually recruited from tertiary care settings, and the resources available in clinical trials to help maximize patient compliance and follow-up are rarely available to most clinicians. A number of other threats to generalizability have been described.87 It is important for patients, treatments, and study conditions to be adequately reported so readers can determine whether they would be likely to apply to their own situations. Related to generalizability is the concept of efficacy versus effectiveness. Most clinical trials are designed to evaluate efficacy: the 569

benefits of an intervention in optimal populations and under ideal conditions. Such studies generally focus on narrow, short-term outcomes. Effectiveness studies, on the other hand, are designed to evaluate whether an intervention will actually work under conditions encountered in usual practice.88 Of course, there is a continuum between efficacy and effectiveness, although most randomized trials fall squarely on the efficacy side of the spectrum. Factors that can enhance the ability of clinical trials to evaluate effectiveness are use of less stringent eligibility criteria, enrollment of patients from primary care populations, evaluation of multiple clinically relevant outcomes, and longer duration of follow-up.89 Observational studies can also be helpful for evaluating effectiveness once efficacy has been established in randomized trials.

SUBGROUP ANALYSES Sometimes, analyses are performed to examine whether the effects of an intervention differ in clinically relevant groups of patients defined by some factor (such as baseline pain score, sex, or age).90 For example, a trial of glucosamine for osteoarthritis found no overall treatment benefit, but a subgroup analysis found that it was effective in patients with high baseline pain scores.91 There is a great risk that subgroup analyses may be overinterpreted, as results could simply represent chance effects, particularly when data are “mined” to look for significant results. Confidence in subgroup analyses is enhanced if the treatment effects are large, are unlikely to have occurred by chance (low P value), occur in an analysis based on a prespecified and plausible hypothesis, come from a small number of subgroup analyses, and are replicated in other studies.

EFFECTS OF FUNDING SOURCE Commercially funded clinical trials are consistently more likely to report results that favor the funder than trials that are not commercially funded.92,93 This appears to be true for devices, such as surgical implants, as well as drugs.94,95 Why might this be? One reason is publication bias. This refers to the differential tendency for studies to be published depending on the strength and direction of results.96 Generally, studies that report statistically significant and more strongly positive results are more 570

likely to be published compared to those that report statistically insignificant or less striking results. The result is inflated estimates of treatment effects. Publication bias can occur no matter what the source of funding is, but commercially funded clinical trials appear to be particularly susceptible due to either overt or more subtle pressures.93,97,98 A related situation is the selective reporting of outcomes.99–101 This leads to bias because more favorable results tend to be reported and publicized, and there is often no indication to readers that other (less favorable) outcomes were even assessed. Results can also be “spun” to appear more favorable than they really are. One study found that of 36 industry-sponsored new drug approval trials of antidepressants viewed by the U.S. Food and Drug Administration (FDA) as having negative or questionable results, 22 had not been published, and another 11 were reported in a way that conveyed positive outcomes.102 Another questionable strategy that has begun to receive increased scrutiny is the practice of “seeding” trials following new drug approvals.103 Such trials are framed as scientific research but in reality are marketing tools designed to increase familiarity and use of the medication by experienced clinicians and often utilize scientifically suspect study designs driven by marketing staff, recruit underqualified investigators who prescribe competing products, overcompensate investigators, and utilize poor data collection methods.104 This is not to say that commercially funded trials can not be conducted and reported rigorously. However, replication of results in non– commercially funded trials may be required to increase confidence in the findings of commercially funded trials, even when methodologic shortcomings are not readily apparent. Statistical and graphical methods are available to formally assess for the likelihood of publication bias, although all have some limitations.105 The FDA Web site can be a useful resource for identifying unpublished trials and unreported outcomes, but data are often incomplete or redacted. Ideally, publication and selective outcomes reporting bias would not only be detected but would also not occur in the first place. The development of clinical trials registries and mandatory requirements for researchers to submit trial protocols and full results in order to be considered for journal publication or for new drug approvals may help reduce the effects of these biases.106,107 The 571

usefulness of clinical trials registries will depend on how assiduously and quickly researchers comply with reporting requirements.

ASSESSMENT OF HARMS In order to generate balanced conclusions about an intervention, it is important to understand both its benefits and harms.108 However, benefits have been accorded far greater prominence than harms when conducting and reporting clinical trials. In fact, most randomized trials lack prespecified hypotheses for harms. Rather, hypotheses are usually designed to evaluate beneficial effects, with assessment of harms a secondary consideration. As a result, the quality and quantity of harms reporting in clinical trials is often inadequate.109 There are other problems with relying solely on clinical trials to assess harms.110 Few clinical trials have large enough sample sizes or are long enough in duration to adequately assess uncommon or long-term harms. For example, one systematic review found that trials of opioids for chronic noncancer pain averaged only 5 weeks in duration, even though patients frequently remain on these medications for years or indefinitely.68 In addition, patients who are more susceptible to adverse events are often excluded from clinical trials, although they may commonly receive the therapy in clinical practice. For example, all trials of opioids for chronic noncancer pain that reported information on history of drug addiction excluded such patients.68 Harms may also be downplayed or misrepresented if there is a vested interest in doing so.111 Aggressive promotion of unsubstantiated claims of lower abuse, diversion, and withdrawal risks of OxyContin (Purdue Pharma, Stamford, CT), a sustained-release formulation of oxycodone, eventually resulted in a criminal conviction and $634 million fine against the Purdue Frederick Company, along with three company executives.112 Assessment and reporting of harms in clinical trials can certainly be improved. This is also an area where observational studies can be a very useful source of information. Unlike assessments of treatment benefits, confounding by indication is usually not an issue with unexpected or unpredictable adverse events because such outcomes are not related to the decision to use the therapy.34,113 An example is observational studies on 572

risk of myocardial infarction associated with cyclo-oxygenase-2 selective nonsteroidal anti-inflammatory drugs. Those conducted prior to knowledge regarding the cardiovascular risks of rofecoxib were unlikely to be affected by confounding by indication related to the baseline risk of heart disease. Observational studies can also provide important information on rare or long-term adverse events and in populations underrepresented in clinical trials (such as pregnant women, children, older adults, or those with important comorbidities). Even uncontrolled studies such as case reports have been invaluable for evaluating harms and may be the first or primary signal of a rare adverse event.

TRIAL-BASED COST-EFFECTIVENESS ANALYSIS Even if the balance of benefits to harms of a treatment is acceptable, widespread implementation may not make sense if costs are very high. Clinical trials can also be designed to assess the question “Is it worth it?” by collecting cost data alongside clinical outcomes.88 Unlike decision analytic studies that model costs and clinical outcomes, such trial-based cost-effectiveness analyses directly measure the cost per some increment of clinical utility (often a quality-adjusted life-year). A challenge with cost-effectiveness analyses of clinical trials is that cost data are often associated with large variability, so estimates can be imprecise unless sample sizes are large.114 In addition, distributions of cost estimates are often quite skewed, which can pose a statistical challenge, and costs are frequently highly variable depending on locale and reimbursement factors and can rapidly change over time.

Alternative Study Designs CLUSTER TRIALS For certain interventions, it may be undesirable or unfeasible to randomly allocate individual patients to a treatment or a control group. For example, if one were testing a guideline that involved changes in clinic organization and changes in management by nurses or other ancillary staff, it might be extremely difficult to ensure that all involved gave one particular approach to some patients and not to others. Furthermore, individual physicians 573

would have difficulty treating certain patients according to a guideline and others not according to the guideline, which could increase treatment group contamination. In such a circumstance, one might wish to allocate clusters of patients, such as entire clinics, to intervention or control arms. Such studies are referred to as cluster randomized trials.115 When these designs are used, specific statistical methods are needed to account for the similarities among patients of a single physician or facility, which can inflate estimates of treatment effects. Analytic techniques such as the “cluster correlation correction” for such studies have been well described,116 and computer software is available to perform these analyses.

CROSSOVER TRIALS In a standard parallel group randomized clinical trial, patients are randomized to a single treatment out of two or more possibilities. In a crossover trial, patients each receive two or more treatments in a random order, typically separated by a washout period.117 This allows a patient’s response to one treatment to be compared with the same patient’s response to another treatment. The crossover design confers a statistical efficiency advantage over parallel group trials because with the same number of subjects, the use of paired data enables more precise estimation of treatment effects. A key drawback of crossover trials is the potential for carryover effects, with effects of one treatment “carrying over” to the next. Thus, the washout period must take into account the likely duration of action for each treatment involved and may require testing for crossover effects. Attrition can also occur during the initial treatment period, making within-subject comparisons impossible for those persons lost to followup.118 Other factors that may impact the interpretability of crossover trials are period effects (due to changes in the underlying condition over time) or sequence effects (due to changes in effectiveness of treatments based on the order in which they are given).119 Crossover trials are most appropriate for chronic pain conditions in which the symptoms are relatively stable, generally inappropriate for acute pain, for which symptoms change rapidly, and should be reserved for treatments that do not have permanent effects on the underlying condition. Results of crossover trials tend to agree with those of parallel group trials, although some research indicates 574

a trend toward larger effect estimates in crossover trials.120

FACTORIAL DESIGN In a factorial design, patients are simultaneously randomized to receive or not receive two different treatments.121 In the United Kingdom Back Pain Exercise and Manipulation (BEAM) trial, for example, patients were allocated to receive exercise therapy versus no exercise therapy and to receive spinal manipulation or no spinal manipulation.122 Such factorial designs have important efficiencies if the dropout rate is low. If there is no statistical interaction between the two treatments (in this example, exercise therapy and spinal manipulation), then a factorial design provides an unbiased assessment of the effect of each treatment. Such designs might be useful in studying combinations of therapy such as an analgesic plus a muscle relaxant, drug therapy plus physical therapy, and other clinically relevant combinations. Indeed, factorial designs may be the best way to evaluate the multicomponent approach that is widely advocated for the treatment of chronic pain. If there is no synergy between treatments, the investigator essentially has two trials for the price of one. If there is synergy or additive effects between treatments, the factorial design can identify this effect. Factorial designs introduce analytical complexities that are avoided in simple parallel designs, but in some circumstances, the benefits may outweigh the disadvantages.123

New Directions in Clinical Trials PRAGMATIC TRIALS With increased attention to effectiveness has come an increased demand for “pragmatic” trials that attempt to inform routine clinical practice better than traditional efficacy trials. Key features of pragmatic trials are that they are set in normal practice settings rather than highly specialized or controlled settings, apply few exclusion criteria, allow flexibility in use of treatment interventions, and assess key, patient-centered outcomes.124 For example, a pragmatic trial of acupuncture for chronic low back pain was conducted in general practice and private acupuncture clinics in the United Kingdom, enrolled anyone aged 18 to 65 years with nonspecific low back 575

pain of 4 to 52 weeks duration (with few exclusion criteria), allowed acupuncturists to determine the content and number of treatments, and evaluated bodily pain as well as outcomes related to use of analgesics and patient satisfaction.125

ENRICHED ENROLLMENT RANDOMIZED WITHDRAWAL TRIALS A design that has become increasingly common, particularly for evaluation of pharmaceuticals, is the enriched enrollment randomized withdrawal design. In this design, potential study participants all receive the study drug for a specified period of time during an open-label prerandomization phase.126 Only persons who report benefits and can tolerate the drug proceed to the randomization phase, in which patients either continue to receive the medication or are randomized to a control (usually placebo). The enriched enrollment randomized withdrawal design has been proposed as a useful method for studying drugs for whom only a small proportion of patients benefit by focusing on those in whom the drug works and do not experience bothersome side effects.127 However, this design could exaggerate treatment benefits and underestimate harms because the population enrolled is purposefully skewed toward those who have already demonstrated good outcomes and few side effects on the treatment; blinding may be ineffective because all patients are familiar with the treatment due to exposure during the prerandomization phase; and for certain medications (e.g., opioids), development of tolerance from prerandomization exposure could lead to withdrawal symptoms in persons randomized to placebo, confounding interpretation of results. One analysis of clinical trials of opioids for chronic pain found that compared to standard trials, the enriched enrollment randomized withdrawal design did not appear to bias results for efficacy but underestimated adverse effects.126

EXPERTISE-BASED TRIALS For nonpharmacologic interventions such as surgery that are highly dependent on the skill and training of the clinician, “expertise-based” randomized controlled trials have been proposed.128 In the traditional 576

randomized controlled trial, participants are randomized to one of two interventions and individual clinicians provide intervention A to some patients and intervention B to others. In the expertise-based randomized trial, participants are randomized to individual clinicians with expertise in intervention A or to clinicians with expertise in intervention B. Proposed advantages of expertise-based randomized trials are that they can reduce the effects of differential expertise bias. In the case of surgery, this can be important, as many procedures require considerable experience to gain proficiency. In addition, the expertise-based design reduces potential effects of differential enthusiasm or skepticism for the different procedures, as each surgeon provides only the procedure that he or she believes is the best. As yet, however, there is relatively little evidence on the validity of expertise-based randomized trials.

COMPARATIVE EFFECTIVENESS Another direction in clinical trials is toward increased evaluations of not just effectiveness of interventions versus placebo but comparative effectiveness of two or more interventions.129 Head-to-head trials that compare two interventions are the most direct method for evaluating comparative effectiveness. However, head-to-head trials are not always available. An alternative method for evaluating comparative effectiveness is through indirect comparisons. This refers to assessments of the relative benefits and harms of competing interventions based on how well each performs against a common comparator (usually placebo). Methods are available for conducting indirect comparisons that preserve some of the benefits of randomization as well as for more complex network analyses and mixed treatment comparisons that incorporate both indirect and direct evidence.130 In all cases, the validity of indirect comparisons is based on the critical assumption that treatment effects are consistent across all trials. This assumption can be violated due to a number of factors, including differences in study quality, patient populations, settings, outcomes, and other factors. In fact, large discrepancies between indirect and direct studies have been reported. For example, in patients with neuropathic pain, an indirect comparison found tricyclic antidepressants associated with a much higher likelihood of achieving pain relief compared to gabapentin, 577

but head-to-head trials found no significant difference.131 Indirect comparisons should only be used when the critical assumption of similarity of treatment effects is met and verified against results from head-to-head trials as they become available.

EQUIVALENCE AND NONINFERIORITY TRIALS Traditional clinical trials are designed to determine whether an active treatment is superior to another treatment (often placebo). The null hypothesis is that there is no difference between the treatments being compared. In equivalence trials, on the other hand, the purpose is to determine whether one (typically new) intervention is therapeutically similar (equivalent) to another, usually established, treatment.132 This requires testing of a different null hypothesis—specifically, the null hypothesis that there is a difference being treatments. Noninferiority trials are similar to equivalence trials but are designed to focus on whether a new treatment is no worse than (rather than therapeutically similar to) an established treatment. For either type of trial, boundaries for what will be considered “equivalent” or “noninferior” must be defined in order to perform appropriate hypothesis testing. Unfortunately, many trials that report equivalence do not define these boundaries, or are based on misapplied or misinterpreted statistical analyses, often based on standard superiority hypotheses or inadequate sample sizes.133 Guidance is available to help improve the conduct, reporting, and interpretation of equivalence and noninferiority trials.132

STEPPED WEDGE DESIGN The standard cluster randomized trial utilizes a parallel design, in which patients receive different interventions according to their cluster at roughly the same time. The stepped wedge design is a variant on the cluster framework in which each cluster begins in the control condition and receives the intervention by the end of the study.134,135 The time to receive the intervention condition varies from cluster to cluster. The stepped wedge design may be more feasible to implement than a standard parallel group cluster design when the cost of implementing an intervention simultaneously in many clusters is high because the intervention is 578

implemented across the clusters in a stepped fashion, or when withholding an intervention is considered unethical or may pose a barrier to recruitment because all clusters will receive the intervention by the end of the study. As in crossover trials, the crossover from the control condition to the intervention within each cluster allows for within-cluster comparisons that may increase statistical efficiency; similarly, stepped wedge studies must guard against carryover effects.

BAYESIAN STATISTICAL INFERENCE AND ADAPTIVE DESIGNS Another direction in clinical trials is the use of Bayesian frameworks of statistical inference instead of the standard classical (frequentist) framework.136 Although a full discussion of Bayesian statistical inference is beyond the scope of this chapter, in essence, the Bayesian framework incorporates new evidence or observations to update probabilities that a hypothesis might be true. Bayesian adaptive trials use Bayesian methods to incorporate data collected during the course of a trial in order to inform decisions regarding the need to update, modify, or stop the trial.137

Systematic Reviews The relatively rapid advances in other fields of medicine, such as oncology and cardiology, occur because a succession of large randomized trials, typically implemented in multiple centers, results in cumulative knowledge. Such large, multicenter trials are still the exception rather than the rule in pain treatment, perhaps in part because of lower research funding for nonfatal conditions. Nonetheless, more pain research trials are being conducted, resulting in an ever-growing body of literature. This growth has been exponential. Between 1950 and 1990, more than 8,000 randomized controlled trials of pain research were published, with over 85% appearing during the last 15 years of that period.138 Given the amount of evidence, it is difficult for clinicians to keep up with the literature on even a circumscribed area of medicine. Review articles can be a useful way to summarize the evidence on a given topic. A systematic review is a particular type of review article that applies explicit 579

methods to reduce bias and error when summarizing evidence.139 This is in contrast with traditional or “narrative” reviews, which do not use explicit methods to identify, select, and assess evidence. Such review articles are relatively subjective and are apt to be based on incomplete, outdated, or flawed evidence. This increases the likelihood of incorrect or unsubstantiated conclusions. A “systematic” review attempts to bring the same level of scientific rigor to the review article as should be used when conducting original research. Systematic reviews can be qualitative or quantitative. The latter are also referred to as meta-analyses, although strictly speaking, a metaanalysis is not necessarily based on systematic methods. Potential advantages of systematic review over traditional review articles are shown in Table 10.8. A high-quality systematic review minimizes bias and random error by using transparent, reproducible, and objective methods. In addition to summarizing existing data, systematic reviews can also increase statistical power for evaluating low-frequency events, provide more precise estimates of treatment effects, permit formal comparisons between studies, permit formal assessments of publication bias, and help delineate areas of uncertainty. TABLE 10.8 Potential Advantages of Systematic Reviews over Narrative Reviews Designed to address a focused clinical question Describes explicit methods used to identify as many of the relevant trials as possible Reports literature search dates Describes and applies predefined study inclusion criteria Formally assesses characteristics of studies associated with biases Follows explicit methods for weighing and synthesizing studies Can pool studies quantitatively, leading to more precise estimates and increased statistical power Can test for statistical heterogeneity and explore reasons for heterogeneity through subgroup, sensitivity, and other analyses Research gaps and areas of uncertainty more clearly delineated Can test for and estimate effects of publication bias on results Conclusions more directly linked to data and analyses

Before trusting the results of systematic reviews, it is important to critically evaluate whether rigorous methods were used. In fact, results of lower quality reviews can be misleading, as they are more likely than 580

higher quality reviews to produce positive conclusions about the effectiveness of interventions.138,140 Table 10.9 lists some factors that can influence whether a systematic review is likely to be reliable. A number of other methods for assessing the quality of systematic reviews are available, including the more detailed list of criteria in the Assessment of Multiple Systematic Reviews (AMSTAR)141 and AMSTAR 2 tools.142 All quality rating methods are based on the idea that systematic reviews that are comprehensive, up-to-date, and use appropriate methods to identify, select, assess, and synthesize the literature are more likely to provide a complete and unbiased picture than those that use suboptimal methods. TABLE 10.9 Factors to Consider when Assessing Quality of Systematic Reviews Was the search comprehensive? Was selection of studies unbiased? Is the systematic review current? Was quality of included studies appropriately assessed? Was evidence combined and summarized appropriately? Was publication bias assessed? Are the conclusions justified?

The Cochrane Collaboration is an international effort to systematically review the results of multiple randomized clinical trials and make the results widely available via the Internet. The number of Cochrane reviews on pain topics is rapidly expanding, and many have been published in conventional journals as well as in the Cochrane Library.

Conclusion Despite the rapid growth of research literature on the treatment of pain, there remain wide variations in care and the successive use of fads that are later demonstrated to be ineffective when well-designed studies are performed. Both the prevalence of painful conditions and their associated disability are increasing, and there is only a limited professional consensus on optimal approaches to many painful conditions. The disappointing pace of progress may be partly the result of few comprehensive theories that would guide treatment innovations. However, an equally important factor 581

may be the methodologic inadequacy of the research used to justify the introduction of new or innovative therapies to clinical care. Flaws in research design jeopardize not only the internal validity of research results but also their generalizability to routine clinical practice. Greater attention to scientific principles in the design of clinical research should accelerate progress in this area, lead to more consistent clinical practices, and improve patient care. References 1. Cherkin DC, Deyo RA, Loeser JD, et al. An international comparison of back surgery rates. Spine 1994;19:1201–1206. 2. Weinstein JN, Lurie JD, Olson PR, et al. United States’ trends and regional variations in lumbar spine surgery: 1992-2003. Spine 2006;31:2707–2714. 3. Volinn E, Mayer J, Diehr P, et al. Small area analysis of surgery for low-back pain. Spine 1992;17:575–579. 4. Deyo RA. Fads in the treatment of low back pain. N Engl J Med 1991;325(14):1039–1040. 5. Eidelman RS, Hollar D, Hebert PR, et al. Randomized trials of vitamin E in the treatment and prevention of cardiovascular disease. Arch Intern Med 2004;164:1552–1556. 6. Herrington DM, Howard TD. From presumed benefit to potential harm—hormone therapy and heart disease. New Engl J Med 2003;349:519–521. 7. Turner JA, Deyo RA, Loeser JD, et al. The importance of placebo effects in pain treatment and research. JAMA 1994;271:1609–1614. 8. Freburger JK, Holmes GM, Agans RP, et al. The rising prevalence of chronic low back pain. Arch Intern Med 2009;169:251–258. 9. Friedly J, Chan L, Deyo R. Increases in lumbosacral injections in the Medicare population. Spine 2007;32:1754–1760. 10. Martin BI, Deyo RA, Mirza SK, et al. Expenditures and health status among adults with back and neck problems. JAMA 2008;299:656–664. 11. Martin BI, Turner JA, Mirza SK, et al. Trends in health care expenditures, utilization, and health status among US adults with spine problems, 1997-2006. Spine 2009;34(19):2077– 2084. 12. Briss PA, Zaza S, Pappaioanou M, et al. Developing an evidence-based guide to community preventive services—methods. The Task Force on Community Preventive Services. Am J Prev Med 2000;18(suppl 1):35–43. 13. Carey TS, Boden SD. A critical guide to case series reports. Spine 2003;28:1631–1634. 14. Taylor RS, Van Buyten J, Buscher E. Spinal cord stimulation for chronic back pain and leg pain and failed back surgery syndrome: a systematic review and analysis of progressive factors. Spine 2005;30(1):152–160. 15. Pengel LHM, Herbert RD, Maher CG, et al. Acute low back pain: systematic review of its prognosis. BMJ 2003;327:323–327. 16. Bingel U, Wanigasekera V, Wiech K, et al. The effect of treatment expectation on drug efficacy: imaging the analgesic benefit of the opioid remifentanil. Sci Transl Med 2011;3(70):70ra14. 17. Tuttle AH, Tohyama S, Ramsay T, et al. Increasing placebo responses over time in U.S. clinical trials of neuropathic pain. Pain 2015;156(12):2616–2626. 18. Whitney CW, Von Korff M. Regression to the mean in treated versus untreated chronic pain.

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PART TWO

Economic, Political, Legal, and Ethical Considerations C H A P T E R 11 Transdermal Pain: A Sociocultural Perspective DAVID B. MORRIS “Chronic pain is a transdermal phenomenon and the environment is always a player in the chronic pain patient’s predicament.” —J. D. Loeser1

“A threshold has been crossed,” writes sociologist Nikolas Rose.2 Rose is director of the BIOS Centre for the Study of Bioscience, Biomedicine, Biotechnology and Society at the London School of Economics and Political Science. He wants to avoid what he calls “breathless epochalization”—hyperbolic claims that human history is undergoing a single, abrupt, massive upheaval—and he understands the present instead as the unfolding of “multiple histories” that emerge from the intersection of numerous “contingent pathways.” Nonetheless, he also provides in The Politics of Life Itself (2007) an indispensable framework for considering how much has changed since the first edition of John Bonica’s groundbreaking text The Management of Pain (1953). Pain too has changed, especially chronic pain, as pain has moved from the status of symptom to diagnosis, from the category of what humans passively endure (a mark of our changeless humanity) to what patients and health professionals 589

together, as partnered agents of somatic change, now actively manage. These recent transformations in understanding pain hold important implications for pain management. The dimension of change might be traced in the invention of the new discipline of pain medicine. “Prior to 1960,” writes distinguished pain specialist John D. Loeser, “there were no pain specialists.” He adds, “There were no journals devoted to pain, no dedicated research laboratories, and no funding programs aimed at pain research or training for clinicians. . . . Pain was always described as a byproduct of a disease state; the implication was that proper treatment of disease would relieve pain. The sensory nervous system was envisioned as a passive set of wires that conducted incoming impulses to the brain.”3 The Management of Pain in its first edition, reflecting this earlier and clearly imperfect state of knowledge, contained no discussion of relations between human pain and the sociocultural environment. The rich biomedical literature currently exploring relations between human pain and the sociocultural environment is sometimes difficult to appreciate because we are in the midst of another momentous change. Nikolas Rose describes this change as what he calls “a molecular vision of life.” Contemporary medicine and the biotechnologies on which it relies increasingly understand life at a subcellular level—with consequences that extend far beyond such familiar categories as illness and health, pathology and normality, and treatment and enhancement. The new techno-medicine, Rose argues, does not just cure disease or correct organic damage but, in its promise to refigure human vital processes at the molecular level, even changes “what it is to be a biological organism.” What it is to be a biological organism has always included vulnerability to pain, but it is not only our understanding of pain that has changed dramatically since 1953. Pain patients too have changed. A large subset of patients now regard themselves as well-informed, self-educated medical consumers, alert to the documented dilemma of medical error and actively embracing the apparent promise of what has been called our “genetic citizenship.”4 Women who carry the BRCA1 gene, for example, now understand that they face both an 87% risk of developing breast cancer and difficult medical options. Pain patients may expect that researchers simply 590

need to find the gene for pain and knock it out—without understanding that most researchers do not seek a single specific “gene for” but rather variations in multiple loci within multiple gene systems. Although older infectious diseases have almost disappeared, chronic pain seems almost ineradicable, even on the rise, less a predictable companion of old age or an image of the human condition than an unaccountable failure of the molecular gaze to identify a local culprit neuron. It leaves the modern patient locked out from the molecular promise of somatic optimization. The “incrementalism” required for slow, steady improvement (that likely falls far short of cure) is also frequently difficult for doctors to grasp.5 Thus, damage that chronic pain inflicts on body, mind, and spirit leaves many patients not at the threshold of a shining future but in a dark limbo or dystopia that negative psychosocial and sociocultural influences can turn into a prison or hell. What follows, then, is an effort to place the new understandings of pain within a conflict-laced field where sociocultural and psychosocial forces may actively impede or assist treatment. In the new era of the molecular gaze, it is increasingly clear to health care professionals (if not to patients) that chronic pain in its numerous types, from migraine to cancer to gardenvariety low back distress, is often more amenable to sociocultural analysis and to psychosocial therapies than to biomedical cure. Drugs and surgeries —perhaps the first choice of patients or insurance providers—may be exactly the wrong approach. Pain specialist Scott Fishman puts it this way: “When somebody comes in with 25 years of chronic pain, I might sit with them for 90 minutes to get the beginning of the story, to really understand what is happening. The insurers would rather pay me $1,000 to do a 20minute injection than pay me a fraction of that to spend an hour or two talking with a patient.”6 The pain that patients experience in certain medical settings, as new research unmistakably demonstrates, also reflects racial, ethnic, and provider biases in health care professionals that directly or indirectly affect real-world assessment and treatment.7–11 One quick caution. An attention to sociocultural and psychosocial influences on chronic pain does not imply rolling back decades of biomedical progress in which we now understand gout, for example, as a type of congenital arthritis and not—as in this 19th-century etching by 591

satirist George Cruikshank (Fig. 11.1)—a justified moral punishment for luxurious aristocratic lifestyles.

FIGURE 11.1 Introduction of the Gout by George Cruikshank, 1819 (this impression 1835). Colored etching. (Courtesy of Wellcome Library, London.)

Cruikshank, however, is not wholly wrong. The pain of gout correlates not only with molecular processes affecting serum uric acid levels but also with cultural and psychic forces underlying diet and socioeconomic position.12 Even today, gout has a sociocultural impact on patients’ lives that differs between African-American and Caucasian men and women.13 Bottom line: What most patients do not know about chronic pain— especially its concealed link with social institutions, cultural practices, and individual personal belief—is exactly what evidence-based pain treatment in the era of the molecular gaze cannot ignore.

What Is Transdermal Pain? Pain, especially chronic pain, is a transdermal phenomenon in that it occurs not only within an individual nervous system, including the brain, but also within a social and cultural environment. “Our concepts of pain, impairment, and disability,” writes Wilbert E. Fordyce, “must consider environmental factors as well as the person.”14 Clinical practice frequently reduces environmental factors to three main stressors—employment, family, and alcohol or drugs—but this trio can serve as placeholder for a more extensive mix of sociocultural variables. The fundamental question is whether the sociocultural environment merely influences pain that already 592

exists as a purely biologic phenomenon, simply modulating it, or, alternatively, if the sociocultural environment (beyond mere influence and modulation) helps to construct and to constitute pain. The difference between influence and construction is important, but its significance for assessment and treatment is unclear because chronic pain often reflects multivariate influences. Some pain—often called psychogenic—seems produced almost wholly by the brain or with little more than an innocuous trigger from the environment. In one study, researchers attached volunteers to an electrical stimulator and told them that its current might possibly produce a headache. Volunteers were not told that the stimulator was set to produce nothing beyond a low humming sound. The result? Half the volunteers reported pain.15 The environment need not cause or trigger pain in the way a hammer blow impacts a thumb. Positive or negative influences from the sociocultural environment may be as indirect as a whisper. Researchers, utilizing the molecular gaze, recently found that simply looking at the picture of a romantic partner reduced moderate pain by 40%.16 The sociocultural environment, in contact with human consciousness, may not create or construct pain, but it clearly possesses a resource for pain management too important to neglect or dismiss, and its importance increases in proportion to acceptance of the now widespread recognition that distinguishes between nociception and pain. The transmission of nociceptive impulses may at times generate autonomic responses, the human equivalent of a rodent’s tail flick, but nociception alone does not constitute human pain. Pain, according to the prestigious International Association for the Study of Pain (IASP), is “always subjective” and “always a psychological state.”17 The subjective, psychological quality of pain, as human consciousness interacts with the sociocultural environment, is true in spades of chronic pain. The crucial point here is that most pain specialists today attribute a significant role to the sociocultural environment—a truly historic change in thinking about pain and pain management. Moreover, the new managers of pain, from a sociocultural perspective, are now doctors and health care professionals, working within complex interrelated systems in which health care costs in 2014 rose to 17.5% of 593

the U.S. Gross Domestic Product.18 Pain management now cannot be cordoned off from the surrounding medicalized culture and subcultures, where the molecular vision of life has (selectively but broadly) replaced a reliance on shaman, priest, or astrologer. This pervasive medicalization of pain, however, is not without consequences, especially when medical care seems to fail patients. Pain medicine thus is not a neutral or inevitable byproduct of scientific knowledge but rather a presence within the new sociocultural environment that influences pain. Many patients today, that is, experience pain only within a context that includes various specialists who deal with pain, from orthopedists, oncologists, and neurologists to acupuncturists, homeopaths, and practitioners of alternative and complementary medicine. Pain specialists cannot excuse themselves from discussion as if they were mere impartial technicians, objective researchers, or altruistic caregivers—who assess and treat pain but do not affect how patients understand or experience it. Lous Heshusius, a Canadian academic born in The Netherlands, suffered excruciating chronic pain in the aftermath of an automobile accident. Over an 11-year period, she lists some 240 appointments with doctors and specialists; nearly 500 appointments with alternative professionals; a dozen appointments for tests and assessments; and countless hours keeping track of prescriptions, bills, and insurance.19 Pain specialists are among the key players in the new sociocultural environment that not only indirectly influences pain but also helps constitute the chronic pain patient’s predicament. The new active role for pain specialists is certainly driven by patient demand but not solely by patient demand, nor are its effects inconsequential. When clinicians employ evidence-based practices, chart pain as the fifth vital sign, or “game” insurance systems on behalf of their patients, such actions contribute to the maintenance of a significant sociocultural environment within which patients now experience pain. Although pain medicine did not invent insurance providers or disability systems, it operates today within a field of economic compensation that sets patients in a new relation to their pain. In a controversial recommendation, an IASP task force argues that chronic nonspecific low back pain in the workplace, in the absence of an organic lesion and under specified circumstances, should be reclassified not as a medical problem 594

but as “activity intolerance.”20 Activity intolerance is less a diagnosis than a tone-deaf counter-narrative meant to contest the implicit sociocultural narrative that regards chronic low back pain as redeemable for disability payments or for time off. The almost seamless but culturally mandated transition from person-in-pain to pain patient—whose inner life is now under the implicit surveillance of the molecular gaze—also involves an invisible agenda of forms to fill out, waiting rooms, secretaries, insurance companies, drugs, side effects, referrals, more waiting rooms, indignities, task forces, protocols, and still more waiting rooms.21 It situates pain and the pain patient within a web of sociocultural relations that reframe pain as transdermal.

Ethnicity, Race, Sex, Gender, Age: Whose Pain? A molecular vision of life enfolds the modern pain patient within layers of unappreciated irony. That is, while patients increasingly adopt the expectations of a molecular gaze, pain medicine finds increasing evidence to support nonmolecular and sociocultural understandings of pain. Culture and biology both contribute to pain, of course, as the standard biopsychosocial model implies, but patients committed to the molecular gaze fail to grasp the extent to which human pain is not only always subjective but also always intersubjective. It intersects with shaping social systems from family, church, and nation to jobs and prisons, just as it meshes with variable cultural practices and beliefs from stoic dispassion to pharmaceutical trials. Such sociocultural environments are not necessarily material locales, like a doctor’s office, but bear more resemblance to internalized, individual subsets of what anthropologists would call a lifeworld—a lifeworld that we experience as a state of body, mind, and emotion. Consciousness is the hard-to-define locus of such complex states, and chronic pain (as a classic mind/body state) is thus inextricable from the individual, intersubjective lifeworlds that shape as well as frame it. The clearest instance of how sociocultural environments shape as well as frame pain comes in long-standing medical undertreatment for pain.22,23 The hospital, that is, constitutes a distinctive microenvironment that demonstrates how sociocultural forces help alter the experience of pain. 595

The prestigious 1996 SUPPORT study found that 50% of hospitalized seriously ill or dying patients failed (according to family members) to receive adequate pain medication.24 Hospitals, like doctors, belong to the larger sociocultural environment where both drug abuse and fear of opioids have a strong presence, and the hospital as a distinctive microenvironment in some sense reproduces the mixed or selfcontradictory beliefs and practices that surround it. Anesthesia belongs to the sociocultural environment of the hospital, where it is accepted as necessary, just as illegal street drugs belong to the environment of the street, where other necessities prevail. Pure pain—pain free from all direct or indirect sociocultural influences, including the artificial, scientific subculture of the laboratory—is a pain that exists nowhere except in theory. Pain as it inhabits the social world outside the laboratory proves always open to the modifying environmental influences of (among other often imprecise categories) race, ethnicity, sex, gender, and age. Racial disparities in the assessment and treatment of pain are the focus of numerous medical studies.25 Differences in pain tolerance provide conflicting data, as in laboratory studies about racial tolerance for thermal pain.26 Some facts, however, are incontrovertible. In New York City, nonwhite patients who lived in disadvantaged neighborhoods (often black and Hispanic) had substantially less access to pharmacies than did white patients in more affluent neighborhoods. The pharmacies in disadvantaged areas moreover did not maintain adequate stocks of pain medication.27 A sociocultural environment that reduces access to analgesia has an indirect but powerful impact on pain. Although reduced access does not directly cause pain, sociocultural practices that unfairly burden racial and ethnic minority populations indirectly both maintain currently unrelieved pain and, in effect, permit the emergence of new pain that does not exist in primarily white, affluent, more pharmacofriendly communities. There is even neurologic evidence indicating brain and autonomic correlates with empathetic responses to pain in persons of other races.28 Fortunately, studies are now underway to improve clinician awareness concerning pain management disparities.29,30 Race and ethnicity, then, are frequently discussed in recent studies on pain—but discussion is often impeded by failures to clarify underlying 596

concepts. Classic articles describe ethnocultural differences in the perception of pain and of chronic pain.31,32 Numerous researchers report ethnic differences in the prevalence and severity of pain, and they find interethnic differences in tolerance levels for clinical and experimentally induced pains. For example, attitudes toward pain show sharp differences along ethnic lines among surgical patients in Australia.33 Cancer pain among southwest Native Americans has its own specific ethnic signature.34 Race affects how we view others’ pain.35 It influences analgesia use in pediatric emergency departments.36 It affects analgesic access for acute abdominal pain in the emergency department.37 Among patients with arthritis and rheumatic conditions, race and ethnicity even impact treatment outcomes.38 Yet, exactly what are ethnicity and race? Pain specialists need to engage with recent thinking about how to understand race and ethnicity. Bio-anthropologists contend that there is no genetic signature for race. In general, there is more genetic variation within (so-called) races than across races, which means that race and ethnicity are primarily sociocultural rather than genetic categories.39 Skin color alone links population groups as diverse as their languages: say, Italians and Swedes, Scots and Russians, and Belgians and Croats. Blackness, as a supposed racial marker, links West Africans with the historically very different East Africans, as well as with Haitians, African Americans, some Hispanics, and various hyphenated groups identified, roughly, by the mere color of their skin. Migration, intermarriage, and global travel have produced a wave of mixed-race offspring. The census term “Asian” has a different meaning in Europe than in America, and census data in Western democracies now define race and ethnicity not through genes, skin color, or geography but rather as a matter of selfidentification. In a movement away from reductive ideas of racial science, the most helpful recent turn in health care discussion emphasizes population groups, where biology and genetics are relevant but far from determinative. “Key, here,” as Nikolas Rose explains, “is not so much race, but the belief that a particular community has specific health needs that may have a genomic basis, and that research on the genomic basis is essential if these needs are to be met.”40 Pain assessment and pain management are caught up in the shifting 597

sociocultural and historical web of attitudes and practices that envelop race and ethnicity. Over half of Hispanics who presented at emergency rooms with long bone fractures, for example, were twice as likely as similar white patients to go without pain medicine.41,42 Hispanic ethnicity, according to a recent prospective 10-year evaluation, continues to impact pain management decisions in the emergency department.8 We need not posit conscious racism on the part of health care providers, although its presence in medicine (whether conscious or nonconscious) is well documented.43,44 It is enough to observe that medical degrees do not confer immunity from nonconscious acts of discrimination that reflect the racism of a surrounding culture. This fact should be cause for vigilance in health care settings. Although many blacks carry a gene that puts them at risk for sickle cell disease, their need for pain relief too often runs up against tacit medical stereotypes of drug-seeking behavior.45,46 Like the infamous Tuskegee syphilis experiments on black airmen, the history of sickle cell pain warns that sociocultural biases concerning race and ethnicity—not race or ethnicity themselves—pose a significant continuing danger to the achievement of color-blind, discrimination-free, equitable pain management. A means to identify and combat racial bias in pain treatment is now an urgent ethical issue in medicine.10 Telltale absences of equitable pain management unfortunately continue to appear in multiple medical sites not limited to the pain clinic. African American cancer patients in nursing homes were 63% more likely than whites to receive no pain treatment.47 Other minorities with cancer pain also experience inadequate pain relief.48 The unequal worldwide distribution and consumption of morphine means that medication for pain is far more available to first-world and mostly white patients than to nonwhites in the developing world.49,50 This difference is not mainly a function of income, although in the United States, there is a strong association between pain prevalence and socioeconomic position.51 The US campaign against illegal drug trafficking makes inadequate pain relief for Mexican patients also political in origin.52 Pain management teams, as they confront questions about clinical policy and research design, need to recognize that race and ethnicity are ill-defined, socially explosive classifications with little basis in genetic science. The laudable recent 598

interest in developing “cultural competence” among health care professionals who treat patients in pain cannot allow generic descriptions of group traits to replace a focus on the individual patient.53 Geronimo was not a typical Chiricahua Apache, and modern Apaches may share few cultural connections with modern southwestern pueblo peoples. Stereotypes based on race or ethnicity—often flawed or at least slippery concepts—are the enemy of good pain medicine. Sex and gender raise additional complications in assessing sociocultural influences on pain. Sex differences appear real, if limited. Animal studies indicate differences between male and female rodents in pain processing, including a greater efficacy of µ-opioids in males. In humans, κ-opioids produce significantly greater analgesia in women than in men.54 Even among women only, red-haired women (in a study that did not test men) show increased sensitivity to thermal pain and reduced responsiveness to subcutaneous lidocaine because of specific mutations of the melanocortin1 receptor.55,56 Biologically based sexual differences clearly play a role in women’s pain across a range of chronic pain conditions from migraine to irritable bowel syndrome, although the precise mechanisms are often unclear.57 Sex steroid hormones in men and women appear to modulate different nociceptive behaviors. Pregnancy, for example, whatever the television-dramatics associated with morning sickness and labor pain, creates an antinociception that involves δ-opioid and κ-opioid but not µopioid systems.58 Such biologic differences, however, are likely modest when compared with the exaggerated and shifting sociocultural representations of female and male pain—from Freudian hysteria to John Wayne machismo—that undoubtedly have a shaping influence on the experience of pain. Pain researchers have been slow to investigate potential differences due less to sex than to gender. Sex, that is, depends on the biology of male/female difference, whereas gender splinters the standard male/female binary into a rainbow of orientations from gay and lesbian to bisexual and transgender. One prominent argument in the field of gender studies holds that gender is largely performative, meaning, gender—no matter how individual, eccentric, or dependent on hormone therapies—constitutes a quasi-public social role.59 The women whom Charcot in the 19th century 599

photographed in his famous hysteria wards clearly “performed” their illness for the camera, even if unknowingly, and today women tend to perform specific gender roles (e.g., as overextended caregivers) that are sociocultural and not entirely unrelated to pain. Caregivers, for example, are at increased risk for multiple maladies, from depression to heart disease. Men, too, perform certain gender roles directly or indirectly related to the capacity to endure pain, where the power to endure pain is a sociocultural rather than biologic trait. A pain treatment program that recognizes the complicating sociocultural role of gender—in addition to well-known differences in sex, race, and ethnicity—will be best equipped to grasp the multiple lines of influence, both biologic and psychosocial, that so often converge in chronic pain. Age might stand as an icon for the multiple biologic and sociocultural convergences that influence chronic pain. Pediatrics and geriatrics both depend on biologic changes that accompany human growth, but childhood and old age are both also the site of numerous, tacit, culturally specific expectations. Pain research has devoted considerable resources to children, whose limitations in language and in perception require ingenious techniques for assessment. Techniques such as drawings that indicate the location and intensity of pain depend equally on the biologic facts of human linguistic development and on the sociocultural skills and learning associated with graphic design. Pain treatment geared to children also requires, in addition to carefully age-adjusted medications, an attention to childhood fears and feelings that belong to particular cultures. Much like ethnicity and race, age (especially cultural stereotypes of the elderly) has an impact on pain management decisions.60 Even in the emergency department, there appear to be disparities in pain treatment afforded to younger and older adults.61 Old age, however, whether defined by chronology alone or by organic and developmental changes, has received less attention than childhood in pain research, although the new field of palliative medicine is bringing rapid change.62 Indeed, one area in particular need of increased study is pain at the end of life.63 Dying is clearly a biologic process, but the funeral industry alone indicates how far death and dying are endowed with significance that is both economic and sociocultural. American and European medical attitudes clearly differ 600

about continuous deep sedation until death.64 Clear ethical guidelines on pain treatment at the end of life are greatly needed. Edmund Pellegrino,65 a giant of modern bioethics, defines the challenge to modern end-of-life pain medicine in what resembles a blunt, if indirect, ultimatum: “Not to relieve pain optimally is tantamount to moral and legal malpractice.” Why is it important for medicine to recognize the sociocultural influences on human pain as reflected in race, ethnicity, sex, gender, and age? First, although drugs and surgery sometimes erase or control pain associated with clear organic sources, many conditions such as chronic nonspecific low back pain expose the limits of drugs and surgery, especially where sociocultural influences—such as family, job, and disability—are involved. Furthermore, organic lesions do not map exactly onto pain. Most adults who complain of back pain have lumbar disk disease, but so do many adults without pain complaints.66 In America, long-term functioning of patients treated for back pain is similar whether doctors prescribe medication and bed rest or self-care and education.67 Pain simply does not provide an accurate report of tissue damage. “The truth is that pain is a very poor reporting system,” writes Patrick Wall. He adds, “The doctrine that pain is a useful signal needs heavy qualification.”68 The erroneous belief that pain is a reliable alarm system not only justifies countless unnecessary surgeries but also cannot begin to explain why the two strongest signs predicting that an American worker will develop chronic back pain are job dissatisfaction and unsatisfactory social relations in the workplace.69,70 It is as if the American low back is wired directly into the sociocultural work environment. A study covering 18 countries found large international variation in the prevalence of disabling forearm and back pain among occupational groups carrying out similar tasks.71 Second, the recognition of sociocultural influences on pain opens up possibilities for system-wide changes in pain management. In 1999, a memorandum directed to over 1,200 sites required the entire U.S. Veterans Health Administration to make policy and procedural changes implicit in the new principle that pain is the fifth vital sign.72 In one VA outpatient clinic, this change produced no measurable improvement in pain management quality.73 The possibilities for system-wide change are 601

impressive, however, especially when hospital accreditation now depends on requirements to chart pain levels. A similar requirement altered policies in pain management and in palliative medicine throughout all the hospitals in the vast southwest region of the U.S. Indian Health Service.74 Such changes acknowledge that pain management belongs to a surrounding sociocultural environment that includes the changing subculture of medicine. Systemic changes in pain management thus affect not only individual patients but also the wider sociocultural environments (from clinics and hospitals to digital media reports) within which both patients and nonpatients understand and experience pain. The IASP in its glossary of terms describes pain as “always subjective” and “always a psychological state.”17 Pain, by implication, may change when a person’s subjective, psychological state changes sufficiently. Systemic changes in the sociocultural environment of medicine— including efforts to reduce provider bias based on age, gender, sex, ethnicity, and race—can materially alter individual experience and help relieve pain. Such changes also recognize that a patient’s race, ethnicity, sex, gender, and age have demonstrable effects on the experience of pain. Suppose that a woman from a minority group in a low-income neighborhood repeatedly fails to receive adequate pain medication from her local pharmacy. Frustration, humiliation, and rage, compounding the fear that she may already feel about her health, constitute a significant change in her subjective state not unrelated to pain. Fear, as researchers show, elevates pain intensity.75 Pain specialist Mark Sullivan76 argues that pain itself is best understood as an emotion. Patient education and improved access to care offer two additional and specific areas for systemic change, with consequences that promise a difference in both the psychology of individual pain patients and in the surrounding, interpenetrating sociocultural environments within which people of any sex and gender—patients, doctors, nurses, adults, children, workers— understand and experience pain.

Across Cultures: Beliefs, Attitudes, Perceptions, Behaviors 602

Pain varies across individuals, cultures, and times. This strong claim contradicts the universalist view that pain is a changeless sensory signal, identical in everyone, everywhere. Dental research has identified an effect of culture on pain sensitivity.77 Culture, of course, is a broad general concept and not a sufficient explanation for pain or for pain sensitivity. In women, sensitivity to a variety of experimental thermal, mechanical, and chemical pain-producing stimuli has a proven genetic contribution.78 Individual variations in reported pain intensity produced by exposure to an identical noxious stimulus correlate directly with altered brain patterns, which can hardly be explained solely as an effect of culture.79 Most researchers agree, however, that pain includes both sensory and affective components, and affective components of pain show wide variation across individuals and cultures. The 1950s era surgically lobotomized patients could still feel pain, reportedly, but said that the pain no longer bothered them. It may require a philosopher to decide if pain that fails to bother us still counts as pain. (It will not show up at pain clinics.) It did require philosophers to compile a volume of essays entitled Cultural Ontology of the Self in Pain80 (a rough translation: The Self in Pain as a Cultural Being). Pain that is both affect-free and culture-free constitutes almost a self-contradiction because researchers agree that personal emotions—far from being bio-hardwired at birth—are fundamentally cultural.81 Real-world pain, then, is characterized by an affective quality of aversiveness open to wide modulation. This aversiveness depends on corticolimbic networks, much as anxiety correlates with activity in the septohippocampal system.82 Emotions associated with aversiveness, however, also in part socially constructed and socially modified, need not prove static or unresponsive to additional sociocultural input. Stoic philosophers in the age of Nero exalted the use of reason to overcome pain, and many Greek texts retell the story of the Spartan boy (trained in courage and in military discipline) who remains silent as a fox hidden in his cloak gnaws him to death. Athletes, dancers, yogis, and religious celebrants continue to demonstrate how minds and emotions, as shaped by differing sociocultural environments, help to modify pain and pain behavior. Such sociocultural environments are not neutral containers for bodies in pain—like stage sets—but rather, the setting and its sociocultural 603

forces shape the pain. Even pain clinics and research labs are, in a specialized sense, sociocultural spaces. They help to shape expectations and to reinvent pain as surely as ancient religions shaped and reinvented pain through authoritative teachings about demonic possession and original sin. Whatever the surrounding culture teaches us or shows us about pain (including false information, erroneous recommendations, and harmful tales) holds the power to modulate what we feel—for better or worse—with direct and indirect implications for the medical discipline of pain management. Culture as a crucial force in shaping human pain across various eras, disciplines, and practices, from legal punishment to religion, is a subject of wide-ranging books and articles.83–85 An evidence-based pain medicine can draw particularly persuasive data from cross-cultural studies. For example, researchers compared chronic low back pain patients in Japan with a similar group in the United States and found the Japanese patients to be significantly less impaired in social, psychological, vocational, and avocational function.86 A cross-cultural comparison matching Portuguese chronic pain patients with English-speaking chronic pain patients showed strong similarities in associations between psychosocial factors and measures of pain experience: intensity, physical function, and psychological function.87 Just as various psychosocial factors may differ across cultures, psychosocial factors themselves (likely rooted in particular cultures) regularly affect the experience of pain. Of course, pain evoked in a lab or studied in reviews of medical literature may not replicate everyday pain experienced outside various controlled environments, and real-world sociocultural environments include not only visible institutions such as families, schools, and workplaces but also less visible currents of thought and feeling conveyed in advertisements, songs, sports, and personal interactions. Even parental models have an influence on how individuals understand specific pain events.88 Aboriginal people in Australia deal with pain in culturally specific ways.89,90 Hispanics and non-Hispanics show significant differences in their knowledge about hospice care, with a resulting impact on pain management at the end of life.91 Although similar illustrations might be greatly multiplied, they all tend to demonstrate how cultural attitudes and understandings permeate the experience of pain, 604

especially chronic pain. Nowhere is the interpenetration of culture and chronic pain so clear as in the growing medical literature on so-called pain beliefs. Pain beliefs exist in an individual mind, but they also reside within cultures so that cultures are the effective origin of most individual pain beliefs. We cannot name or discuss pain except in a natural language— English, Spanish, Farsi—that inevitably colors our understanding and subtly shapes our experience.92 Pain thus comes always already interpreted, and pain beliefs silently infiltrate behavior through implicit cultural scripts or narratives, much as athletes often play out a prescribed role in which tolerance for pain affirms male courage, team loyalty, and physical strength. Such normative social practices and behaviors, like the beliefs that support them, often prove amenable to observation. In fact, observation of pain beliefs (mostly via questionnaire) is a robust subdiscipline within pain medicine. Research shows that specific beliefs affect the pain we experience, especially beliefs about cause, control, duration, outcome, and blame. These beliefs affect not only chronic pain but also acute pain and postoperative pain. Pain beliefs, moreover, are often linked with emotions: anger toward a negligent employer, fear of financial disaster, hope for monetary compensation, or the desire for caring attention from a spouse. Some pain beliefs strongly correlate with pain intensity. Patients function better, this research shows, who believe they have some control over their pain, who believe in the value of medical services, who believe that family members care for them, and who believe that they are not severely disabled. In one study, specific pain beliefs correlated directly with treatment outcomes.93–97 If you believe that your pain is disabling, this internal pain belief (played out as human consciousness alters feeling and behavior) already predicts that you will be disabled by pain. The pain belief research that got underway in the 1990s shows no sign of slowing down. The vocabulary sometimes shifts from beliefs to perceptions to attitudes—and the patients under study now reflect an extended ethnic and global reach—but the findings consistently recognize the effect of culture on the understanding and experience of pain. It is important for pain management professionals in the United States to 605

understand African Americans’ distinctive perceptions of pain and pain management.98 New Zealand practitioners need to understand the attitudes and beliefs about back pain shared by New Zealanders.99 Studies of pain beliefs now extend to Somali women, inner city veterans, French Canadians, the general populace of India, as well as such distinctive groups as children and the obese.100–104 Research still tends to focus on what we might call the big three pain beliefs—catastrophizing, control, and disability—but researchers are beginning to study more diverse cognitive/emotional states associated with religious faith and spiritual practices.105 Especially important is pain-related research into attitudes about personal identity and self-efficacy.106 One review article posed the crucial question whether pain-related beliefs influence adherence to multidisciplinary rehabilitation. Conclusion: Treatment adherence is determined by a combination of pain-related beliefs either supporting or inhibiting chronic pain patients’ ability to adhere to treatment recommendations over time, and self-efficacy appears to be the most commonly researched predictor of treatment adherence, with its effects also influencing other pain-related beliefs.107 Future studies might well expand their methods and focus to include a larger sense of meaning—its presence, absence, or indeterminacy—as intrinsic to human pain. Meanings of Pain (2017), a collection of multiauthored essays with a philosophical turn, offers a rich lode of thought.108 In adults, chronic pain often implies a continuous process of interpretation—conscious, nonconscious, personal, cultural—that both builds up and deconstructs meaning. Why me? Is it serious? Will I get better? Such questions about meaning as well as the responses that they elicit, even nonconscious responses, illustrate how meaning is not merely an add-on to pain. Meaning is intrinsic to pain even at the zero degree where patients (hooked on biomedical myths) assert the belief that pain is meaningless. Pain in its social functions often reverts to its etymologic (Latin) meaning of punishment. Childhood discipline, spouse abuse, and even self-punishing guilt belong to a punitive semantics of pain. Although drugs temporarily stop pain and bypass meaning, meaning does not therefore die out. The brief pharmaceutical erasure can simply perpetuate the belief that consumer purchases and drug therapies buy relief. Meaning 606

here passes imperceptibly into cultural myth, and myths matter for pain management when the meanings that they encode prove harmful. A growing medical literature now explores false, erroneous, or harmful pain beliefs.109,110 Such harmful pain beliefs are as damaging to patients as unsupervised multiple drug cocktails. Detoxification is often a necessary step in pain treatment programs, and it makes sense to consider various clinical techniques of semantic detox. Catastrophizing—a toxic compound of fears and of beliefs anticipating disastrous outcomes—proves the single most important predictor for lower quality of life in chronic pain patients.111 Transdermal pain, then, is not a subclass of pain, but rather an encompassing tautology: All pain, especially chronic pain, is transdermal. It is shaped, invisibly, by sociocultural and intersubjective forces. This counterintuitive claim seems berserk to a weekend handyman who has just hammered his thumb, but pain (in addition to various neural networks and organic systems) depends on developmental learning and cultural editing. Ice packs on a throbbing thumb invoke an elementary cultural education, as does the commonsense but erroneous belief that pain correlates directly with tissue damage. Chronic pain requires a personal and cultural reeducation in which talk of genetic susceptibilities and neurotransmitters is compatible with research into modulating sociocultural variables.112 Even neuropathic pain in laboratory rats appears to show the impact of rodent-specific social variables.113 The medical literature on sociocultural variables in pain is too vast to review here, but future researchers might wish to explore what it might mean for pain management when sociocultural perspectives expand far enough to put assessment and treatment in contact with quasi-philosophical issues as large as narrative, ethics, and globalization.

Pain and Narrative: Culture, Meaning, Ethics Philosopher Alasdair MacIntyre114 identifies the widest importance of narrative knowledge when he writes that “we all live out narratives in our lives” and “we understand our own lives in terms of the narratives that we live out.” Life, as the discipline of narrative psychology puts it, is 607

inherently “storied.”115,116 In acknowledgment of this so-called narrative turn, Rita Charon writing in JAMA describes a new clinical approach she calls “narrative medicine.”117 Narrative (from Latin narrare = to tell) can be defined as simply as “someone telling something to someone about something.”118 Narrative medicine sets out to reframe the everyday act of talking with patients. Charon also reframes narrative as a specific form of knowledge—narrative knowledge—as distinct from what she calls the logicoscientific knowledge so valued in medicine. Narrative knowledge, as Charon describes it, is not in conflict with logicoscientific knowledge but rather, especially as an instrument for understanding pain, offers a valuable supplement or complement to the molecular gaze. The IASP multiauthored collection Narrative, Pain, and Suffering (2005) explores a series of relevant and illustrative cases.119 Narrative can offer insights into human pain sometimes otherwise unavailable. As a vehicle for the communication of cultural beliefs and social practices, narrative clearly plays a role in transmitting attitudes and perceptions that pain patients may imagine to be strictly their own unique personal beliefs. A personal narrative may also convey fine nuances of meaning and troubling webs of self-contradiction that offer a significant tool for understanding treatment-related attitudes that elude the coarse grid of generic questionnaires. There is also a downside to narrative that affects pain management. Pain narratives, that is, sometimes encode mistaken beliefs, such as the dominant biomedical myth that regards pain as the invariable consequence and symptom of organic tissue damage. In truth, as the IASP explains, many people report pain “in the absence of tissue damage or any likely pathophysiological cause.”17 A narrative medicine for pain, as Rita Charon puts it, promises significant therapeutic benefits where other approaches fail or fall short.120 A narrative medicine for pain might find one specific use in explicating the dilemma that occurs when chronic pain engages patients in the dynamics of what anthropologists call damaged or spoiled identity. Narrative, in this instance, offers insight into a patient’s experience of self and, in some cases, can provide a means for patients to construct a new or revised selfhood: an important step toward exiting the role of chronic pain sufferer.121 The findings in a study of fibromyalgia patients, for example, 608

suggest that narrative approaches helped participants both invent their own coping strategies and discover identities other than as pain patients.122 Participants in experiments asked to write about trauma demonstrate the astonishing power of narrative to moderate pain. Rheumatoid arthritis patients who wrote in narrative form about stressful experiences, for example, showed significant symptom reduction.123 Indeed, writing about trauma is associated with various measurable health benefits.124,125 The beneficial writing very often takes the specific form of narration. “Using our computer analyses as a guide,” explains psychologist James Pennebaker,126 “we realized that the people who benefited from writing were constructing stories.” Narrative, like a scalpel or questionnaire, has limits to its uses as a therapeutic instrument.127 Pain can push both narrative and meaning to an extreme point of collapse, where nothing can be written or spoken: a black hole from which meaning cannot emerge. Victims of torture may undergo experience so horrific and chaotic that it blocks any possible narration.128 In less traumatic situations, however, stories offer helpful public and private uses through their explicit or inexplicit commerce with ethics. Narrative had no relevance to bioethics at its modern beginnings in the 1970s as a branch of analytic philosophy, wedded to a rationalist, universalist discourse of principles, often referred to as principlism. From a sociocultural perspective, ethics is not strictly a discourse about universal truths and timeless principles but, like medicine, an intersubjective project shot through with narrative meaning.129 Although pain medicine has developed ethical guidelines concerning research on animals and on humans, there is room and need for an ethics of pain that moves beyond professional guidelines and beyond principlism.130 Pain, like love, can call into question our relations with others, not only spouses or friends but also people who are radically other, nothing like us, enemies perhaps. Narrative ethics challenges us to understand pain as always embedded in the distinctive life-stories of individuals, where ethical choices may fail to map precisely onto a rationalist logic of universal principles. A narrative ethics can illuminate contingent choices and variable contexts in which universalized moral rules are less important for health than the clarification of contingent values. 609

Values, intricately layered with beliefs, have proven correlations with pain. Among adult patients in a pain management unit, success at living in accordance with one’s values correlated with measures of disability, depression, and pain-related anxiety.131 Religion and spirituality also engage value-based beliefs—relevant to pain—that narrative helps illuminate. Among predominantly white, Christian, mid-Western patients with chronic musculoskeletal pain, the religious and spiritual beliefs of patients differ from the beliefs of a healthy population, and long-time pain patients received less support than other patients from their church community, tending to lose hope and to grow bitter: angry at themselves, at society, and at God.132 The Journal of Pain and Symptom Management in 2010 published an article evaluating the FICA tool for spiritual assessment.133 In Europe, a spiritual-needs questionnaire has proved useful for treating patients with chronic pain and cancer pain.134 Such instruments are not attuned to narrative meaning, but spiritual needs regularly imply an underlying narrative structure of belief. Pain narratives turn especially complex, however, when personal, spiritual, and social values clash. Should pain management—in such instances, or perhaps generally—be understood as a basic human right?135 A response based on timeless principles or universal truths may prove less persuasive than extended discourse that identifies underlying narrative beliefs and ultimately hammers out a shared agreement on values. Pain management implicitly affirms a set of values perhaps less applicable to illness in general than specific to pain: values that attribute to pain the status of an imperative call. Pain in this sense—as in the familiar biblical narrative of the good Samaritan—calls out for (or requires) active assistance. Reason, like justice, is not timeless and universal but temporal and contextbound.136 Pain management in an era of increased global diversity may find more common ground in shared professional narratives—narratives of human rights or of service to others—than in principles at odds with the values of a surrounding culture.

Beyond the Gate: Consciousness and the Limits of a Molecular Gaze 610

The molecular vision of life—or its precursor in Foucault’s well-known clinical gaze—made its dramatic entry into pain studies in 1965 when anatomist Patrick Wall and psychologist Ronald Melzack published their influential gate-control theory.137 The gate-control theory focuses on the process of nociception and on neural impulses blocked or transmitted at specific organic locales, and it pays particular attention to the “gating mechanism” located in the dorsal horn of the spinal cord. This innovative gaze inside the anatomy of human pain certainly changed medical thinking in the latter half of the 20th century, when the gate-control theory achieved iconic explanatory status, and some 21st century pain specialists find the gate-control theory entirely adequate: It has stood the test of time.138 The legacy of the gate-control theory can be traced, for example, in research into molecular approaches to treat neuropathic pain.139 Others, however, remain quiet or uneasy. The uneasiness occurs in part because the gatecontrol theory applies far better to acute pain than to chronic pain. Ronald Melzack has radically revised or quietly abandoned talk of a dorsal-horn gate and now emphasizes what he calls a cortical “neuromatrix.”140 Distinguished pain specialist and neurosurgeon John D. Loeser—in a 1991 article entitled “What Is Chronic Pain?”—reflects a similar change in perspective when he asserts, “The brain is the organ responsible for all pain.” “All sensory phenomena,” he adds, “including nociception, can be altered by conscious and unconscious mental activity.”141 Neuromatrix theory proposes numerous networked brain connections that, beyond nociception, call into play a range of conscious and nonconscious human mental–emotional activity often rooted in the sociocultural environment. A molecular gaze that focuses on a few anatomical “gates” may prove adequate for specific chronic conditions such as neuropathic pain, although treatment for neuropathic pain remains extremely difficult, but an explanatory theory that reduces all chronic pain to neural impulses blocked or passing through a spinal gate risks ignoring the complex mind/body interrelations characteristic of a transdermal perspective. The dilemma is clear: Insurers and peer reviewers want hard evidence, although chronic pain is often characterized by multiple influences not easily amenable to cellular repair or reducible to sound quantitative data. Research on chronic low back pain, for example, is 611

mostly restricted to high-income countries, where rates of low back pain run 2 to 4 times higher than in low-income countries. Within low-income countries, rates of low back pain are higher in urban populations than in rural populations.142 These socioeconomic variations suggest that low back pain—a signature instance of chronic pain—is not a likely candidate for molecular cure. Many multidisciplinary treatment programs now recognize the impact of psychosocial factors and emphasize cognitivebehavioral therapies, but “psychosocial factors”—reducible to the influence of families, jobs, and alcohol or drugs—often merely nestle uncertainly within a dominant, evidence-driven, biomedical model. The challenge for pain management in the decades ahead is perfectly captured in the title of a recent research paper: “Cognitive Behavioral Therapy for Chronic Pain Is Effective, But for Whom?”143 The authors point out that the oldest and most educated patients showed strong treatment effects, whereas younger and less educated patients did not. It will require extensive additional research to confirm and to explain these findings. Unless the impact of age and of education are due entirely to anatomical or neural development, however, it appears that even the success of cognitive-behavioral therapies depends in part on changes ascribable to a sociocultural environment. Success, most patients would agree, is the goal of any pain management program, and a totally pain-free state is no doubt an unrealistic definition of a successful outcome. Pain management programs may at times unknowingly prove countertherapeutic if they provide an official confirmation of disability status or rigorously transform people in pain into long-term pain patients. Patienthood as an official or unofficial status brings its own sociocultural baggage. In pursuit of success, there is value in studying communities in which people who do not seek medical care for chronic pain—by choice or because modern medical care is unavailable—nonetheless lead, by their own accounts, happy, productive, successful lives. How do they do it? Success for a person living with pain ultimately is a matter of consciousness. Of course, consciousness is a concept difficult enough to occupy teams of philosophers, neurologists, and students of artificial intelligence, but success for people in pain ultimately plays out in their conscious and nonconscious mental lives. Even chronic pain patients who 612

master coping skills have somehow changed their mental and emotional architecture. The new field of positive psychology argues persuasively for shifting focus away from dysfunction and instead seeking to understand what specific beliefs, attitude, and practices appear to promote effective function and personal happiness.144 Positive psychology suggests that there is value in identifying “success stories”: another narrative genre relevant to medicine.145 Such success stories might be drawn not only from people in pain who benefit from cognitive-behavioral therapies but also, perhaps especially, from people in pain who lead successful lives and do not enter pain treatment programs or research protocols. Hope and fear take on unusual, even primal power when pain strikes, as reflected in both the placebo effect and the nocebo effect. (“Voodoo death” is a documented fact.) Prayer and the belief structure reinforced in a church-centered community suggest resources that a biomedical or gate-control model of pain too often ignores in its quest to identify organic processes. An additional danger or limitation in an unrevised gate-control theory is that it may excuse specialists from an opportunity—ethical or medical—to address social and political pain-related conditions outside the nervous system.

Pain and Globalization: Power, Money, Systems Sociologist Elliott A. Krause146 in Power & Illness (1977) shows how health and health care are “intimately involved with the political, economic, and social struggles of the present day.” Krause146 studied power as oppressive and coercive—a perspective that is relevant to current legal, military, and medical discussions of pain in torture, say, or in capital punishment. Michel Foucault,147 however, moves beyond his early focus on power as oppressive, top–down, and hegemonic, expressed in prohibitions and restraints. In his later work, Foucault147 views power as horizontal, distributed, even demotic, expressed as usable energies always circulating within a social system, like electricity coursing unseen and productively through the walls of medical facilities. This later perspective illuminates the recent, ongoing transformation of patients from passive (powerless) subjects of a colonizing biomedical gaze to active agents, 613

whose limited but real powers range from noncompliance and litigation to undisclosed alternative and holistic modes of self-care.148 Such changes, reflected in hospitals that openly post a patient’s bill of rights to adequate pain relief, suggest that pain management inescapably takes place now within the vast, disruptive, social, and economic power shift called globalization. Globalization holds potent implications for the sociocultural dimensions of pain and of pain management. It brings patients from far-flung nations whose indigenous belief systems and whose inabilities to handle spoken English create new challenges across medicine. It also alters the commercial landscape within which medical care and pain management occur. For example, the publicly owned, family-run, mid-Western US pharmaceutical company Upjohn, which marketed ibuprofen and its overthe-counter (OTC) spin-off, Motrin, merged in 1995 with European conglomerate Pharmacia, headquartered in Sweden; the merged company Pharmacia & Upjohn in 2000 merged with Monsanto and took the name Pharmacia Corporation; and in 2002, Pharmacia Corporation was bought by the international colossus Pfizer in pursuit of full rights to the (now disgraced) blockbuster pain drug Celebrex. Marketplace dominance consolidated in a few transnational monoliths that underwrite activities, journals, and organizations in support of pain specialists justifies Foucault’s149 concept of biopower. Biopower refers to a modern, medical, state-sponsored, and corporate-inflected authority over health-related activities from sexuality to population control. Nikolas Rose150 proposes the related term biopolitics to describe a postmodern extension of biopower to far broader supra-state manipulations of human vitality, morbidity, and mortality. Pain management, not fully separable from the influence of a transnational pharmaceutical industry, cannot today be fairly represented as individual encounters between a patient and a caring doctor or health care provider. A full sociocultural analysis of modern pain management would need to situate the traditional doctor/patient dyad within a new supradyadic, globalized biopolitics as dominant (if unnoticed in most everyday affairs) as the force of gravity. Money and pain? Pain patients are, of course, cared for largely within complex, high-tech, financially stable systems assuring—to put it crassly 614

—that health care professionals are paid. Local compensation issues are often influenced by national or international forces, such as the traffic in illegal drugs and its effect on domestic licensing and disciplinary boards charged with regulating opioids.151 Financial and political questions cannot be dismissed as merely crass in any full sociocultural perspective on pain. Who is eligible for treatment in a pain center or pain clinic? Political issues concerning citizenship and insurance coverage may be highly relevant. Is “likelihood of improvement” a formal criterion for enrolling patients? If insurance coverage is held to enhance the likelihood of improvement, then uninsured patients are de facto excluded. Some 10.4% of the US population still has no health insurance, despite recent changes, with percentages far higher among black and Latino minorities.152 These bland statistics reveal pain silently enfolded within larger, invisible systems of biopower and of biopolitics. Biopower and biopolitics are not soft concepts but hard realities that influence the profound inequalities (in access to care and in treatment of pain) that face individual patients as the consequences of race, socioeconomic status, and the fast-changing configuration of national and international health care systems. In Haiti, for example, anthropologistphysician Paul Farmer struggles against global pharmaceutical companies and cost-driven policies of the World Health Organization to provide medication for HIV/AIDS patients with multiple drug-resistant tuberculosis (TB).153 Even national systems of universal health care cannot ignore cost in decisions about whom to treat and how. Among postoperative patients, patient-controlled analgesia (PCA) lessens pain, shortens hospital stays, and reduces pain medication, but it is also expensive, raising unresolved questions about cost-effectiveness, social justice, and access to care.154 Who gets it? In a balancing act that weighs cost against temporary discomfort, many patients and systems cannot afford adequate pain control.155 There is no mechanism for creating balance—indeed, no agreement about what constitutes balance. For HIV/AIDS patients in sub-Saharan Africa who may barely find enough to eat, pain medications and nondrug therapies alike are an unaffordable luxury.156 Here, too, the operations of biopower and biopolitics in a nonWestern sociocultural environment help bring to light the less obvious 615

(more accepted) ways in which liberal democracies do or do not deal adequately in the management of pain. The impact of changing worldwide health systems shows up in pain management as patient concern for alternative and complementary medicine. Patients today pick the latest secularized healing art from a menu of eclectic, health-related therapies marketed like vitamin pills to late-capitalist consumers in a new global “ethnomedicine.”157 In 1990, Americans made 425 million visits to providers of complementary and alternative medicine (CAM) or, as it was first called, “unconventional therapy.”158 This figure startled many analysts because it exceeded the population of the United States. It did not express an outright rejection of biomedicine, as 83% of these patients also sought treatment for the same condition from a medical doctor: Significantly, they also paid 75% of all costs out-of-pocket. A sense of the illicit nonetheless surrounded these excursions outside the biomedical model. The vast majority (72%) of patients who used unconventional therapies did not tell their physicians. Official discourse and unofficial practice—including the practice and discourse of pain medicine—has begun to change in response to this new populist, eclectic self-care that draws its principles and therapies from around the globe. From 1990 to 1997, there was an almost 50% increase in visits to so-called “alternative medicine practitioners.”159 The number of visits soon exceeded the total visits to primary care physicians, and in 1998 the usually slow-footed US Congress established the National Center for Complementary and Alternative Medicine (NCCAM)—with a mandate to explore approaches to health and wellness “that the public is using, often without the benefit of rigorous scientific study.”160 CAM research increasingly supports the use of nontraditional treatments for symptom control among seriously ill and elderly patients.161 No mere lifestyle fad, this change extends even to cancer patients, who show a high prevalence of CAM use, especially among patients who are well-educated, well-off, young, and female.162 Three quarters of US medical schools now require coursework in CAM, and CAM therapies crossover to pain medicine with surprising ease. Among people reporting back or neck pain within the last 12 months, a national telephone survey in the United States found that 54% used complementary therapies (especially chiropractic, massage, and 616

relaxation techniques), compared with 37% who saw a conventional provider.163 Indeed, mind–body therapies have been shown both to cut the number of physician visits and to reduce arthritis pain.164 As attitudes change and as science catches up, American physicians and patients can now consult research-based data on topics from acupuncture to zinc enfolded within the Internet site of a new National Center for Complementary and Integrative Health. Pain is now the focus of significant research into CAM therapies, and today the NCCAM has an annual budget over $100 million, representing not only a major institutional shift but also changes in the application of biopower. Review articles give mixed reports concerning the costeffectiveness and clinical benefit of CAM therapies for various pain syndromes, especially chronic low back pain.165–167 Back pain is certainly the most common reason for visits to acupuncturists, chiropractors, and massage therapists.168 Although CAM mind–body therapies are not a popular treatment for pain as yet, most patients with chronic back pain expressed at least an interest in CAM therapies.169,170 The inconclusive and scattered data boil down to a strong initial preference among back pain patients for acupuncture, chiropractic, and massage: a view that pain management programs need to take into account not least because patient preferences encode pain beliefs and because beliefs as well as preferences change. Beyond an individual choice of therapies, however, a sociocultural perspective would emphasize how complementary and alternative therapies reflect changes in a globalized medical marketplace where drugs and surgeries for pain face increased competition from homeopaths, multicultural Internet remedies, mind–body meditation techniques, and assorted unconventional therapies. Consumer activism, global options, and perhaps even a discontent with traditional biomedicine are changing the culture of pain patients, and additional related changes are predictable for pain management. The cultural system that has received most attention in its impact on chronic pain is disability insurance. Like most developed nations, for example, Scandinavian countries face rapidly mounting claims for pain associated with automobile accidents. Lithuania, however, which has no auto insurance, also shows no significant difference between accident 617

victims and a control group in reports of headache and neck pain.171 Chronic whiplash syndrome appears to be partly an artifact of social systems of accident and disability insurance. It is the systems, as much as persons in pain, that produce a call for pain treatment. This new post1950s postmodern cash-driven disability narrative, however well intended, entails emotional costs for patients and financial costs for health care systems; it sometimes puts pain management programs in adversarial roles in relations to patients or to stage agencies; and it often makes successful treatment more difficult.172–175 Pain today, in short, exists inside cultures where national health care systems and third-party insurers may inadvertently establish potential careers for patients as damaging as hysteria in the 19th century. Even the decision to become a patient is a cultural artifact: In a small Aboriginal community in Australia, back pain is not regarded as a health issue, people do not show public pain behaviors, and sorcery is a standard resource.176 Law as well as sorcery has an impact on pain. Some organizations require pain patients to sign contracts that transform prescription drug abuse into legal grounds for denial of treatment. Employers too play a role in reframing pain, as monotonous jobs and lack of workplace autonomy are predictors of chronic pain disability.177 The category of repetitive stress injury shows how sociocultural changes create new patterns of pain. Older employees with lower education and lower occupational status appear at increased risk for disabling chronic pain.178 Women of so-called “deprived” socioeconomic status run higher risk of pain and experience pain as more severe and disabling.179 Families as a sociocultural system, like jobs, add significant complications to pain.180 Large-scale changes in family structure create new challenges for clinicians, as postmodern families emerge reconfigured as unstable, nuclear units fractured by divorce, blended across multiple marriages, mixed in race and gender, and marked by significant demographic shifts. The family dynamics of chronic pain has so far yielded inconclusive data.181 Researchers agree, however, that pain and families exist in an intricate loop of reciprocal relations, such that the patient’s pain affects the family and the family affects the patient’s pain.182,183 Among people with rheumatoid arthritis, spousal interaction 618

has a complex influence on pain-related catastrophizing.183 The precise family dynamics across specific disease conditions is less important here than identifiable links between family life and chronic pain patterns. As various emerging social roles and responses within the family structure grow clearer, pain specialists have particular reason to examine the related narratives and cultural forces that inescapably impinge on the individual experience of pain.

Conclusion: Summary and Synthesis A sociocultural perspective is imperative for a full and adequate understanding of pain, especially chronic pain. The limitations of a molecular gaze for understanding chronic pain would seem clear in proposals that seek to reduce all pain to a single organic cause: for example, inflammation.184 Inflammation is a biologic process common in chronic pain, but chronic pain is always both biologic and cultural. Neither inflammation nor any other single molecular process can wholly explain the peculiar difficulties of treating chronic pain in children, for example, where cognitive development, linguistic abilities, and family relations are central.185 It cannot illuminate the challenges that face elderly chronic pain patients,186 people with HIV/AIDS,187,188 or dying patients.189 Pain, from a transdermal perspective, is never simply a matter of molecules, nerves, or neurotransmitters, just as the practice of pain management is never just or entirely a matter of unambiguous evidence or of applied science. Overdetermination, in psychoanalytic theory, refers to the concept that multiple causes combine to produce a single behavior, emotion, symptom, or dream. Chronic pain, usually overdetermined in spades, is often described today not as a symptom but as a disease, although it is less a classic disease state than a complex, changing, multivariate event staged within human consciousness as always open to and modified by the surrounding sociocultural environment. Contemporary Barcelona sculptor Jaume Plensa, in his gigantic figure entitled Wonderland, offers a powerful image of how we might reimagine the human figure in pain—not so much contorted in agony but rather (no matter what the outward expression) as semitransparent: embedded within a surrounding, interpenetrating, and 619

changing sociocultural environment (Fig. 11.2).

FIGURE 11.2 Wonderland, by Jaume Plensa, 2012. Calgary, Alberta. Painted stainless steel, 12 m high. (Courtesy of the artist and Richard Gray Gallery, Chicago. Photographer: Thomas Porostocky.)

The sociocultural environment today as it impinges on human pain includes skyscrapers, banking centers, multinational pharmaceutical corporations, civic plazas, monumental artworks, and pain management programs even as it includes less tangible beliefs, attitudes, behaviors, and perceptions—all flowing through whatever individual organic neuromatrix or brain state gives rise to the phenomenon (as yet invisible to the molecular gaze) that we call consciousness. Human consciousness is ultimately where the organic processes of nociception culminate in pain. Consciousness—arguably, an emergent property of human brains, but no matter how we define or imagine it—modifies and interprets nociceptive sensory input in ways consistently responsive to the changing sociocultural forces within an individual’s immediate environment. It is an environment that for pain patients necessarily includes the clinician. Researchers recently confirmed, at least in electronic simulation, the hypothesis that patients who believe they share core beliefs and values with their clinician will report less pain than patients who do not.189 Such findings extend our general understanding that chronic pain is open to significant modification—for better or worse—from workplace, gender, ethnicity, belief, emotion, money, age, racial stereotypes, and narrative, to name a few. Children, in part because of a distinctive cultural, social, and linguistic background, may experience pain very differently than adults do. 620

First-generation immigrants may experience pain differently than their assimilated second-generation children do. Persons with HIV/AIDS may face a pain that is distinctive depending on how, in individual cases, a specific infectious disease engages the highly variable forces of geography, nation, social class, race, religion, stigma, and access to care. New media (such as Flickr and Tumblr) that combine visual images and multimodal elements are already extending and transforming traditional chronic pain narratives.190 Future media and new social forces, as their energies flow through the open mesh of human consciousness, will doubtless bring new changes to the experience of intractable pain. Chronic pain, in short, cannot be reduced to a static diagram of cellular processes. It is the always extracellular, nonmolecular, sociocultural dimensions of chronic pain that promise to offer difficult and continually changing challenges that pain management programs in the 21st century will need to confront and to address effectively.

ACKNOWLEDGMENT For his assistance, I am grateful to John Loeser, who attributes the phrase “transdermal pain” to his colleague Wilbert Fordyce. Many thanks as well to Daniel B. Carr. References 1. Loeser JD. Economic implications of pain management. Acta Anaesthesiol Scand 1999;43(9):957–959. 2. Rose N. Introduction. In: The Politics of Life Itself: Biomedicine, Power, and Subjectivity in the Twenty-First Century. Princeton, NJ: Princeton University Press; 2007:1–8. 3. Loeser JD. The future: will pain be abolished or just pain specialists? Pain Clin Updates 2000;8(6):1–7. 4. Heath D, Rapp R, Taussig KS. Genetic citizenship. In: Nugent D, Vincent J, eds. A Companion to the Anthropology of Politics. Oxford, United Kingdom: Blackwell; 2004:152– 167. 5. Gawande A. The heroism of incremental care. The New Yorker. January 2017. Available at: http://www.newyorker.com/magazine/2017/01/23/the-heroism-of-incremental-care. 6. Wallis C. The right (and wrong) way to treat pain. Time Magazine. February 2005. Available at: http://content.time.com/time/magazine/article/0,9171,1029836,00.html?iid=sr-link2. 7. Bartley EJ, Boissoneault J, Vargovich AM, et al. The influence of health care professional characteristics on pain management decisions. Pain Med 2015;16(1):99–111. 8. Craven P, Cinar O, Fosnocht D, et al. Prospective, 10-year evaluation of the impact of Hispanic ethnicity on pain manage practices in the ED. Am J Emerg Med 2014;32(9):1055– 1059. 9. Dickason RM, Chauhan V, Mor A, et al. Racial differences in opiate administration for pain

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pain expressions on social media. New Media Soc 2016;18(8):1455–1472.

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CHAPTER 12 Ethical Issues in Pain Management BEN A. RICH The fourth edition of this book was the first to include chapters specifically addressing the ethical dimensions of pain management. This is curious because the duty of physicians to relieve pain and suffering has been acknowledged for centuries. Indeed, this duty has been deemed an essential component of the ethos of medicine, as fundamental as the diagnosis and treatment of maladies. The rise of ethical discourse on the relief of pain and suffering in the late 20th century was prompted by a growing recognition that all too often pain was not adequately treated, and far too many patients unnecessarily endured the pain and suffering engendered by their illness. The fact that failure to adequately treat pain was not viewed until relatively recently as an ethical problem may have been due in large measure to the prevailing perception in medicine that pain was a necessary concomitant of illness which the “good” patient must bear with equanimity. Indeed, that is a common dictionary definition of the adjectival form of the word patient. In light of the preceding text, one can argue that the traditional view of the ethics of pain management, to the extent that it was articulated at all in the professional literature, provided a basis for undertreating pain, particularly if what was required to adequately relieve pain involved the administration of opioid analgesics. From the time of its development and inclusion in the medical pharmacopeia, morphine, and subsequent synthetic derivatives, has been recognized as a two-edged sword, carrying both the benefit of pain relief and the burden of potential addiction. The widespread phenomenon of undertreated pain seemed to be a product of a risk/benefit calculation by physicians that the risks of addition to opioids were unacceptably high, whereas the benefits of pain relief were relatively inconsequential. Particularly, in the second half of the 20th century, the clinical focus was on formulating a diagnosis and implementing disease631

directed therapies, not palliating symptoms. During the last several decades, however, there has been a gradual but highly significant paradigm shift in the ethics of pain management. Until quite recently, as David Morris insightfully notes in his book, The Culture of Pain, “The everyday medical dealings with pain conceal unacknowledged ethical questions.” Even in the care of cancer patients, Morris continues, the clinical ethos has been tainted by “an unacknowledged moral code expressing half-baked notions about the evil of drugs and the duty to bear affliction.” He concludes with the grim observation that “the ethics of pain management, unfortunately, may not receive proper attention until the first doctor is successfully sued for failing to provide adequate relief.”1 There was a remarkable prescience to Morris’s suggestion, for in the very year in which his book was published, a jury awarded millions of dollars in both compensatory and punitive damages to the family of a patient whose terminal cancer pain was undertreated. That case is discussed in detail in Chapter 15 of this book. Similarly, the ethical issues pertaining to the care of the dying patient are discussed in depth in Chapter 13, and the laws and policies relating to opioid analgesia are surveyed in Chapter 14. In the decade and a half since the publication of The Culture of Pain, the ethics of pain management has finally begun to receive the attention, discussion, and debate that had been so starkly absent before. This was the result not only of a heightened sensitivity to the phenomenology of pain and the suffering which it can engender or exacerbate but also of recognition of its multiplicity of sequelae. Also during this period, there was a remarkable shift in the prevailing view about the risk of addiction associated with medically directed opioid use. It is this last item that has undergone yet another significant transformation in the years since the fourth edition of this book was published. In the sections that follow, I consider the evolutionary process of the ethics of pain management and the current state of affairs.

Pain, Suffering, and the Core Values of Health Care For centuries, the core values of medicine and the other health professions

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never seemed to be in doubt. They were often, however, encapsulated in vague maxims of uncertain origin and authenticity such as primum non nocere (first do no harm) or “to cure when possible, to relieve often, and to comfort always.” The core ethical principles on which these maxims were grounded—beneficence and nonmaleficence—were unquestionably formulated by physicians during the long reign of paternalism as the overarching paradigm for the professional–patient relationship. What constituted benefit and harm, and when the zealous pursuit of cure should yield to the provision of comfort, or more radically still, occur simultaneously, was for the physician, not the patient, to determine. In the latter half of the 20th century, particularly but certainly not exclusively in the United States, the evolution of medical jurisprudence and the revolution in bioethics challenged the legitimacy of the paternalistic paradigm. This challenge was grounded on an emerging principle of bioethics—respect for individual patient autonomy. Indeed, by the end of that century, paternalism had been almost completely discredited, replaced by a new paradigm grounded on the legal duty to obtain informed consent (and to accept an informed refusal) supported by and in turn operating in affirmation of the most recent bioethical principle.2 The new paradigm for the professional–patient relationship became that of shared decision making.3 Although beneficence and nonmaleficence were retained among the core principles of modern bioethics along with a fourth justice, the clinician was no longer considered the ultimate authority on what constituted benefit and harm in the care of any particular patient. It is, after all, the patient who must endure the rigors of medical interventions and/or the burdens of disease. Thus, in the case of intractable disputes between clinician and patient, the patient has come to be recognized as the final arbiter. The dissenting clinician’s option is to disengage from the relationship (but not precipitously to constitute abandonment) when and if respecting the patient’s wishes compromises professional ethics or personal conscience.4 The relief of pain and suffering, however, was not an integral part of this transformative process. Only quite recently have the legal, ethical, and public policy dimensions of pain management and palliative care begun to receive due consideration, thereby properly 633

placing them within the emerging bioethical, jurisprudential, and sociocultural framework. Providing the details of this process is the task of this chapter, and the others in this section of this book.

THE DUTY TO RELIEVE PAIN AND SUFFERING When, over three decades ago, Eric Cassell began his seminal article on suffering and medicine in The New England Journal of Medicine, he did not think it necessary to build an extensive case for the proposition that physicians have a duty to relieve pain and suffering. Nevertheless, his initial inquiries into the attitudes of physicians and patients about pain and suffering revealed a curious phenomenon: Contemporary patients and laypersons attached appreciably more significance to that duty than did his physician colleagues.5 It is this disparity between laypersons and health care professionals in the prioritization of the need for and duty to provide not only treatment of disease but also relief of distress associated with it that caused, or at least significantly contributed to, the jury verdicts in legal cases alleging undertreatment of pain, which we consider in Chapter 15. If, in the ethos of ancient medicine, the relief of pain and suffering was the essence of beneficence (doing good) and nonmaleficence (avoiding harm), then something transformative took place in the transition to modern medicine. Otherwise, the opening passage of the preface to this book, which substantially expanded on Cassell’s original article, would be incomprehensible. That passage, a remarkably stinging indictment of his own profession, reads, “The test of a system of medicine should be its adequacy in the face of suffering . . . modern medicine fails that test.”6 In it, he analyzes in great depth important distinctions between pain and suffering, including notable instances in which a person can experience pain but not suffer as well as suffer in the absence of pain. However, most pertinently to this chapter and book is his observation that pain is the most common cause of suffering, and people in pain experience suffering when it is severe, uncontrolled, and seemingly without end.

CURATIVE VERSUS PALLIATIVE PARADIGMS OF PATIENT CARE Continuing with Cassell’s analysis, the willful blindness that afflicts 634

modern medicine with regard to pain and suffering (with the exception of those who specialize in pain management and palliative care) relates to the complex nature of persons and the reductionistic tendencies of modern medical science. He cogently expresses the nub of the problem when he declares, “Bodies do not suffer; persons suffer.” The implications of this proposition are clear but nonetheless potentially controversial: If a clinician cannot relate to the patient as a person, rather than as a body that is merely the locus of some disease process, then he or she cannot even recognize suffering and certainly cannot begin to competently and compassionately respond to it. Unsurprisingly, many clinicians view this as a gross exaggeration, verging on caricature. However, other credible sources bolster Cassell’s point. Consider, for example, the following panegyric of the late Yale surgeon and writer Sherwin Nuland7 in his book How We Die the curative paradigm of medicine: . . . the challenge that motivates most persuasively; the challenge that makes each of us physicians continue ever trying to improve our skills; the challenge that results in the dogged pursuit of a diagnosis and a cure; the challenge that has resulted in the astounding progress of late-twentieth century clinical medicine—that foremost of challenges is not primarily the welfare of the individual human being, but rather, the solution of The Riddle of his disease. Nuland7 is describing, with only a bit of grandiosity, one of the essential elements of the curative model cogently presented several years later by Ellen Fox.8 For ease of analysis, her delineation of the essential features of the curative and palliative models of patient care is illustrated in Table 12.1. TABLE 12.1 Models of Patient Care Curative Model Analytic and rational Clinical puzzle solving Mind–body dualism Disvalues subjectivity Biomedical model Discounts idiosyncrasy Death = failure

Palliative Model Humanistic and personal Patient as person Mind–body unity Privileges subjectivity Biocultural model Respects idiosyncrasy Unnecessary suffering = failure

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As illustrated in the table, point by point, the core elements of the reigning curative model are the diametric opposite of those in the palliative model, the latter being the one that presumably must be followed in order to respond appropriately to the pain and suffering associated with both acute and chronic illness. The clinical puzzle-solving element is precisely what Nuland7 waxes so euphorically about in his discussion of the zealous pursuit of “The Riddle,” which he maintains is the primary motivator and the ultimate goal of the best clinicians. As previously indicated, ethical issues in end-of-life care will be the special focus of Chapter 13 of this book. Nevertheless, it is worth noting the stark contrast in the perspective on death and dying between the two models. The view of many clinicians in the full grip of the curative model that a patient’s death is the ultimate medical failure has led, as Nuland7 himself admits, to situations in which medical specialists have “convinced patients to undergo diagnostic or therapeutic measures at a point in illness so far beyond reason that ‘The Riddle’ might better have remained unsolved.” The type of clinical situations to which Nuland7 refers, particularly when patients are intentionally deceived or kept in the dark about the grimness of their prognosis or the dismal prospect that additional disease-directed interventions will produce any benefit, constitute a form of what might reasonably be characterized not only as “medical futility” but also as “therapeutic belligerence.”9

The Phenomenon of Undertreated Pain The zealous, single-minded pursuit of a diagnosis and the relentless delivery of disease-directed interventions means, as a practical matter, that precious little professional time, energy, or attention is available for assessing and managing pain or suffering, even for those patients in the intensive care unit (ICU) who may be unlikely to leave the hospital alive. That is the bleak conclusion reached by the investigators in the formidable Study to Understand Prognoses, Preferences for Outcomes, and Risks of Treatments (SUPPORT) project in the mid-1990s.10 The SUPPORT principal investigators sought to evaluate the quality of care in the ICUs of certain premier academic medical centers across the country. The ICU, of 636

course, is the locus of patient care in which the curative (disease-directed) paradigm of high-technology patient care reigns supreme. The findings of the SUPPORT investigators are quite concerning with regard to such considerations as the relief of pain and suffering, the extent to which a patient’s plan of care had been discussed with the patient or her proxy, or the likelihood that code status was consistent with what was known about the patient’s wishes or values. For purposes of this discussion, at least three fundamental principles of bioethics were frequently violated in ICU care: respect for patient autonomy, beneficence, and nonmaleficence. More particularly, SUPPORT revealed that there was at best a 50–50 chance that the care provided to patients was consistent with their wishes, values, or written directives, and half of the patients studied were believed to be experiencing significant pain or distress in the last days of their lives. Similar disappointing findings about pain and symptom management have been reported in the care of pediatric ICU patients,11 nursing home patients,12 and in outpatient care of cancer patients.13 The pervasiveness of deficiencies in pain and symptom management encompasses virtually all patients regardless of age, type of disease, or locus of care and thus strongly suggests a problem that emanates from certain core issues in medicine and society to which we now must turn. Otherwise, we would be compelled to consider a highly implausible proposition; that is, that health care professionals are truly indifferent to the pain and suffering of their patients.

IDENTIFYING THE BARRIERS TO PAIN RELIEF Beginning in the 1990s, an unprecedented amount of attention has been paid to the root causes of undertreated pain. A consistently cited set of barriers has been identified. At a basic level, these barriers exist with regard to all types of pain: acute, chronic noncancer, and pain associated with terminal illness. However, certain barriers are exacerbated in patients with chronic pain. The general categories into which these barriers are divided are professional, patient, and societal in nature and origin.

Professional Barriers In one sense, as I will endeavor to make clear, the professional barriers to 637

pain relief are the most ethically significant, given the fiduciary nature of the clinician–patient relationship. The key elements utilized in assessing professional competence are knowledge, skills, and attitudes. Deficiencies in any one of these elements can result in inadequate and hence substandard patient care. Deficiencies in more than one for any type of patient care will markedly increase the likelihood that substandard care will result. Marked deficiencies in each of these dimensions have been documented in physicians (of all specialties), nurses, and pharmacists.14–16 What is most important from an ethical perspective is how deficiencies in one or more of these categories translate into behavior, that is, professional conduct. Given the pervasiveness of pain across the clinical spectrum, and the by now well-recognized sequelae of pain, only rarely may any clinician legitimately claim that such deficiencies pose no threat of harm to patients. As we shall further consider shortly, however, even clinicians who possess the requisite knowledge, skills, and attitudes may be reluctant to translate them consistently into effective pain management, particularly when what is clinically indicated may be opioid analgesia because of fears of regulatory scrutiny or other forms of potential legal liability. More recently, with the exponential increase in prescription drug abuse, addiction, and associated overdose deaths, deficiencies or other problems associated with a prescribing physician’s knowledge, skills, or attitudes may also imperil the lives or well-being of patients by inappropriately prescribing or failing to properly monitor a patient’s use of these medications. None other than John Bonica himself pointed out many years ago that no medical school has been so bold and innovative as to establish and maintain a formal, required curriculum in assessing and treating the most common problem of patients who seek medical care—pain.17 This glaring deficiency that he described nearly 20 years ago persists. In data ascribed to the Association of American Medical Colleges in 2003, only 3% of medical schools have a separate required course in pain management, and only 4% require students to take a course in end-of-life care.18 The absence of any solid evidence of a formal curriculum in the assessment and management of pain in most medical schools warrants the conclusion that none actually exists. Some defenders of the status quo have 638

argued that the requisite knowledge, skills, and attitudes are imparted in other less formal but perfectly acceptable ways, such as in the care of actual patients in the clinical years of medical education. What undermines these assertions is the strong evidence that health care professionals continue to graduate and obtain licensure with major deficits in knowledge, skills, and attitudes concerning pain management and its relevance to quality in patient care. The ethical significance of this phenomenon is the aforementioned “culpability of cultivated ignorance.” The absence of a pain curriculum in medical and other educational programs in the health professions may be an important reason why pain is often undertreated but is not an excuse for it. Medical schools have been, and continue to be, major culprits in the epidemic of pain. Evidence of the persistence of this epidemic continues to accumulate. The 2011 Institute of Medicine report Relieving Pain in America conservatively estimated that one-third of the adult population of the United States experience chronic pain.19 It is not merely an absence of required course work on up-to-date pain assessment and management techniques but also myths and misconceptions about the risks and purportedly unmanageable side effects of opioids that are deeply entrenched in the minds of clinical faculty and which are passed on from one generation of physicians to the next.20 However, it is axiomatic that good ethics begins with good facts. In the past decade, further research and examination has suggested that with regard to the long-term use of opioids for the management of chronic pain, the purported benefits may have been exaggerated, whereas the real risks of abuse and addiction underestimated.21 Recognizing the curricular deficiencies in pain assessment and management that have plagued physician training for decades, when the American Medical Association developed the Education for Physicians on End-of-Life Care Project (EPEC), it adopted a train-the-trainer approach in the hope of maximizing the dissemination of current thinking on palliative care to experienced practitioners rather than medical students or residents.22 Entering a profession entails a moral responsibility to ensure that one possesses and consistently applies the knowledge and skills essential to minimal competence. That one may in some instances enter the 639

profession with certain deficiencies does not provide a legitimate basis for cultivating ignorance that may be originally attributable to curricular deficiencies. The medical school curriculum should reflect the current standard of care and anticipate future improvements to it, but it does not set that standard in any definitive sense. In California, the continuing absence of a pain curriculum in medical schools, combined with increasing public awareness of and outrage over a national, indeed international, epidemic of undertreated pain, moved one crusading member of the California Assembly to introduce and successfully pursue a statute mandating two things: (1) that pain management and end-of-life care be part of the medical school curriculum for applicants seeking a license as a California physician after June 1, 2000, and (2) that inpatient health facilities include pain as a fifth vital sign assessed along with other vital signs and noted in the patient’s medical record.23 In yet another example of lawmakers interceding to address professional deficiencies, the California Assembly in 2001 enacted a statute requiring that all licensed physicians in the state (with the exception of radiologists and pathologists) receive a minimum of 12 hours of continuing medical education prior to January 1, 2007.24 The statute, however, had a sunset provision. Because the California Assembly did not vote to extend it, this continuing medical education mandate is no longer in force. These and the other legislative measures described hereinafter actually run counter to a well-established tradition in American government to leave the professions, particularly the health professions, virtually unfettered latitude and discretion to manage their affairs. Only when substantial evidence accumulates—and results in a high level of public concern—are lawmakers prompted to intercede. When morally troubling circumstances are allowed to persist by those who ostensibly have the power and authority to address them through nonlegal measures, the law has been invoked to address the problem. A graphic example was the Nuremberg Code that emerged from the Nuremberg tribunal’s prosecution of the Nazi doctors. The first principle of the Nuremberg Code was the right of human research subjects to informed consent. Twenty-five years later, when the public became aware that a number of clinical trials 640

conducted by prominent medical researchers in the United States were openly and notoriously violating the Code, which was an ethical– professional, not necessarily a legal mandate, the federal government stepped in with the first of what became many regulations of federally funded research involving human subjects.25 Similarly, in the early 1980s, a phenomenon known as “patient dumping” became the subject of significant public awareness and concern. When indigent or uninsured patients presented to emergency rooms, they were with increasing frequency shunted off to other (usually governmentoperated) hospitals for care, often with deleterious consequences from the delay in properly addressing an unstable medical condition. When neither the health professions nor national hospital organizations demonstrated any inclination to address the problem, the Congress of the United States passed the Emergency Medical Treatment and Active Labor Act (EMTALA), which imposed a mandate on all emergency departments to provide a medical screening examination to patients upon arrival, and to prohibit transfer of any patient found to be in an unstable medical condition prior to stabilization except under certain carefully described situations.26 Notably, EMTALA recognized pain as an indication of an unstable medical condition requiring prompt attention and effective remediation. These instances indicate that it is often the failure or refusal of health care institutions and/or professionals to put their own houses in order that prompts major governmental intervention in order to address an otherwise seemingly intractable problem. One must ask whether there is a causal connection between the failure of health professional schools to recognize the need for a pain curriculum and the failure of the health professions and the institutions in which health care is delivered to make the prompt, effective, and consistent assessment and management of pain a priority in patient care. We noted early in this chapter how Eric Cassell was perplexed by the seeming indifference to the phenomenon of suffering on the part of physicians given the traditional core values of medicine. The same is true for pain because another professional barrier has been characterized as the failure of health care institutions and professionals to make pain relief a priority in patient care. One of the primary objectives of many of the policies discussed in Chapter 641

14 of this book, particularly the Federation of State Medical Boards (FSMB) Model Policy and The Joint Commission Accreditation Manual standards on pain management, was to disabuse their target audience of the perception that effective pain management was not an essential element of sound patient care. The final professional barrier to effective pain management is fear of regulatory scrutiny and potential legal liability (civil or criminal). There is little question that the nidus of this concern relates to opioid analgesia. There is quite simply no discussion about such concerns arising out of nonpharmacologic pain management strategies. When one looks at the record of disciplinary actions by state medical boards, those relating in any manner to pain management practices were invariably characterized as excessive prescribing of opioids. Such cases are addressed in detail in Chapter 15 of this book. It is for this reason that the previously mentioned FSMB policy is of such potential significance, for it seeks to shift the focus of medical boards from “overprescribing” or “underprescribing” of opioids to inappropriate prescribing because both extremes pose risks to patients. From an ethical perspective, it is a troubling state of affairs when clinicians fear that they are at risk of disciplinary action by their professional licensing board if they follow current national clinical practice guidelines on the use of opioid analgesics. Their concerns have not been without foundation, for an initial survey of the knowledge and attitudes of state medical licensing board members regarding opioids and pain management revealed significant knowledge deficits and attitudes that were at best unsupportive and at worst hostile toward the use of opioids, especially for patients with chronic noncancer pain.27 One analysis of the prevailing attitude among medical board members concerning opioid analgesia characterized it as an “ethic of underprescribing.”28 A follow-up study conducted after the promulgation of FSMB guidelines on prescribing opioids and a series of workshops across the country on pain management for medical board members not only revealed some improvement in areas that might be reassuring to those whom boards are charged with regulating but also noted the need for further education and wider acceptance of the FSMB model guidelines/policy.29 642

When medical and other health professions’ boards issue new and presumably more enlightened policies on pain management, one cannot presume that most affected clinicians will become aware of them. There is still less of a basis to expect that these policies will, in the short term, have a direct and immediate impact on clinical practice even among clinicians who become aware of them. In the event that these new or updated policies were to become part of a mandatory continuing professional education program, there is nevertheless reason for concern that they would in fact be likely to significantly improve the usual custom and practice of minimizing the clinical significance of pain that has been mentored, modeled, and followed by generations of professionals.30 Concerted efforts must be made to reform practice patterns and the underlying clinical culture that sustains them by infusing more enlightened attitudes about the importance of pain relief to patient health and well-being. The regulatory barriers also include the federal Controlled Substances Act, the policies and procedures of the U.S. Drug Enforcement Administration, and criminal prosecutions of physicians for drug diversion or trafficking when their prescribing practices are deemed far outside the ambit of mainstream medicine. These issues are dealt in depth in Chapters 14 and 15 of this book. The ethics of public policy formulation and law enforcement strategies and tactics are somewhat beyond the scope of this chapter. Nevertheless, such practices are fraught with moral implications because they affect the lives of many people. Much of the impetus for the new emphasis on balance intended to moderate between seemingly competing considerations of preventing drug abuse and diversion, on the one hand, and ensuring that patients in pain receive the analgesics they require for effective relief has been based on legitimate concerns that state and federal regulatory and law enforcement measures have been obsessively focused on the former and virtually indifferent to the latter. We consider the moral dimensions of pain policy and law further from the perspective of the health care professional in a subsequent section of this chapter as well, when we take up the demands of professionalism to make the patient’s needs and interests primary in a fiduciary relationship. As the full scope of the national opioid overdose epidemic became apparent, the political and societal pressure to discourage physicians from 643

routinely and indiscriminately prescribing opioids has understandably increased. The statistics are striking. In 2014, roughly one in three accidental drug overdose deaths were related to prescription pain relievers.31 This data calls into question one of the lynchpins of the original challenge to the ethic of underprescribing of opioids for chronic pain, which was that the risks of addiction or abuse of such medications was relatively low.

Patient Barriers Patient barriers to effective pain relief are in important ways related to physician barriers. Traditionally, clinicians were the primary source of patient information on medicine and health. If they did not themselves possess accurate and up-to-date information about the risks and benefits of pharmacologic and nonpharmacologic modalities of pain relief, they would not be able to fulfill their professional responsibility to educate their patients. Indeed, that is why pain management has historically been an area of clinical practice in which truly informed patient consent was virtually nonexistent. Now, however, in the Internet age, patients and family members may actually access up-to-date information on pain and its management as or more often than their physicians. Without adequate information concerning the available range of pain management interventions and their relative risks and benefits, patients had no basis on which to formulate reasonable expectations with regard to pain relief. A major public survey on pain in the United States conducted in 1997 revealed that not only is pain pervasive, but the most common reason why people avoid seeking medication to relieve their pain is fear of addiction or physical dependence.32 Once again, recent data on prescription drug abuse and overdose deaths indicate that patient concerns about this risk are neither groundless nor frivolous. The clinical and ethical challenge for physicians is to accurately assess the risks and benefits of each pain relief option based on the patient’s particular circumstances. Patients may also avoid seeking medical care when they experience pain because they fear it may be caused by some serious, perhaps even lifethreatening, condition. Finally, patients experiencing pain that is associated with conditions for which they are currently receiving treatment 644

may not complain about their pain and seek more effective pain relief because of a mistaken assumption that pain is an unavoidable concomitant of therapy or that their physician would certainly be providing as much pain relief as possible. It is these latter perspectives that help explain how, until the legal cases discussed in Chapter 15 arose, no malpractice claims based on negligent pain management had been brought despite an epidemic of undertreated pain.33

Societal Barriers Pain and suffering are not just immensely complex and highly individualized human experiences. They occur within familial and other interpersonal contexts as well as social, organizational, and governmental configurations. Pain in particular may not only be a symptom of an underlying condition, but it may also, in the case of chronic noncancer pain, become a condition itself, hence the appropriateness of the term chronic pain syndrome. These are often, as Arthur Kleinman34 has observed, “Conditions in which the degree of pathology does not seem to explain the severity of perceived pain or the limitations in bodily functioning the pain produces.” This marked disparity between the patient’s pathophysiology and reports (often interpreted as complaints) of pain and disability produces a strong element of skepticism not only on the part of clinicians from whom the patient seeks care but also from family and friends. These doubts about the veracity of the patient’s experience of chronic pain can exacerbate the feelings of isolation and abandonment that characterize the chronic pain patient. At the end of this chapter, we further consider the special challenges for the clinician posed by the chronic pain patient. American culture in particular has precious little patience with or sympathy for the chronically ill. Indeed, much of the recent momentum within the disability rights movement has been an understandably strong reaction to the widespread perception among the healthy and able-bodied that certain profoundly disabling conditions are categorically incompatible with any quality of life whatsoever. In response to such pervasive attitudes, perhaps the most high-profile disability rights organization took the name “Not Dead Yet.” Their message is clear to society in general and 645

health professionals in particular: We do not seek your assistance in ending what you consider our miserable existence but rather in enhancing what we consider to be our quality of life and our ability to be active and engaged members of our community.

Ethical Implications of the Barriers There is a new emphasis in both undergraduate and graduate medical education on professionalism and communication.35 In some small measure, such curricular reforms may begin to address the larger and more fundamental problem identified by previously cited commentators such as Cassell, Fox, Kleinman, and Morris that is posed by medicine’s predilection for biologic reductionism and obsession with diagnostic and disease-directed interventions. The none-too-subtle point is that one does not enter into a professional relationship with or provide care to a disease process. Although a certain cadre of clinicians may romanticize the pursuit of “The Riddle” of disease, the professional relationship (fiduciary in nature) and communication are necessarily with the personhood, not the disease of the patient. The assessment of pain, for example, is all about effective communication between patient and physician concerning the subjective experience of pain. If effective pain assessment is absolutely essential to providing effective pain relief, then the clinician must be able to understand and appreciate the patient’s experience of illness in a manner and to an extent that may not be true for other aspects of patient care. As previously noted, the concept of holding oneself out as a professional and the ethical demands of entering into a fiduciary relationship with another person entail the acquisition, utilization, and maintenance of the knowledge, skills, and attitudes necessary to ensure minimally sufficient competence. When a significant percentage of the practitioners of a profession such as medicine or nursing have been found to have major deficiencies in something as pervasive as pain and as integral to good patient care as are its assessment and management, invariably major ethical issues arise. It is in the recognition of these ethical issues that one demonstrates a grasp of the close relationship between ethics and professionalism. Yet, there was a period in the early years of the

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movement to address the widespread phenomenon of undertreated pain when there was little acknowledgment of, and hence attention to, the ethical dimensions of these professional deficiencies. Turning from barriers associated with knowledge deficits and problematic attitudes toward the significance of pain and its relief to those associated with legal and regulatory concerns, we encounter a challenging ethical quandary. As described in detail in Chapter 14, the regulation of opioid analgesics created a hostile environment toward their widespread use in pain management. Regulatory barriers, including a pattern of medical board disciplinary actions against physicians for so-called “overprescribing” of opioids, have, as previously noted, caused physicians to feel at risk even if they are scrupulously following state-of-the-art clinical practice guidelines. A fundamental ethical question posed by this situation is as follows: To what extent is it reasonable to expect, indeed to demand, that physicians routinely engage in acts of moral courage in order to ensure that their patients with pain receive the medications and/or other therapies that they require for relief? The essence of the duty imposed on a professional when entering into a fiduciary relationship is that the other person’s interests become primary and any potential conflict of interest shall be resolved in favor of the person to whom the professional duty is owed. Therefore, prescribing inadequate doses of analgesics or opioids from a lower schedule of the Controlled Substances Act (e.g., Schedules III to V) when those from a higher schedule (e.g., Schedule II) are medically indicated in order to avoid regulatory scrutiny would constitute a breach of fiduciary duty. It is also the case, however, that a public policy posture and regulatory regime that routinely demands acts of moral courage on the part of professionals is a fundamentally flawed system that is vulnerable to strong moral critique. Such a critique is at least implied in the Report Card on state and federal pain policies that has been issued by the Pain & Policy Studies Group and which is discussed in some detail in Chapter 14.

Embracing a New Ethic of Pain Relief Although it is important to understand the historical context in which

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formerly prevailing attitudes toward pain and its relief with opioids developed and ultimately became so pervasive and persistent, continuing the momentum that has followed from more enlightened attitudes is necessary to address emerging ethical concerns. The clinical specialty of pain medicine has played a major role in the progress that has been achieved in the last two decades. Ultimately, however, each of the health professions has a responsibility to cultivate within its practitioners the knowledge, skills, and attitudes that are essential to the provision of effective pain management. The need for highly trained physicians and nurses in pain and palliative care will continue to grow but so too will the need for all physicians and nurses to possess certain minimal core competencies in the assessment and management of pain. The clinical and ethical challenge of providing appropriate pain and symptom management has, if anything, increased in the last decade with the mounting evidence of two previously noted phenomenon: (1) the epidemic of prescription drug abuse and resulting deaths from overdose and (2) studies indicating that long-term high-dose opioid therapy in many instances is at best nonbeneficial and at worst harmful. Primary care physicians, on whom most patients must rely for management of their pain, find it increasingly difficult allocate the time and energy necessary to deliver state-of-the-art pain assessment and management. This potential conflict of commitment between fiduciary duties to individual patients and contractual duties to employer or health care institutional policy and procedural mandates or limitations is yet another source of ethical dilemmas. One of the new shibboleths in pain management is “pharmacovigilance.”36 Of course, the judicious prescribing of medications is an essential element of sound clinical practice in all domains of medicine. However, with the prescription drug abuse epidemic primarily associated with opioid analgesics, the insistence on pharmacovigilance appears disproportionately in the pain management literature. The implicit premise of this concept is that clinicians are not truly confronted with a genuine moral dilemma of providing effective pain relief for patients or preventing drug abuse and diversion. The basic presupposition appears to be that the parameters delineated by 648

pharmacovigilance, as conceived by some of the thought leaders in pain medicine, enable a responsible prescribing professional to provide appropriate and effective pain relief to patients while at the same time significantly minimizing the known risk of addiction posed by opioids or their diversion to persons who have no legitimate need for them. In other words, pharmacovigilant pain management recognizes the need in clinical practice for a kind of balance that is similar to the balance sought in laws, regulations, and public policies affecting opioid analgesics as discussed in Chapter 14 of this book. Even within the domain of pain management, the term has most often been invoked in the context of chronic pain management. Patients who have just undergone major surgical procedures, who have been the victims of traumatic injury, or those who are facing terminal conditions do not encounter the same credibility problems when they report high levels of pain and seek relief. The phenomenon of pseudoaddiction, in which patients with genuine pain that has been undertreated engage in behaviors that cause them to appear to be drug seeking (in some illegitimate sense), is most prevalent in the population of chronic noncancer pain patients.37 With regard to end-of-life care, it was once thought that undertreatment was the driving force behind the movement to legalize the prescribing of lethal doses of medication at the request of patients with terminal illnesses. However, the data accumulated as a result of the Oregon Death with Dignity Act reveal that undertreated pain is actually not even among the five most frequently cited reasons why dying patients seek a lethal prescription.38 Some of the practices that have come to be advocated with increasing frequency under the rubric of “pharmacovigilance” or “responsible opioid prescribing” are opioid contracts and random urine drug screens. Both approaches raise critical questions of an ethical nature about the role of trust in the clinician–patient relationship as well as questions about why patients with chronic pain are special cases that require such measures when other patients whose conditions necessitate treatment with potentially dangerous medications and strict adherence to clinician recommendations do not. We focus here particularly on the contracts/agreements that are being so widely promoted, the form that they 649

take, the benefits that are claimed by their proponents, and the risks they pose to the establishment and maintenance of trust in the clinician–patient relationship. There is an ethically more and less benign way in which to view and characterize the nature and role of these documents. The more benign approach is to simply consider the contract or agreement under the traditional rubric of a written informed consent document. Informed consent is a foundational concept in both medical ethics and medical jurisprudence and the primary mechanism by which respect for individual patient autonomy is demonstrated.39 The execution by patients of consent forms is a routine practice for any invasive medical procedure or other therapeutic measure. Thus, to the extent that an opioid contract were nothing more than a patient’s written informed consent to undergo opioid therapy, acknowledging thereby both the risks and benefits associated with it, there would be nothing remarkable about it and certainly nothing that would raise serious ethical concerns. The authors of one important article on the subject state, “The contract is ideally intended to enhance the therapeutic relationship by initiating and supporting an alliance between the patient and the physician. It may enable a patient to have an active role in treatment. . . . ”40 The keyword in this passage may be “ideal,” for there is growing concern among some that the primary reasons why opioid contracts are becoming routine among those physicians who are willing to consider opioid therapy for chronic noncancer pain patients relate to risk management and regulatory/law enforcement considerations rather than patient empowerment or wellbeing. For example, one review of opioid contracts that are currently in use revealed that over 90% had specific conditions warranting disciplinary termination of the agreement by the physician (e.g., if the patient were to violate a provision of the contract or miss appointments without adequate justification) and nearly 70% required submission to random drug screens, whereas only 5% stated the potential benefits of opioid therapy and just 3% provided general information regarding treatment.40 Because the latter two elements are most typically found on consent forms, their absence seriously undermines the argument that these contracts are merely more elaborate or formal consent documents. 650

Such contract provisions emphasize the physician’s power to impose conditions of treatment on patients rather than the autonomy of the patient to participate meaningfully in the consideration of therapeutic options according to the paradigm of shared decision making.41 The American Academy of Pain Medicine (AAPM) features a sample “Consent for Chronic Opioid Therapy” on its Web site. This agreement/consent form includes the more common provisions such as obtaining all opioid prescriptions from a single physician and filling them at a single pharmacy. The form states that the patient agrees to such random urine or blood tests as well as pill counts as may be “requested.”41 The absence of such detailed therapeutic agreements in most other clinical settings in which the modalities of treatment and the need for patient adherence to the therapeutic regimen are of equal importance to patient well-being (e.g., cancer chemotherapy) suggests that chronic noncancer pain patients who require opioid analgesia for effective relief warrant a heightened level of suspicion. Furthermore, the widespread and routine use of opioid contracts by many physicians for all of their chronic noncancer pain patients receiving opioid therapy, but not for acute pain or pain associated with terminal illness, implies that there is something intrinsically untrustworthy or suspicious about this category of patient.42 Clearly, however, merely being a victim of chronic noncancer pain that happens to be refractory to nonopioid analgesics is not inherently suspicious. Such patients and syndromes exist, and a consensus of thought leaders in pain medicine has emerged in support of the position that opioid analgesia should generally be offered to these patients unless there are specific and significant contraindications.43 Recent acknowledgment that earlier estimations of the risk of addiction associated with opioid analgesia were much too low does not undercut this consensus view. The best current evidence is that the incidence of addictive disorders (of all types) in the general population ranges from 3% to 26%, whereas the rate for hospitalized patients is 19% to 25%, and for major trauma patients as high as 40% to 60%.44 It is important to note that recently formulated model pain policies do not recommend the routine use of either opioid agreements or urine drug screens in all patients—even all chronic noncancer pain patients—but rather those patients who in the 651

exercise of sound clinical judgment are deemed to pose a “high risk for medication abuse or have a history of substance abuse.”45 Approaches to screening for addiction prior to the initiation of chronic opioid therapy as well as assessing for addiction during therapy (exclusive of urine toxicology screening) have been identified and utilized.46 The imposition of random urine drug screening as one condition precedent to offering opioid therapy to a patient appears to have become a common practice among clinicians whose practice includes patients with persistent pain problems. As with opioid agreements themselves, random drug screens may be required of all patients who receive opioid analgesia for an extended period, not simply those whose histories raise questions or concerns about the likelihood that they will take the medications as directed. In this way, it might be argued that all patients for whom opioid analgesia is indicated are treated the same rather than certain patients being stigmatized by differential treatment that calls their capacity to adhere to the treatment protocol in question. Nonadherence to chronic opioid therapy may take a variety of forms, including consuming more (or less) than the amount of the prescribed drug directed by the prescribing clinician, using opioids obtained from other sources, and failing to take the drug prescribed, whether or not the drug is then sold or otherwise diverted from legitimate medical use. Failure to comply with instructions concerning the taking of medication is not unique to chronic pain patients, and the risks of such behaviors by patients can have serious consequences in many different clinical settings, including diabetes, hypertension, epilepsy, and cancer therapy, to name only a few.47 Nevertheless, it has not yet become routine to insist on prescription medication agreements and laboratory screening for those patients, even when studies suggest that in some patient populations nonadherence to therapeutic regimens may exceed 50%.48,49 One important distinction between nonadherence to opioid therapy and nonadherence to other pharmacologic regimens that do not involved prescription medications that are subject to diversion and abuse is the risk posed to society. A patient who must take a prescription medication for a serious medical condition but who fails to do so as directed in most instances places only himself or herself at risk of adverse consequences. 652

However, when nonadherence to opioid therapy takes the form of selling or otherwise diverting these medications, there are significant adverse societal implications. There is no question that clinicians have responsibilities to their communities and the society at large and not only to their individual patients. Sometimes, as in the case of public health emergencies, there may be genuine conflicts between these two responsibilities. However, minimizing the risk of opioid addiction and diversion through the responsible use of treatment agreements and adherence monitoring enables the clinician to meet his or her obligations to both individual patient and society. As with the informed consent and information disclosure process itself, the manner in which such approaches are taken is as important as the details of the approach itself. Moreover, it may well be the case that the wider use of measures to warn patients about the risks of nonadherence to prescription medication regimens and to monitor such adherence may be a necessary and appropriate response by the health professions to the data documenting the extent to which patients fail to take their medications as prescribed. What is needed but presently does not exist are rigorous empirical studies evaluating the effects of patient agreements and drug screening on adherence to or the outcomes of treatment regimens.40 This is a problem with regard to many other aspects of pain medicine as well in that in the absence of sufficient evidence, clinical practice guidelines are often consensus-based. It would not be surprising to find that some of the high-profile federal prosecutions of physicians with very liberal prescribing practices described in detail in Chapter 15 of this book have fueled the widespread adoption of rigorous opioid contract provisions. Those physicians were alleged to have, among other things, engaged in a form of willful blindness to a host of red flags that some of their patients either had no legitimate medical need for opioids or were flagrantly abusing or selling their medications. The recordkeeping and monitoring by the physicians was poor to nonexistent.

Conclusion The ethics of pain management are in a profound state of flux. Neither the

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term evolution nor revolution seems to be an apt characterization, for such terms suggest a gradual and organic development process on the one hand or a transformational paradigm shift on the other, neither of which can be supported by the existing evidence. Rather, the current state of affairs might well be characterized, without risk of serious exaggeration, as a battle for the soul of medicine. For as we noted at the very beginning of this chapter, seminal works on the place of pain and suffering in the context of the patient’s experience of illness consistently remind us that their relief is a core value of medicine with roots running back to the very origins of the profession.50 In the modern era, when organized medicine has confronted phenomena such as physician-assisted suicide (aid in dying) or physician participation in lethal injection, prominent voices in opposition to the legitimacy of the physician’s role in such practices have consistently invoked statements of principle such as the following: “Healing the sick and alleviating suffering is the primary role of physicians in U.S. society.”51 Yet, those same voices have, for the most part, been silent in the midst of an epidemic of undertreated pain that afflicts chronic noncancer pain patients disproportionately. It has fallen to organizations such as the World Health Organization (WHO) and the International Association for the Study of Pain (IASP) to call for the recognition of pain relief as a human right.52 In no other aspect of patient care has the fundamental role of trust in the clinician–patient relationship become more of a pivotal issue than in the care of patients with chronic noncancer pain. With the proliferation of detailed opioid contracts including provisions for routine urine drug screens and rigidly specified grounds for terminating the relationship for nonadherence, we may be at risk of distrust becoming the reigning paradigm.53 A byword of the cold war era notably used by President Reagan but originally traced to Vladimir Lenin was “trust but verify.” This approach may well have a place in patient care and the standard of care with which clinicians must comply. The challenge to the health professions posed by the current ambivalence toward patients requiring opioid analgesia for moderate to severe noncancer pain is formidable. On one hand are prominent voices such as the WHO and the IASP calling for recognition of a human right to pain relief for all patients. On the other 654

hand are dire warnings to clinicians about deceptive, drug-seeking patients who must be engaged with extreme caution, a robust skepticism, and rigorous scrutiny as well as all of the other essential elements of pharmacovigilance. The establishment of a solid consensus among clinical and regulatory stakeholders as to where we ought to situate a healthy and reasonable balance between extreme, unrealistic naivete and a rigid, pervasive cynicism about the role of trust in the care of patients with persistent pain should become a high priority for all conscientious and caring professionals. References 1. Morris DM. The uses of pain. In: The Culture of Pain. Berkeley: University of California Press; 1991:174–197. 2. Faden RR, Beauchamp TL, King NMP. A History and Theory of Informed Consent. New York: Oxford University Press; 1986. 3. Rothman DJ. Strangers at the Bedside: A History of How Law and Bioethics Transformed Medical Decision Making. New York: Basic Books; 1991. 4. Veatch RM. The Patient-Physician Relationship: The Patient as Partner. Bloomington, IN: Indiana University Press; 1991. 5. Cassell EJ. The nature of suffering and the goals of medicine. N Engl J Med 1982;306:639– 645. 6. Cassell EJ. Preface. In: The Nature of Suffering and the Goals of Medicine. New York: Oxford University Press; 1991:vii–xiii. 7. Nuland SB. How We Die: Reflections on Life’s Final Chapter. The Lessons Learned. New York: Knopf; 1994:248–249. 8. Fox E. Predominance of the curative model of medical care. A residual problem. JAMA 1997;278:761–763. 9. Pellegrino ED, Thomasma DM. For the Patient’s Good: The Restoration of Beneficence in Health Care. New York: Oxford University Press; 1988. 10. The SUPPORT Principle Investigators. A controlled trial to improve care of seriously ill hospitalized patients. The study to understand prognoses and preferences for outcomes and risks of treatments (SUPPORT). JAMA 1995;274:1591–1598. 11. Wolfe J, Grier HE, Klar N, et al. Symptoms and suffering at the end of life in children with cancer. N Engl J Med 2000;342:326–333. 12. American Geriatrics Society. The management of persistent pain in older persons: AGS panel on persistent pain in older persons. J Am Geriatr Soc 1998;46:635–651. 13. Cleeland CS, Gonin R, Hatfield AK, et al. Pain and its treatment in outpatients with metastatic cancer. N Engl J Med 1994;330:592–596. 14. Von Roenn JH, Cleeland CS, Gonin R, et al. Physician attitudes and practices in cancer pain management. A survey from the Eastern Oncology Group. Ann Intern Med 1993;119:121– 126. 15. Sanderson L. Review. Attitudes to and knowledge about pain and pain management of nurses working with children with cancer: a comparative study between UK, South Africa, and Sweden. J Res Nurs 2007;12:517–519. 16. Joranson DE, Gilson AM. Pharmacists’ knowledge and attitudes about pain medication in

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relation to federal and state policies. J Am Pharm Assoc (Wash) 2001;41:213–220. Weiner RS. An interview with John J. Bonica, MD. Pain Pract 1989;1:2. Silverman J. Students need more pain management training: education effort underway. Available at: http://www.obgynnews.com/article/S0029-7434(03)70079-2/fulltext. Accessed October 15, 2003. Institute of Medicine. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Washington, DC: National Academies Press; 2011. Hill CS Jr. When will adequate pain management be the norm? JAMA 1995;274:1881–1882. Ballantyne JC, Shinn NS. Efficacy of opioids for chronic pain: a review of the evidence. Clin J Pain 2008;24:469–478. Education in Palliative and End-of-life Care. Available at: http://www.epec.net/EPEC/Webpages/index.cfm. Accessed May 5, 2009. Thomson H. A new law to improve pain management and end-of-life care. West J Med 2001;174:161–162. California Business and Professions Code, § 2190.5. Frankel MS. The policy-making environment. In: The Public Health Service Guidelines Governing Research Involving Human Subjects: An Analysis of the Policy-Making Process. Washington, DC: George Washington University Program of Policy Studies in Science and Technology; 1972:19–29. Emergency Medical Treatment and Active Labor Act, 42 USC §1395dd (1986). Joranson DE, Cleeland CS, Weissman DE, et al. Opioids for chronic cancer and non-cancer pain: a survey of state medical boards. Fed Bull 1992;79:15–49. Martino AM. In search of a new ethic for treating patients with chronic pain: what can medical boards do? J Law Med Ethics 1998;26:332–349, 263. Gilson AM, Joranson DE. Controlled substances and pain management: changes in knowledge and attitudes of state regulators. J Pain Symptom Manage 2001;21:227–237. Max MB. Improving outcomes of analgesic treatment: is education enough? Ann Intern Med 1990;113:885–889. American Society of Addiction Medicine. Opioid addiction: 2016 facts and figures. Available at: http://www.asam.org/docs/default-source/advocacy/opioid-addiction-disease-factsfigures.pdf. Accessed July 11, 2016. Bostrom M. Summary of the Mayday Fund Survey: public attitudes about pain and analgesics. J Pain Symptom Manage 1997;13:166–168. Dawson R, Spross JA, Jablonski ES, et al. Probing the paradox of patient’s satisfaction with inadequate pain management. J Pain Symptom Manage 2002;23:211–220. Kleinman A. Vulnerability of pain and the pain of vulnerability. In: The Illness Narratives: Suffering, Healing & the Human Condition. New York: Basic Books; 1988:56–74. Whitcomb ME. Professionalism in medicine. Acad Med 2007;82:1009. Fishman SM. Responsible Opioid Prescribing: A Physician’s Guide. 2nd ed, Rev ed. Washington, DC: Waterford Life Sciences; 2014. Weissman DE, Haddox JD. Opioid pseudoaddiction. Pain 1989;36:363–366. Oregon Health Authority. Oregon Death with Dignity Act: 2015 data summary. Available at: https://public.health.oregon.gov/ProviderPartnerResources/EvaluationResearch/DeathwithDignityAct/Docume Accessed July 31, 2016. Meisel A, Kuczewski M. Legal and ethical myths about informed consent. Arch Intern Med 1996;156:2521–2526. Fishman SM, Bandman TB, Edwards A, et al. The opioid contract in the management of chronic pain. J Pain Symptom Manage 1999;18:27–37. Arnold RM, Han PK, Seltzer D. Opioid contracts in chronic nonmalignant pain management:

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objectives and uncertainties. Am J Med 2006;119:292–296. American Academy of Pain Medicine. Consent for chronic opioid therapy. Available at: http://www.painmed.org/files/consent-for-chronic-opioid-therapy.pdf. Accessed July 31, 2016. Miller J. The other side of trust in health care: prescribing drugs with the potential for abuse. Bioethics 2007;21:51–60. Savage SR. Assessment for addiction in pain-treatment settings. Clin J Pain 2002;18:S28– S38. American Academy of Pain Medicine. Use of opioids for the treatment of chronic pain: a statement from the American Academy of Pain Medicine. Available at: http://www.painmed.org/files/use-of-opioids-for-the-treatment-of-chronic-pain.pdf. Accessed July 31, 2016. Federation of State Medical Boards of the United States. Model policy for the use of controlled substances for the treatment of pain. Available at: http://www.fsmb.org/pdf/2004;usgrpol;usControlled;usSubstances.pdf. Accessed May 6, 2009. Fishman SM, Wilsey B, Yang J, et al. Adherence monitoring and drug surveillance in chronic opioid therapy. J Pain Symptom Manage 2000;20:293–307. Cramer JA, Mattson RH, Prevey ML, et al. How often is medication taken as prescribed? A novel technique. JAMA 1989;261:3273–3277. Levine AM, Richardson JL, Marks G, et al. Compliance with oral drug therapy in patients with hematologic malignancy. J Clin Oncol 1987;5:1469–1476. Beauchamp TL, Childress JF. Principles of Biomedical Ethics. 4th ed. New York, Oxford University Press; 1994:163–170. Black L, Sade RM. Lethal injection and physicians: state law vs medical ethics. JAMA 2007;298:2779–2781. World Health Organization. Pain relief a human right. Available at: http://www.who.int/mediacentre/news/releases/2004/pr70/en/. Accessed May 6, 2009. Victor L, Richeimer SH. Trustworthiness as a clinical variable: the problem of trust in the management of chronic, nonmalignant pain. Pain Med 2005;6:385–391.

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CHAPTER 13 Ethical Issues in the Care of Dying Patients DAVID BARNARD

Introduction THE QUEST FOR MORAL ORDER AMID EXISTENTIAL DISORDER To the dying person, his doctor, however much he is trusted and regarded as a source of treatment, is no longer one with the power to cure; to the doctor, the patient has become one whose death, despite every possible effort, he is impotent to prevent. This gives rise to problems in the special professional relationship which often develops between a patient and his doctor, and besides that, they have the difficulties that face any two people trying to adjust to the fact that one of them is shortly going to die.1 This comment by John Hinton is a pointed reminder that the patient’s nearness to death places the patient and the doctor in a challenging and disturbing place, both in their relationship with each other and in their sense of personal identity. The direct encounter with death—in the guise of the death of the patient—has the power to disrupt the doctor’s relationship and communication with the dying person, throw rational decision making into confusion, and capsize carefully wrought treatment plans. Robert Burt has commented on the “inherent unruliness of death and the persistence of individual and social ambivalence about death” as features that limit our ability to fashion social policies and practice guidelines that are free of moral ambiguity or the possibility for evil and abuse. At the conclusion of his study of the conflict-ridden policies governing abortion, the death penalty, and physician-assisted death in the United States during the last half-century, Burt writes, Here is the paradox that we must learn to live with in regulating 658

death: that we must teach ourselves, through our rational intellectual capacities, that our rational intellect cannot adequately comprehend, much less adequately control, death. We are no more compassionate, honorable, or intelligent than our predecessors who embraced the pursuit of rational mastery over death and were led, without acknowledgment, into unreasoned evil. We would do better to admit, as W.H. Auden acknowledged, that “Death is not understood by Death; nor You, nor I.”2

THE CONTRIBUTIONS AND LIMITATIONS OF ETHICAL ANALYSIS IN END-OF-LIFE CARE Hinton and Burt suggest that the psychological and existential dimensions of the encounter with death destabilize the doctor–patient relationship and rational decision making. These dimensions also require that we acknowledge the limitations as well as the contributions of ethical analysis in end-of-life care. At the most general level, the discipline of ethics itself embodies the cacophony of voices, worldviews, cultural frameworks, and value systems characteristic of postmodernity. As philosophers such as McIntyre3 and Englehardt4 argue, no single, overarching standpoint or scale of values commands universal allegiance in a secular, pluralist society that is committed to the peaceable resolution of differences. Yet, without such a universally compelling standpoint, there is no means short of force to eliminate the contradictions between philosophical systems or the competing claims of multiple moral communities. Two aspects of uncertainty more specifically related to clinical ethics near the end of life are worth particular note at the outset. Consider the commonly accepted public consensus on the ethics of end-of-life care. Its main points include the following: 1. Competent adults may refuse medical treatment. 2. Treatment refusals may include all forms of life-sustaining medical treatment, including artificially provided nutrition and hydration. 3. Complying with a competent adult’s informed wishes to refuse or discontinue life-sustaining treatment should be considered neither homicide nor assisted suicide. 4. From a moral and legal point of view, there is no difference between 659

withholding a treatment (not starting it) and withdrawing a treatment (stopping it after it has been started), if the treatment in question is inconsistent with a competent patient’s informed preferences. 5. For a patient who is terminally ill and who values comfort over prolongation of life, symptom control that has as a side effect the shortening of life is morally permissible and is not the moral equivalent of active euthanasia. 6. Incompetent or otherwise nonautonomous people have the same rights as competent people in these matters, with their wishes expressed either in the form of an advance directive or by a person authorized to make health care decisions for them. To call these points the “public consensus” means that they capture a broad agreement in the bioethics literature, policy statements of professional organizations, judicial decisions, and the actions of state legislatures on the matters in question.5 It is probably safe to say that these points organize the notes of nearly every medical school and nursing school lecturer on the topic of “the ethics of end-of-life care” and that they are the guiding principles brought to bear on individual cases by the vast majority of clinical ethics consultants at large in the corridors of US hospitals. And yet, it must be admitted that the consensus, although undoubtedly broad-based intellectually and influential clinically, masks substantial differences and disagreements within the health professions and the larger society. These differences encompass matters such as the relative weight to be accorded to individual autonomy and the general welfare; the validity of the distinction between, say, “killing” and “allowing to die”; or the proper characterization of artificially provided nutrition and hydration as either “medical treatment” or “basic, humane care.” A second aspect of uncertainty stems from the potential disconnect between an individual health professional’s espoused values and ethical commitments and his or her ability to act according to those commitments in specific clinical situations. To take one of many examples, since the 1960s, there has been an enormous shift in physicians’ stated attitudes toward disclosing bad news to their patients. Whereas physicians have historically been reluctant to discuss bad diagnoses such as cancer directly 660

with patients for fear of depressing them or eliminating hope,6 by the late 1970s, physicians who responded to surveys overwhelmingly favored full disclosure of a cancer diagnosis to the patient.7 Patients themselves, especially in Western societies, usually want to know the truth of their cancer diagnosis, and most also want a realistic estimate of how long they are likely to live. Yet, when Baile and his colleagues8 surveyed more than 500 oncologists attending a meeting of the American Society of Clinical Oncology (ASCO), nearly one-half rated their ability to break bad news as only fair or poor, and two-thirds rated themselves as not very comfortable or uncomfortable dealing with their patients’ resulting emotions. Only half had received any training in the subject.8 These findings are consistent with the fact that although many studies report general satisfaction on the part of patients and families with the information disclosure process,9 other studies report significant dissatisfaction with the level of information or emotional support that patients receive from their doctors.10,11 With these considerations and qualifications in mind, this discussion of ethical issues in end-of-life care attempts to bring to bear the public consensus mentioned earlier on four major themes: 1. The transition from curative to palliative and end-of-life care 2. Surrogate decision making 3. Responding to demands for nonbeneficial treatment 4. Physician-assisted death Although ethical analysis cannot pretend to eliminate moral doubt and disagreement—particularly on some of the most contested issues in these domains—some goals are quite realistic. These include (1) providing a blueprint or template for careful and systematic ethical scrutiny of a clinical situation; (2) organizing the dialogue among the various parties to an ethical dispute, thereby assuring that the concerns and perceptions of everyone with a stake in the outcome of a clinical decision are taken seriously; (3) providing a method for isolating particular sources of ethical disagreement, thereby making possible either the marshalling of additional facts or arguments to produce agreement or allowing people unable to agree to recognize their mutual good faith; (4) pointing to areas of agreement as the basis for creative problem solving that leads to decisions and actions consistent with people’s most important values; and (5) 661

encouraging educational efforts for health professionals—especially in the realm of patient–provider communication—to bring professionals’ behavior more fully in line with their avowed values and beliefs.

The Transition from Curative to Palliative and Endof-Life Care Patients with serious disease and their physicians usually share three goals for the patient’s care: cure or long-lasting remission, prolongation of survival, and comfort and quality of life. As prospects for the first and second goals dim with the progression of disease and the exhaustion of curative therapies, physicians have the opportunity, and the challenge, of recommending that the third goal become the main focus of the patient’s continuing care. The World Health Organization12 defines palliative care as “the active total care of patients whose disease is not amenable to curative treatment. Control of pain, of other symptoms, and of psychological, social, and spiritual problems is paramount. The goal of palliative care is the achievement of the best possible quality of life for patients and their families.” J. Andrew Billings has suggested a more patient- and family-friendly definition: Palliative care is a special service, a team approach to providing comfort and support for persons living with a life-threatening illness and for their families. We are nurses, social workers, chaplains, and physicians who work with your current health-care team to assure that you and your family receive excellent pain control and other comfort measures, get the information you want to participate in decisions about your care, receive emotional and spiritual support and practical assistance, obtain expert help in planning for care outside the hospital, continue getting good services in the community, and overall enjoy life as best you can, given your condition. We try to coordinate and tailor a package of services that best suits your values, beliefs, wishes, and needs in whatever setting you are receiving care.13 For the doctor, arriving at the decision to focus primarily on palliative care rather than active, disease-modifying therapy can be complicated. It 662

usually combines scientific and technical skills related to prognosis and clinical judgment; communication skills, often involving bad news and the need to respond sensitively to the patient’s emotions; and negotiation of treatment preferences. Billings’ description of the doctor’s role at this juncture is: The patient and the family need a doctor who respects their expertise and can help them clarify and choose what they want, yet who is authoritative, helping to bring clarity and control by saying, “Let’s keep trying” or “Let’s face the music, it’s time to stop.”14 Billings’ formulation strikes a balance between the two poles that have characterized ethical debates about the doctor–patient relationship for the past several decades: the doctor as neutral respecter of patient autonomy and the doctor as authority figure under whose guidance patients suspend their own preferences in favor of the doctor’s superior insight into their best interests. Despite the strong emphasis on patient autonomy and selfdetermination in the bioethics literature, when patients are faced with very serious disease and complicated choices, few want to be left completely on their own to make treatment decisions. Billings’ formulation captures this reality by emphasizing both respect for the patient’s ultimate decisionmaking authority and the commitment not to abandon the patient by withholding the physician’s best professional judgment.

NEGOTIATING TREATMENT PREFERENCES: THE IDEAL DECISION-MAKING PROCESS From the standpoint of ethics, treatment decisions near the end of life, as at any other juncture in health care, ought to be structured by the notion of informed consent.15 To be valid, the patient’s consent should be informed and free of duress or coercion and should reflect the patient’s genuine values and preferences. An ideal decision-making process for medical care would include the following elements: • Joint participation of doctor and patient, with additional participation of significant others of the patient’s choice • Clear and truthful communication by the physician • Clear and thoughtful deliberation by the patient 663

• Consideration, by both doctor and patient, of medical and nonmedical factors, including The patient’s medical condition and options for treatment (including no treatment) The reasonable probabilities that particular goals can be achieved The reasonably expected proportion of benefits of treatment to harmful or painful side effects The patient’s values and life goals The patient’s assessment of his or her quality of life and the essential elements for a positive quality of life The patient’s tolerance for risks and uncertainty • So that, the resulting decision Reflects a reasonable accommodation to the medical facts Is consistent with the patient’s values and the physician’s conscience

DEPARTURES FROM THE IDEAL In the end-of-life context, several factors are likely to complicate the ideal. They can be divided into two large groups: factors related to the uncertainty of prognosis and clinical judgment and factors related to attitudes and values of both patients and physicians. After some discussion of each of these, this section concludes with some suggestions for approaching conversations with patients that attempt to accommodate both prognostic uncertainties and emotional reactions.

Prognosis and Clinical Judgment There are now a number of resources available that provide prognostic information across a wide range of diseases and conditions, for example, in advanced cancer,16 heart failure,17 end-stage chronic obstructive pulmonary disease,18 dementia,19 cirrhosis,20 and coma following cardiopulmonary resuscitation.21 Although the general outcomes and trajectories of diseases that are the major causes of death in the United States are known, and a typical patient’s survival (assuming accurate diagnosis) can usually be estimated within a known range of probabilities, when any particular individual will die remains an inexact prediction. 664

Most people appreciate this, however, and the inability to give very precise predictions of a patient’s remaining life expectancy should not be a barrier to physicians’ participating in discussions with patients who want to have some realistic idea of their situation. As described further in the following text, the most important question for the physician is the level of information a patient desires to receive. The question “Doctor, how long am I going to live?” cannot be answered helpfully without some initial exploration of the meaning the question has to the patient, what has motivated the question, and the patient’s preferred level of detail. A physician’s prognostic accuracy seems to vary inversely with the length of time the physician has known the patient. The longer the relationship, the more likely it is that the physician will overestimate the patient’s remaining time.22 Lamont and Christakis23 comment in relation to this data that a palliative medicine specialist, or some other physician with relevant expertise but with no prior relationship to the patient, is likely to be a helpful resource to the treating physician in formulating prognostic information for individual patients. Another tendency of physicians that can diminish the usefulness of prognostic information is to provide it solely in terms of the quantity of remaining life (weeks, months, or years), without attempting to describe the quality of life the patient is likely to enjoy. Especially for people with chronic, degenerative conditions or conditions for which available diseasemodifying therapies have significant side effects, their remaining quality of life is likely to be as important as a bare estimate of survival. Some issues that are likely to be of particular interest to the patient include the pace and timing of decreases in functional and/or cognitive status, pain and discomfort and the availability of the means to relieve them, loss of independence, and the expected burden on caregivers. It bears repeating that the physician’s offer to go into detail on any of these matters should be contingent on a signal from the patient that he or she does in fact want to discuss them. Some people would prefer not to have such a clear image of impending decline to look forward to, although they may wish someone in the family to have this information to be better prepared.

Patients’ Attitudes and Values 665

The physician’s first responsibility in preparing for a conversation about treatment preferences in the setting of end-of-life care is to assess the patient’s emotional and cognitive capacity to participate in the conversation. Among the emotional and attitudinal factors that may cause patients to depart from the ideal decision-making process are the patient’s denial of the seriousness of the disease, or the presence of depression or other psychiatric disorders, as well as other forms of cognitive impairment that may be related either to the disease or its treatment. Appropriate treatment of the underlying causes of the cognitive impairment should be the first order of business. If this is not possible, the physician should consider the availability of a surrogate decision maker, as discussed in the next section. Other emotional factors short of psychiatric impairment can diminish the patient’s capacity to participate meaningfully in these discussions. For example, some patients may appear determined to continue pursuing active treatment for their disease because they believe other people want them to do this, not because it is their own preference. Some patients may worry about family members’ ability to cope with the patient’s worsening illness or about their future security and well-being once the patient has died. Some patients may find it hard to reject treatments because they do not want to disappoint the doctor. On the other hand, patients may reject further treatments not because they genuinely believe this is in their best interest but because treatment refusal is a language for expressing other concerns, such as fear (of being a burden to others, of the treatment, of the process of dying), anger, exhaustion, helplessness, mistrust, or unrelieved physical symptoms. A similar phenomenon can underlie patients’ requests for physician-assisted death. Sensitive exploration of the background and motivations underlying the patient’s stated preferences is essential before the physician concludes that he or she has a clear understanding of the patient’s perspective.

Physicians’ Attitudes and Values Several factors on the physician’s side can also cause a dialogue about treatment preferences to deviate from the ideal. The physician’s counterpart to the patient’s denial is the tendency for physicians to 666

overestimate expected survival, especially for patients with whom they have had long-term relationships. It is often easier to perceive the deterioration in the patients of one’s colleagues than in one’s own patients. A number of conceptual and philosophical commitments may also lead physicians to minimize or avoid open discussion with the patient about the transition from curative to palliative care. For example, medical training is primarily focused on providing the tools and skills necessary for the active investigation, diagnosis, and treatment of pathology. This instills an ideology of intervention, according to which any pathologic state or process that is potentially reversible should be reversed. To stand back and look at the “big picture”—to accompany a patient into death without investigating or treating conditions for which (at least short term) remedies are available—requires a shift in perspective that many physicians find very difficult and contrary to their professional identity. A closely related issue, especially in academic medical centers, is the imperative of research and therapeutic innovation. From this perspective, it is precisely the point in the patient’s illness when all known effective remedies have been exhausted that presents the greatest opportunity for scientific progress. The research imperative demands that these opportunities be seized for trials of new and unproven treatments to push back the boundaries of medical power. Many patients (especially if they are of a socioeconomic status that has entitled them to regular access to health care) are themselves caught up in the ideology of medical progress, having absorbed a lifetime of exhortations from doctors and hospitals to avail themselves of regular checkups and the very latest in medical technology to ensure a longer, happier life. The power of medical technology to forestall the time of death, especially in the intensive care unit (ICU), gives rise, in Daniel Callahan’s phrase, to “technological brinkmanship.”24 This is the idea that we can and should employ our technology for its maximum life-extending benefit and then back off just at the point—but no later—when its marginal benefits begin to be outweighed by its burdens and costs. The reality is that the point of diminishing return is almost always only discernible in retrospect, after the patient has been subjected to a period of intensive and invasive treatments to no positive end and the family is left to wonder why the 667

patient could not have enjoyed a more peaceful death. The availability of technology to forestall death creates an additional psychological pressure that derives from the apparently observable fact that the death of any individual patient (especially in the ICU) almost always results from a decision to withhold or withdraw medical treatment. In other words, although in principle, we ought to be able to take comfort from the fact that death is natural and universal—as in the ancient syllogism, “Socrates is a man; all men are mortal, therefore Socrates is mortal”—death for this patient now seems always to be optional. Its psychological reality for the doctor is that the death occurred only because he or she brought it about when he or she recommended, or acquiesced when the patient or family requested, termination of treatment. Finally, a very common concern for physicians faced with recommending the transition from curative to palliative care (identified by nearly 60% of the respondents to Baile and colleagues’8 ASCO survey as the most difficult part of breaking bad news) is “being honest without taking away hope.” This is particularly the case when “hope” is identified with cure or significantly extended life. In fact, there are many other objects of patients’ and families’ hope that physicians almost always can help them realize; for example, comfort and freedom from pain, companionship, completion of important tasks, and security for those who will be left behind.25 Indeed, as suggested by Billings’ previously quoted definition, these concerns are precisely the focus of palliative care. Nevertheless, the strong association of “giving up all hope” with the shift to palliation from active treatment can lead physicians to dread and put off serious discussion of a patient’s end-of-life treatment preferences.

COMMUNICATION WITH PATIENTS ABOUT TREATMENT PREFERENCES NEAR THE END OF LIFE The physician has four primary goals in the dialogue with a patient in the context of end-of-life decision making: 1. To learn about the patient’s preferences for receiving information and to assess the patient’s coping style when confronting threatening situations 2. To provide the patient with sufficient information about his or her 668

current and projected medical situation and options for treatment and support to enable the patient to make choices that reflect his or her values and preferences 3. To establish rapport and trust in order to enhance the physician’s credibility as a source of reliable information and interpersonal support 4. To balance genuine appreciation of the clinical situation with realistic optimism to empower the patient—by mobilizing his or her adaptive capacities and social supports—to maximize his or her quality of life for as long as possible The goal of effective information transfer, although obviously of cardinal importance, is only one of these several goals. If the others are not also satisfied, information transfer itself may not successfully occur. For this reason, most expert opinion on communication with patients about bad news recommends that the physician address the interpersonal and emotional dimensions of communication as well as the clear presentation of scientific facts. In an extensive literature review, Penelope Schofield and her colleagues26 identified 10 major considerations for communication about the transition from curative cancer treatment to palliative care: 1. Preparation prior to the discussion 2. Eliciting the person’s understanding of the illness and preferences for information transfer 3. Providing information 4. Responding to emotional reactions 5. Negotiating new goals of care 6. Arranging for continuity of care 7. Addressing family concerns 8. Acknowledging cultural and linguistic diversity 9. Concluding the discussion 10. Documenting the discussion and appropriately informing other members of the treatment team Baile and colleagues8 consolidate these dimensions in a six-step protocol with the mnemonic SPIKES. In their formulation, the physician’s communication with the patient proceeds as follows: 669

• Step 1: SETTING UP the interview Mental rehearsal, arranging for a private setting, involvement of significant others, sitting down, making eye contact, and taking steps to avoid interruption • Step 2: Assessing the patient’s PERCEPTION Ask before telling: Ascertain what the patient knows, how they want to receive information; for example, “What have you been told about your medical condition so far?” or “What is your understanding of the reasons we did the MRI?” • Step 3: Obtaining the patient’s INVITATION Ask before telling: Ascertain the patient’s preference for receiving information, recognizing that shunning information is a valid psychological response for some people. Asking this at the time of test ordering can help set the stage; for example, “How would you like me to give you the test results? Would you like all of the information, or just the big picture, with more time for us to talk about a treatment plan? Is there anyone else with whom you would prefer us to discuss this information?” Lamont and Christakis23 suggest, “Some people want to know everything possible about their illness and others prefer to know very little. How much about your illness do you want to know from me today?” • Step 4: Giving KNOWLEDGE and information to the patient Give a “warning shot.” For example, “Unfortunately I’ve got some bad news to tell you. . . ” Start at the patient’s comprehension level, avoiding technical words (say “spread” rather than “metastasize”); give information in small chunks with pauses to check understanding; avoid phrases such as “there is nothing more we can do.” • Step 5: Addressing the patient’s EMOTIONS with empathic responses Another mnemonic, NURSE, is helpful here. Name the emotion: You look (sound) as if this is a real shock to you. Understand: I cannot imagine what it is like to be so sick. Respect: I really appreciate how you have been coping with this. Support: I want you to know that regardless of what happens I will be there for you. 670

Explore: Tell me more. • Step 6: STRATEGY and SUMMARY Ask before telling: Determine whether the patient wants to discuss future treatment plans at the present time; check the patient’s overall understanding of what has been said; present treatment options if appropriate in the moment; offer time for the patient to reflect; offer to be available for questions that may arise after the interview; schedule a follow-up appointment. In summary, the physician–patient dialogue about the transition from active treatment to palliative care can help the physician fulfill several aspects of the ideal decision-making process. By acknowledging emotional aspects of the situation that are likely to be present on both sides, by offering patients the opportunity to receive information—or not—at their own pace, by examining one’s professional biases and assumptions that may hinder an open discussion of the patient’s circumstances, and by attention to the interpersonal as well as factual aspects of information transfer, the physician is most likely to support treatment decisions by patients that reflect their genuine values and also to strengthen the foundations for the physician’s role as a supportive companion to the patient throughout the course of the illness.

Surrogate Decision Making At the time end-of-life treatment decisions have to be made, patients may not be able to speak clearly for themselves. They may be too sick to speak, too confused to listen to medical information or to deliberate about preferences, or completely unconscious. Typical contexts when patients lack decisional capacity near the end of life include patients suffering from dementia or other long-term cognitive impairment; patients suffering from delirium as a consequence of their disease or side effects of its treatment (e.g., metabolic derangements, drug-induced delirium, “ICU psychosis”), severely depressed patients, patients with waxing and waning mental capacity, or who give inconsistent, contradictory answers to treatmentrelated questions within a short period of time; postoperative patients under the influence of anesthetics or medications to promote ventilator

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compliance; patients suffering loss of consciousness due to stroke, cardiac arrest, or other traumatic event; and patients in coma or persistent vegetative state. Surrogate decision making is the process by which these patients may be brought as close as possible to the ideal decision-making process described earlier. It involves the following basic elements: (1) assessment of the patient’s decisional capacity; (2) for patients deemed lacking in capacity, attempts to rule out or eliminate reversible causes; (3) identification of an appropriate surrogate; (4) clarifying the surrogate’s roles and responsibilities; and (5) anticipating, where possible, future needs for surrogate decision making through a process of advance care planning.

ASSESSING DECISIONAL CAPACITY Decisional capacity is task-specific. Someone may be properly judged capable of making some decisions—Jell-O or custard for dessert, baseball or NASCAR on TV—and incapable of making other decisions—financial investments, whether or not to enter a nursing home, or, most relevant here, the choice of medical treatments in the setting of advanced disease. For the latter, the patient’s capacity should be assessed in terms of the following: • Understanding: Does the patient understand the meaning of the diagnostic or prognostic information provided to him or her? Can the patient restate the information in his or her own words in a way that demonstrates this understanding? • Appreciation: Does the patient appreciate the implications of the information for himself or herself? Does he or she appreciate that decisions have to be made from among alternative treatment plans and that his or her input is necessary for these decisions? • Deliberation: Can the patient weigh the alternative treatments according to his or her personal goals and values? • Communication: Can the patient communicate his or her treatment preferences in an understandable manner? Do the patient’s stated preferences appear logically related to the patient’s goals? There is no rigid, quantifiable measure of the patient’s abilities in these 672

domains. In general, the more significant the decision that needs to be made—in terms of risks, benefits, and side effects—the more stringent our standards should be in satisfying ourselves that the patient has the requisite capacity.27 Contrary to common practice, especially in hospitals where psychiatric consultation is readily available, a formal psychiatric consultation is not required to assess a patient’s decisional capacity. Nonpsychiatrist physicians ordinarily are capable of forming a reasonable judgment of the patient’s abilities in these four domains. Moreover, even if a psychiatric consultant judges the patient to have capacity, it remains the attending physician’s responsibility to satisfy himself or herself that the patient is in fact capable of giving informed consent before proceeding with treatment. Where psychiatric opinion is most relevant is when the physician suspects mental illness or delirium as the (possibly reversible) cause of the patient’s lack of capacity or where appointment of a legal guardian is anticipated, in which case the court will be interested in authoritative medical opinion.

RULING OUT OR ELIMINATING REVERSIBLE CAUSES OF INCAPACITY Reversible causes of incapacity can be biologic or situational. Biologic causes include transient delirium, treatable depression, or the side effects of anesthetic or analgesic medications. Situational causes include anxiety or fear as an immediate consequence of receiving bad news, confusion or anxiety due to the effects of hospitalization, the sensory overload of the ICU, and/or separation from familiar people. Before deciding that a patient’s lack of capacity warrants turning to a surrogate, realistically assess the importance of making particular decisions right away. If urgent decisions are not required, attempt to diagnose and eliminate the patient’s incapacity. This could entail adjustments of medication, psychosocial intervention, or simply the passage of time.

IDENTIFYING A SURROGATE If the gold standard for ethical health care decision making is the thoughtful participation of an informed patient, the gold standard for surrogate decision making involves a surrogate who is: 673

• Authorized by the patient because the patient considers the surrogate to be trustworthy and in the best position to advocate for the patient’s best interests • Willing to accept the patient’s trust and to fulfill the role of surrogate in good faith • Informed, through prior acquaintance or explicit conversation with the patient, about the patient’s values and preferences regarding medical care near the end of life • Capable of understanding the physician’s explanations of the patient’s condition and weighing treatment options in light of the patient’s preferences • Available to represent the patient’s interests at the time decisions have to be made Since Congress passed the Patient Self-Determination Act in 1990 in the wake of the Nancy Cruzan decision of the US Supreme Court, there have been many local and national efforts to encourage people to identify a surrogate in case of their own future incapacity. All 50 states have adopted legislation authorizing health care decision making by surrogates. Despite these efforts, most people for whom end-of-life medical decisions must be made have not designated a surrogate in advance.28 A number of states have addressed this gap legislatively by prescribing, in lexical order, the persons who are empowered to act as the patient’s surrogate in the absence of the patient’s prior designation. A typical ordering begins with the patient’s spouse and then moves in descending order through adult children, parents, adult siblings, adult grandchildren, and (only then) other adults who may be in a position to know the patient’s beliefs about medical treatment. In states where this regime applies, physicians as well as patients may be faced with the situation where the prescribed surrogate does not fulfill the criteria noted earlier as well as someone lower on the list—or not on the list at all. Gay partners, for example, have legitimate reason to fear exclusion and disenfranchisement in decision making for each other under strict interpretations of these surrogacy laws. From the point of view of ethics, the physician’s primary responsibility as the patient’s advocate is to identify the surrogate who meets those 674

criteria to the greatest extent. In cases where that person is available and willing to serve in the role, but another, less qualified, person with lexical priority is expressing conflicting preferences for care, it is advisable for the physician to seek consultation from an ethics committee or from a hospital’s legal counsel.

THE SURROGATE’S ROLES AND RESPONSIBILITIES The surrogate’s primary responsibility is to interpret the physician’s recitation of the patient’s medical condition and recommended treatment in light of what the surrogate has reason to believe are the patient’s relevant values, preferences, and life goals. This is the “substituted judgment” standard for surrogate decision making. Unless the surrogate has been instructed differently by the patient, he or she ought to try to the best of his or her ability to express treatment preferences that reflect the patient’s goals and values, and not the surrogate’s, if there is a conflict between them. If the surrogate is not certain what the patient would prefer in a given situation, or if, despite a good faith effort on the part of all who are in a position to know, there is simply no evidence whatsoever of the patient’s likely preference, the surrogate ought to make the decision that appears to be, from an objective point of view, in the patient’s best interests. Ordinarily, this is determined by weighing, in the most informed manner possible, the likely benefits (to the patient) of various proposed treatments—or no treatment—against their likely burdens (again to the patient). This is (not surprisingly) the “best interests” standard for surrogate decision making. Physicians and other members of the health care team have potential roles to play in helping surrogates do their job. Their most obvious role is to provide clear and helpful prognostic information and descriptions of proposed treatments according to the protocols outlined in the previous section. But they may also be able to enhance the surrogate’s ability to represent the patient’s interests and preferences by engaging in dialogue with the surrogate about the patient. The content of that dialogue is suggested by the discussion in the next section of the most useful elements of an advance directive for health care.

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A REALISTIC PROCESS OF ADVANCE CARE PLANNING Most commentators agree that policies to encourage people to use advance directives to prepare for future end-of-life decision making have been largely unsuccessful.28,29 As noted earlier, only a minority (between 20% and 30%) of American adults have filled out an advance directive. Evidence suggests that even for those who have them, advance directives do not influence decision making. Most particularly, if people expect that filling out an advance directive will ensure that the medical decisions made during their future incapacity will match the choices they themselves would have made had they been able to participate in those decisions themselves, they will almost certainly be disappointed. Common difficulties are that the documents cannot be located when they are needed, they are too vague to give useful guidance in the patient’s actual circumstances, or the patient’s stated preferences are ignored in favor of a course of action that physicians and/or family members believe is more in accord with the patient’s present best interests. Hickman et al.29 have listed some of the main factors that may explain these difficulties. These include: 1. An overemphasis on the patient’s legal rights to refuse medical care, as opposed to the more general objective of enhancing people’s ability to influence their care according to their goals and values 2. Insufficient efforts by health professionals to educate patients as to realistic outcomes of various medical interventions 3. Overemphasis on patients’ preferences for specific medical interventions rather than the effort to ascertain the patient’s views about goals and values and about what constitutes an acceptable quality of life 4. The assumption that the planning process is complete as soon as an advance directive has been filled out rather than viewing the process as ongoing and subject to periodic reassessment and revision in light of changing medical circumstances 5. Failure to involve family members or other important people in the patient’s life in discussions about preferences for medical care 6. Absence of system-wide policies and procedures to ensure that 676

patients’ preferences for care are known and respected wherever the patient may be receiving care 7. Low community awareness of issues related to end-of-life planning 8. State advance directive laws that introduce barriers into the advance planning process

Three Basic Problems As significant as Hickman and colleagues’29 barriers are, there are three more basic problems with advance directives that frequently lead to frustration and disappointment even when patients have gone to the trouble of creating one. All three are related to the nature of medical care for the critically ill and the existential predicament of the person facing death. Stated briefly, and somewhat too simply, they are as follows. Unpredictability Because of the probabilistic and uncertain nature of prognosis, it is extremely unlikely that the scenarios a healthy person imagines when filling out his or her advance directive—either sitting at the kitchen table or in the doctor’s office—will match the actual circumstances the patient or surrogate will face in the future. The more general the terms of the advance directive, in order to capture a range of possibilities broad enough to fit an unknown and unknowable future, the less use they will be in providing specific guidance about treatment preferences. This is a structural problem that no preprinted advance directive form—no matter how elaborately or imaginatively it has been constructed—can solve. Uncertainty Related to the unpredictability of the time and manner of death in general is a more specific uncertainty as to the potential benefit of any particular medical intervention or treatment that might be used near the end of the incapacitated person’s life. Consider, for example, treatments such as antibiotics, oxygen therapy, blood transfusions, or even more invasive procedures such as kidney dialysis. All of these are typically among the items that, in advance directives, people indicate the desire to refuse in the case of terminal illness. Yet, each of these, although not capable of reversing the dying process, may be very useful for more particular goals 677

such as alleviating pain, clearing mental confusion, or simply keeping a person alive long enough for family or friends to gather at the bedside for a final farewell. The question “If you were mentally incapacitated and terminally ill, would you want blood products or antibiotics?” for example, is practically meaningless when asked far in advance.30 Ambivalence The desire for a gentle death, free of tubes and machines, coexists in most of us with the powerful desire to stay alive. It is very difficult to predict how, in the moment of truth, a particular patient will respond to even a tiny chance of success for a life-prolonging treatment when the alternative to trying the treatment is likely to be imminent death. The difficulty of extrapolating a patient’s real-time choices from previous discussions is compounded by the “framing effect,” in which those choices will be strongly influenced by the way the alternatives are actually described.31

A Realistic Approach Despite these difficulties, there are some very realistic and meaningful goals that advance care planning can help people achieve. One goal is to promote honest and open communication about important values and life goals within families and between patients, families, and health professionals in the face of serious illness. This type of communication is often of great intrinsic value whether or not it bears any relation to specific treatment choices. Another goal is to arrange for future medical decisions to be made, in case of future incapacity, by someone whose love and care the principal trusts—not on the assumption that this individual will infallibly make the “right” decision (if “right” means matching exactly the decision the principal would have made)—but, because any surrogate is apt to be “wrong,” it is often of great comfort to know that the decision maker is someone who loves and cares about you and is doing his or her best to serve your best interests. Finally, advance planning is an opportunity to reflect on those qualities of life that make life worth holding onto and, conversely, those qualities that might be worse than death and to communicate those values to a surrogate, who can then compare the likely outcomes of real-time medical alternatives to those benchmarks and make

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choices in their light.32 A reasonable and useful advance care planning document should probably contain information along the following lines: 1. Identification of a preferred surrogate decision maker and at least one backup 2. Statement of the extent of the surrogate’s authority and how much flexibility the surrogate has in responding to real-time circumstances in ways that might depart from any specific instructions 3. Evidence that the surrogate is aware of his or her appointment and understands the scope of his or her authority 4. A statement from the principal describing the qualities and aspects of life that the principal considers necessary for a minimally acceptable quality of life, accompanied by instructions to the surrogate to request the application or continuation of any and all medical treatments that have a reasonable likelihood—according to accepted medical judgment—of restoring to the principal that quality of life for a reasonable period of time. Similarly, the surrogate is instructed to decline or insist on the withdrawal of any and all medical treatments if those treatments do not have a reasonable chance— according to accepted medical judgment—of achieving or maintaining that quality of life for a reasonable period of time. 5. In general, the document should not specify particular treatments that the principal does or does not want. The statement in item 4 should provide sufficient guidance for the physician to make these specific treatment decisions in light of the principal’s overall criteria for an acceptable quality of life, combined with the principal’s preference for resolving medical uncertainties—see item 7. However, there may be some special circumstances in which particular treatments should be mentioned; for example, a Jehovah’s Witness may wish to decline blood or blood products, or a person who has previously been resuscitated and placed on a mechanical respirator may have become convinced by the experience that he or she would never want it to be repeated, or in states that require the administration of artificial nutrition and hydration unless they are explicitly included among treatments to be withheld. Otherwise, the broad statement of values 679

(item 4) and preference for resolution of uncertainties (item 7) should suffice for most people. 6. A statement of the principal’s willingness to undergo trial periods of medical treatments when physicians are uncertain of their likely benefit, as defined in item 4, accompanied by a clear statement of the surrogate’s authority to stop those treatments after the agreed-on trial period has ended 7. A statement of the principal’s preference either that genuine medical uncertainties be resolved in favor of more aggressive treatment or less aggressive treatment, with a clear additional statement that the surrogate has the ultimate authority to resolve disagreements between conflicting medical opinions 8. A statement by the principal that he or she wants all necessary measures to maintain comfort and to treat pain and that when medical treatments are deemed incapable of achieving the goals defined in item 4, pain and other symptoms should be treated aggressively even if adequate treatment carries the risk of hastening death. The statement should include the desire for treating physicians to consult with qualified specialists in pain management and palliative care whenever they or the surrogate deems it appropriate. Beyond their value in suggesting what an advance directive should contain, these items are also intended to suggest some of the questions that physicians can ask—directly of patients in advance—or to help surrogates fulfill their roles in order to fashion a treatment plan more likely than not to respect patient values. A further step beyond the preparation of an advance care planning document is the execution of a different sort of document, designed to turn a patient’s statement of treatment preferences into actionable medical orders to be followed by clinicians and emergency medical technicians wherever the patient happens to be. The Physician Orders for LifeSustaining Treatment (POLST), originated in Oregon, was the first such document—whose successful implementation requires intensive efforts to educate clinicians as well as patients about the indications for and scope of the document—although at the present time, well over 30 states have adopted similar programs.33 680

It should be said in conclusion that many people experience end-of-life decision making that is smooth and uncomplicated, and for many survivors, the death of a loved one, although sad, is neither chaotic nor traumatic. When things do go awry, leaving people anguished and bewildered by events that seem to be tumbling out of control, it is usually not the fault of a missing or poorly worded living will or durable power of attorney for health care. Recall the perspectives of Hinton and Burt in the introduction. Death carries enormous power to frighten us and to discombobulate the best laid plans. Despite our rhetoric of management of symptoms, or of directing our health care providers to do (or not to do) this or that, we do not control death. In its presence, we bear witness and do the best we can.

Responding to Demands for Nonbeneficial Treatment The ethical consensus respecting a competent adult’s right to refuse medical treatment—even life-sustaining treatment when the refusal is contrary to the physician’s professional judgment—does not extend to the patient’s or family’s right to demand medical treatments that, in the physician’s professional judgment, offer no prospect of patient benefit. This difference in the moral and legal status of refusals and demands occasionally gives rise to conflicts that are among the most vexing and emotionally draining that can occur in end-of-life care. Taken to their limit, these conflicts can be so destructive not only of the physician– patient–family relationship but also of the atmosphere and milieu of the patient’s dying that loved ones will take with them in memory, that preventing them is the physician’s foremost ethical responsibility. Preventive measures are not always successful, but their chances can be improved through systematic analysis of the nature of a conflict in its early manifestations (“differential diagnosis”) and a range of communication and conflict resolution strategies.

THE ETHICAL BASIS OF THE CONFLICT Ethically, the difference in physicians’ obligations toward refusals of 681

treatment and demands for treatment stems from the way ethics and law customarily interpret the concepts of autonomy and self-determination. In bioethics, respect for personal autonomy and self-determination is rooted in the ideas of privacy and bodily integrity. The idea is that—with very few exceptions, such as a potential public health emergency—a person ought to be able to control what is done to, with, or for his or her own body. This is the foundation for the requirement of informed consent and for the patient’s right to say “No” to the physician’s recommendations for (even life-saving) treatment. Courts have tested the claim of patient selfdetermination, or the patient’s right to say “No,” against potentially competing claims such as the state’s interest in preserving life, the interests of third parties (e.g., spouses or minor children), the integrity of the medical profession, and the prevention of suicide. In every case, almost all courts have come down in favor of self-determination. The competing interests have been seen as too abstract, too remote, or too weak to override the individual’s interests in preventing the violation of his or her bodily integrity and limiting the power of others to enforce values or life goals that he or she does not share.34 The matter is quite different for the person who demands a particular treatment. (This distinction applies equally to requests for physicianassisted death, which are discussed in the next section.) Here, it is no longer a question of an individual protecting his or her bodily integrity by drawing a boundary and saying, “Do not cross.” Respecting this essentially negative right (the right to be let alone) requires physicians and everyone else simply to do nothing. The person who demands a treatment, however, would compel the physician, and potentially many other people, to act affirmatively to supply the treatment. Many more public and professional interests and resources are implicated in the positive satisfaction of a demand than in the negative respect for a refusal. And, especially when the demand is for a treatment that, according to accepted medical opinion, will not benefit the patient, ethical opinion is far more deferential to competing societal and professional interests than in the case of patients who are asserting their negative right to be let alone. It is worth noting that only a very few courts have explicitly addressed the question of patients’ demands for lifesaving treatments that are 682

contrary to widely accepted medical opinion, and up to now, no clear judicial trend has emerged.35 Among the most likely reasons for the relative lack of such cases is hospitals’ reluctance—despite their desire to support their physicians’ professional judgment—to face the costs and potential damage to their public image of going to court to force the removal of life-sustaining treatment over a family’s vehement protests. However, as noted earlier, there are other, better reasons to avoid recourse to the very public, adversarial forum of a court of law to resolve these conflicts. Preserving a therapeutic relationship and protecting the special environment of the deathbed are very worthy motivations for the physician’s efforts to find a more constructive resolution.

THE CLINICAL CONTEXT OF THE CONFLICT Many clinical scenarios have the potential to bring doctors into conflict with patients or their families over the continuation of medical treatments of little or no likely patient benefit; for example, continuous blood transfusion for the patient with inoperable bleeding, full resuscitation efforts for the elderly patient with sepsis and multiorgan failure, and additional courses of high-toxicity anticancer treatment for the patient for whom both standard and experimental therapies have failed to slow the spread of the disease. The paradigm case, however, continues to be the noncommunicative, ventilator-dependent patient, kept alive by mechanical means while suffering inexorable bodily deterioration and discomfort with little prospect of improvement. This is the patient who, in K. Danner Clouser’s words—as vividly applicable today as when he wrote them 40 years ago—“is on the borderline between treatment and torture, where therapeutic hope has vanished, and pain without point has taken over. The doctor’s time-honored admonition to preserve life and lessen pain is at a stupefying impasse.”36 Faced with a family’s continuing insistence that “everything be done,” including, if necessary, chest compressions and electric shocks to the heart in order to keep the patient alive, the medical team chafes in resentment at another “family that does not get it.” Every evening, when the family arrives at the ICU, the same routine plays out: A physician from the team recites the grim medical facts, points to the patient’s deteriorating body, 683

and urges the family to allow them to withdraw the ventilator so the patient can die peacefully. The family listens to the explanations—the descriptions of failing organs, alarming laboratory values, hopelessly long odds—and insists that everything be done. The team wonders why a supposedly loving family is being so selfish and cruel and how it is possible for the obstinacy of one family to commandeer enormous medical resources that could and should be put to much better use. The family wonders why the doctors keep badgering them with their litany of doom and gloom when they should simply be about their business of keeping their loved one alive and how it is possible that the hospital can be so indifferent to the value of the life which the family has entrusted to it.

DIFFERENTIAL DIAGNOSIS OF THE CONFLICT The frustrated medical team’s epithet, “The family does not get it,” is often shorthand for a common diagnosis of the cause of the impasse; namely, that for all of the medical team’s efforts to be clear about the patient’s serious medical condition and grim prognosis, the family has yet to fully comprehend. With every passing day, with its presentation of facts, laboratory values, and statistics, the team’s hypothesis appears to be confirmed by the family’s implacable opposition to changing the patient’s level of care. Perhaps, the team reflects, we are using too many big words. Perhaps, this is not a very well educated family. Maybe English is not their native language. The team redoubles its efforts to educate the family about the seriousness of the situation, only to remain stuck with the same result. In fact, there are several possible explanations for the conflict between the doctor and the family, of which a lack of intellectual understanding is only one and not the most common in any event. But if lack of understanding is not the principal source of the conflict, repeated efforts to lecture the family about the medical facts are no more likely to resolve the impasse than a course of antibiotics is likely to succeed in treating a viral infection. From the outset, therefore, the ethics of prevention requires careful discrimination among the possibilities. Tables 13.1 and 13.2 suggest a differential diagnosis of physician–family conflicts surrounding medically nonbeneficial treatments.

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TABLE 13.1 Conflicts Often Resolvable Lack of comprehension Emotional barriers to processing information Disagreement about the patient’s preferences Narrow understanding of “hope” and “caring” Mistrust of health care team Team conflict and mixed messages

TABLE 13.2 Conflicts Often Intractable Disagreement on legitimate goals of medical care Disagreement on acceptable probabilities of success or trade-offs between potential benefits and burdens Disagreement on an acceptable quality of life Waiting for a miracle

The principal difference between the two tables is that, in principle at least, all of the issues in Table 13.1 are amenable to resolution through sensitive, therapeutic dialogue, whereas the issues in Table 13.2 represent potentially intractable clashes of values or worldviews. Therefore, a good first step for the team is to try to elicit as specifically and clearly as possible all apparent sources of disagreement, sorting them if possible into the two categories and choosing strategies of mediation or conflict resolution accordingly.37 In Table 13.1, for example, even though problems of intellectual comprehension are infrequently the cause of profound disagreements about life-sustaining treatment, the team has the responsibility (always implicit in our ideal decision-making process) of communicating information about the patient’s illness in a language and in a setting that are conducive to patient/family comprehension. It is worthwhile cultivating the skill of inquiring, in a noncondescending way, whether a family can repeat back to the team the essence of the information the team has tried to convey. (A likely apocryphal story recounts the experience of a surgeon who hastily sketched the chambers of a baby’s heart for a new mother, drawing a schematic diagram similar to that shown in Figure 13.1, in an effort to explain the need for a valve repair, only to overhear the mother report to the father that their baby’s problem was that it had been born with a square heart.) Genuine misconceptions and misunderstanding usually can be 685

corrected with appropriate educational strategies.

FIGURE 13.1 Physician’s sketch of infant heart in apocryphal story of miscommunication.

Other issues in Table 13.1 may deserve more consideration. For example: • What may appear as a lack of intellectual comprehension may be a manifestation of emotional barriers to taking in information. The information may be too threatening, too unexpected, or too evocative of a deepest dread to be absorbed without the protective shields of numbing or denial. Most situations permit periods of supportive accompaniment of the shell-shocked, grief-stricken family before pressing forward with the team’s recommendations to change the focus of care. Communication strategies discussed earlier, particularly under the SPIKES and NURSE mnemonics, can be of great value in this setting. • The team and family may have different understandings, or evidence, of the patient’s likely preferences. The patient may have expressed one view to the doctor and another to the family. Language in an advance directive may suggest one thing to the team but something quite different to family members who were present when the document was filled out. A tension-lowering approach in this setting is for someone (perhaps an ethics consultant) to open a physician– family conference with the statement, “Everyone in this room is trying to do exactly the same thing, which is to give [your husband, father, brother] the care that he would want if he could speak with us now. 686

Our challenge is to figure out what that is. Let’s go over what each of us knows about his likely preferences at this point, and how we learned this information.” • Patients as well as physicians may equate “hope” exclusively with cure or prolongation of life and “care” with the provision of maximal medical treatment. Efforts to expand hope to include achievable goals more consistent with the patient’s condition and suggestions to the family of ways to express love and care through their presence, voice, and touch may offer the family emotional space to adjust their expectations of the medical team. • Especially for families from marginalized, economically disadvantaged communities, the recommendation to limit intensive medical care can appear to repeat long-standing patterns of social injustice and deprivation. The medical team may represent one more agent of an oppressive power structure. In this setting, the family is unlikely to trust the team’s recommendations, even when they are made in good faith on the basis of solid scientific evidence. If the team suspects this dynamic may be at work, explicitly naming the lack of trust and offering to call in more trusted individuals from the family’s community may diffuse the conflict and promote eventual agreement on a treatment plan. • Perhaps most common of all preventable or remediable sources of conflict, especially in the ICU, are mixed messages to the family about the patient’s condition. The attending physician may prepare the family for the patient’s inevitable death based on the overall combination of downward-trending prognostic indicators only to have a specialist consultant come by later to tell the family that “the [lungs, kidneys, blood counts] look a bit better today.” A team that repeatedly sends mixed signals to the family should not be surprised when the family holds fast to the most optimistic statements and insists on staying the course. The most urgent task is for the team to arrive at its own internal consensus. A brief checklist (Table 13.3) can be part of a preventive ethics strategy to help the team first ascertain whether it is in fact dealing with a Table 13.1 type of conflict and, second, maximize its chances of resolving it. 687

TABLE 13.3 Checklist for the Team Do team members agree on diagnosis and prognosis? Have team members and family compared sources of information about the patient’s preferences? Is the team speaking to the family with one voice? Has the team identified a spokesperson with the greatest rapport and credibility in the eyes of the family?

Table 13.2 conflicts are more difficult to resolve solely within the context of therapeutic dialogue. This is because the terms of the disagreement reflect value differences or worldviews that are not necessarily amenable to rational persuasion or supply disputants with individually convincing yet mutually incompatible interpretations of agreed on facts. Institutional policies for mediation, which may include mandatory consultations with an ethics committee and—if these efforts fail to break the impasse—offers to transfer the care of the patient either to another physician or to another institution, are options of almost last resort.37 In the extreme case, where none of these options is feasible, the institution may be faced with the choice of going to court to obtain judicial authorization to stop the treatment—with no certainty of success but the virtual certainty of cementing the family’s enduring resentment. Alternatively, it may recognize that there are (fortunately rare) instances where, for reasons of compassion, “professional medical judgment” and “the rational use of medical resources” may yield to a family’s indomitable will. Although the team may view the patient’s dying as needlessly prolonged and even horrible, in the circumstances of a family’s passionate intransigence, it may be the least poor outcome. Support for the likely moral distress of the staff becomes another institutional responsibility in this situation.

Physician-Assisted Death The vast attention paid to physician-assisted death in discussions of ethics at the end of life is far out of proportion to its actual significance in the experiences of most dying patients and their families. For most people, far more important issues are related to maintaining the energy and stamina to pursue valued activities and relationships amid the burdens of illness and 688

obtaining timely, skilled help with pain, anxiety, and other symptoms. Even in Oregon, whose first-in-the-nation Death with Dignity Act legalizing physicians’ prescriptions of lethal doses of medication for terminally ill patients spawned fears of a “suicide mecca” in the Pacific Northwest, the 133 deaths in 2016 that occurred under the law amounted to barely more than one-third of 1% of all deaths in the state that year.38,39 Nevertheless, the issue commands attention in part because of legitimate public concerns about the quality of care that our society makes available to the dying and because active campaigns to expand legalization of the practice beyond Oregon are ongoing in many states across the United States. As of 2017, four states (Washington, Montana, Vermont, and California) have chosen to do so.40

TERMINOLOGY As with many contested social practices, the language used to describe the various ways physicians can be involved in hastening the time of a patient’s death has evolved through many phases and fashions, with people’s preferred language often reflecting their prior moral evaluation of the practices in question. Thus, the literature abounds in discussions of the differences between “killing patients” and “allowing patients to die” or the differences between “passive euthanasia” and “active euthanasia,”41 and— more recently—the preference of organizations such as the American Public Health Association42 and the American Academy of Hospice and Palliative Medicine43 for the term physician-assisted dying rather than physician-assisted suicide. What seems to be at issue in the debates about terminology is the recognition that how we characterize an action (or an omission) often predetermines judgments of its moral status. Because “killing” is nearly universally condemned in all but very carefully circumscribed situations, proponents of physician actions (or omissions) that hasten a patient’s death take pains to argue that those actions or omissions are not instances of “killing.” Similarly, because “suicide” carries wide social stigma and is often associated with mental illness, patients who make use of physician-provided lethal prescriptions and the physicians who provide them prefer to characterize what they are doing in terms other than committing or aiding in “suicide.” In fact, there 689

is usually room for reasonable people to disagree about the most accurate characterization of many actions. This is one reason why, as mentioned at the beginning of this chapter, the public consensus on many aspects of end-of-life care masks considerable uncertainty and debate within society. For convenience, the rest of this section will employ the term physicianassisted death to refer to a spectrum of actions and omissions by which physicians may influence the timing of an incurably ill patient’s death so that it occurs sooner than it probably would have without the physician’s involvement. There is a fairly strong public and professional consensus (with the qualifications previously mentioned) about the moral status of many points along the spectrum.

ETHICAL CONSIDERATIONS ALONG THE CLINICAL SPECTRUM Requests for physician-assisted death confront physicians with troubling questions about the proper boundaries of medical practice and the nature of their duty to relieve suffering. There are at least six reasonably distinct actions or roles that a physician might take in the care of an incurably ill patient that could advance the timing of the patient’s death. Two lie at opposite ends of the ethical and legal spectrum. Respecting a competent patient’s wishes to forego or remove life-sustaining treatment is universally accepted ethically and legally in the United States. Administering a lethal injection with the intent of immediately ending the patient’s life (“active euthanasia”) is universally rejected legally in the United States and—although not universally condemned ethically— commands the least widespread support in the ethical literature. In between are four actions that remain somewhat controversial although in varying degrees, always allowing for the fact that characterizing an action as one of these four is itself often a morally significant choice.44,45 The four intermediate actions are: • Aggressive symptom management, usually with opiates and sedatives, despite the risk of hastening the patient’s death. The paradigm case is the use of large doses of morphine for pain relief that have the effect of causing fatal respiratory depression. In fact, this is an extremely unlikely side effect of skillful opioid administration to a patient who 690

has been receiving chronic opioid therapy for pain relief for a period of time. Nevertheless, the scenario is frequently brought up in discussion of the “rule of double effect.” This is the notion, originating in Catholic moral theology, that an action with foreseeable but unintended bad effects (here, the death of the patient) may under certain conditions be undertaken with the primary intent of bringing about its good effect (here, the relief of pain). The extensive debate over the philosophical coherence and clinical applicability of the rule of double effect is beyond the scope of this chapter.46–48 For present purposes, it is sufficient to note that the basic concept of treating patient suffering aggressively with appropriate medical therapies, even at the risk of the patient’s earlier death as a side effect of the therapy, is well accepted clinical practice and appears also to have received the sanction of at least some justices of the U.S. Supreme Court. • Sedating the consenting, terminally ill patient to the point of unconsciousness to protect the patient from otherwise intractable physical or emotional suffering while also withholding artificially provided nutrition and hydration. This sits on the borderline between the previous action (in combination with the universally accepted practice of respecting patient refusals of medical treatment), on the one hand, and the far more controversial action of injecting patients with a lethal dose of medication. The argument against the practice is that although the sedatives themselves are not administered in an intentionally lethal dose as in the case of “active euthanasia,” when combined with the withholding of nutrition and hydration, the patient’s death is as inevitable as it would be at the lethal dose. That it takes place more slowly, in this view, does not avoid the appropriate characterization of the action as (“slow”) active euthanasia.49 The rejoinder to this is that, unlike active euthanasia, with its clear intent for immediate death, “palliative sedation”—as the practice has come to be known—is in principle always reversible (sedatives can be lightened to give the patient the opportunity to interact and change course if desired) and remains focused on alleviation of discomfort rather than bringing about the patient’s death. 691

• Counseling the patient about voluntarily stopping eating and drinking and, if the patient decides to do this, providing medication as needed to alleviate possible discomforts or anxiety over the ensuing period of the patient’s death from dehydration. This is another borderline action. On the one hand, it seems to avoid the moral conundrum posed by physician-provided prescriptions for lethal injection because the patient is solely responsible for his or her lack of nutrition and hydration. Moreover, the determination required on the patient’s part to persist in refusing to eat or drink until death is a safeguard against subtle manipulation or coercion of the patient. On the other hand, the physician clearly has played some significant role. Without the physician’s education of the patient about the option, his or her assurances of providing comfort measures, and actually providing them, many people would probably never consider this option at all, much less pursue it to its conclusion. • Providing a prescription for a lethal dose of medication at the patient’s request and counseling the patient about how to take the medication to ensure a painless death, after ensuring the patient’s mental competence, providing information about palliative care as an alternative, and requiring both oral and written requests separated by a waiting period. This is the Oregon Death with Dignity Act. As with the previous action, the patient takes all of the decisive steps to bring about his or her death and may decide at many points to change his or her mind—indeed, since Oregon’s law was passed in 1997, a total of 1,749 people have had prescriptions written under the law, whereas only 1,127 have died from ingesting the medications.38 Nevertheless, by calculating the effective dose, writing the prescription, and counseling the patient on how to ingest the medication, the physician is complicit in the patient’s death in a way that he or she would not be were the patient to end his or her life in a completely private act.

TWO LEVELS OF RESPONSE: SOCIAL POLICY AND CLINICAL CARE There are two important levels of response to the issue of physicianassisted death: the level of social policy (i.e., which actions along the 692

clinical spectrum should be legally permitted or prohibited) and the level of clinical care (i.e., how individual physicians should respond to their patients who request help in advancing the time of their death).

Social Policy At the level of social policy, there are once again two positions at the ends of a spectrum, with ongoing active debates about positions in between. One end is occupied by advocates of a thoroughgoing libertarianism: The choice to end one’s life at the time and in the manner of one’s own choosing is so bound up with personal privacy and self-determination that no limits should be set on the actions of fully informed, mentally competent adults, or on those of a physician willing to help a terminally ill, suffering patient achieve a swift and painless death. The other end views physicians’ direct involvement in assisted death in the forms of providing prescriptions or injecting lethal medication as so contrary to the role and professional identity of the physician, and so destructive of important societal values, as to require universal and permanent legal prohibition. Physicians, on this view, should abstain from the practice even where it is legally permitted.50 The most active debate takes place between these extremes. The essential dispute is this: Given the improvement in the science and technique of palliative care and pain management over the last 20 years or so (much of which is documented elsewhere in this volume), is the number of people whose physical or existential anguish near the end of life is beyond the reach of effective palliation large enough to justify the societal risks that could accompany widespread legalization of physician-assisted death in its most direct and active forms? Those who say no—and at the state level that would include, as of now, all states in the United States except Oregon, Washington, Montana, Vermont, and California—worry that the possibilities for various types of abuse in a permissive legal system outweigh the benefits to the very small number of people who truly have no other acceptable options. These abuses might include acts of desperation by people without reliable access to medical care of any sort, much less state-of-the-art palliative care; subtle coercion of people to take advantage of legal means to end their lives, playing on their common 693

desire not to be a burden on others; or misguided compassion of caregivers who are ignorant of comfort measures and social supports that could have provided the patient with more options for maintaining dignity and comfort.2 Those who say yes argue that these hypothetical, even if theoretically plausible, worries should not outweigh the actual suffering of identifiable people who are ravaged by disease and dying in uncontrolled misery or humiliation. Given what even most opponents concede that there are indeed some patients (small though their number might be) whose suffering is not remediable with standard measures of palliative care, proponents of legalization believe the more active forms of physician assistance should be available—and socially permissible—as a last resort.45,51 They contend that the Oregon experience itself should reassure skeptics that safeguards against abuse can work38; and that, even if legally prohibited, physician-assisted death in its active forms is and will be carried out, whereas legalization will allow a more public, well-regulated practice to take the place of the “euthanasia underground.”52

Clinical Care Regardless of the resolution of these issues at the social and political level, individual physicians should be prepared to deal compassionately and therapeutically with patients who raise the possibility of physician-assisted death. Opponents and proponents of legalization of the more active forms of physician involvement usually agree that excellent palliative care—the active management and support for physical, psychosocial, and spiritual distress—is the standard of care for the seriously ill patient near the end of life. Quill and Arnold53 outline a set of responses within the physician– patient relationship and the therapeutic dialogue that can help assess and respond to patients, independent of the physician’s personal moral beliefs or the legal environment of his or her practice. They recommend that the physician who receives a request from a patient to help hasten death: • CLARIFY what the patient is communicating: General thoughts about the desirability of ending his or her life? Wondering about the future if his or her condition deteriorates? Asking for help right now? • SUPPORT the patient by giving reassurance that whatever the patient 694

feels or desires, the physician is prepared to work together to find a mutually acceptable solution. • EVALUATE the patient’s mental state and decision-making capacity; whether the request seems commensurate with the level of unrelieved suffering; whether there is evidence of treatable depression. • EXPLORE the many possible sources of intolerable suffering, for example, poorly controlled physical symptoms, loneliness, sleep disturbances and exhaustion, psychological or spiritual anguish. • RESPOND to the emotions associated with the patient’s request. Take them seriously while also trying to separate your own emotions from those of the patient. • INTENSIFY TREATMENT, with the help of a multidisciplinary team, of any potentially reversible elements of the patient’s suffering. Only when all of these steps have been completed, Quill and Arnold53 recommend, should the physician respond directly to a patient’s persistent request for hastened death. Physicians who believe that affirmative assistance is justified beyond steps that fall within ethically or legally accepted practice have a genuine moral dilemma. Some may feel compelled to inform the patient that, despite their sympathy and solidarity, they cannot cross a particular legal or ethical boundary but may be willing to refer the patient to another physician. Others may be willing to, in Quill’s words—cited in a very valuable essay by John Arras54—“take small risks for people [they] really know and care about.”

Conclusion: Beyond the Patient–Physician Dyad Good care for a dying patient depends on more than the skillful efforts of the most conscientious physician. Dying is both an intensely private and an inherently social process. The ramifications of the patient’s illness spread throughout his or her social network, both in space—to family, intimate friends, workmates, and so on—and in time—lasting throughout the grief and bereavement of the survivors. Palliative care, which sets itself the task of ministering not only to the patient but also to the “family as the unit of care,” necessarily raises ethical and policy questions beyond the patient– physician dyad. 695

Some of these issues are closely connected to some of the familiar topics of clinical ethics, such as protecting the confidentiality of medical information or weighing the preferences or needs of family members against potentially incompatible wishes of the patient (e.g., the patient who insists on remaining at home to die even as family members are pushed beyond their physical or emotional limits by the demands of home-based care). Issues such as these push against an individualistic ethic that places the physician’s obligations to the best interests of his or her patient above all other moral considerations,55 and they often call for skills of negotiation and mediation that are not typically included in the interviewing and communication skills training in medical schools. Other issues touch on broader questions of public policy and the allocation of society’s resources. Excellent palliative care requires systems of care that can match the particular needs of patients and their families across all the sites of care typical of the prolonged, chronic illnesses that precede most deaths in our society.28 These include, at a minimum: • Systems to elicit and document meaningful information from patients about their values, preferences, and goals for medical care and to make sure the documentation accompanies the patient wherever they are in the health care system • Systems to assure quality standards for the provision of palliative care in health care institutions, including hospitals, nursing homes, and personal care facilities • Systems to train health professionals in the principles and practices of palliative care • Systems for family and caregiver support that help families participate meaningfully in the lives and care of their dying loved ones without sacrificing their own physical, mental, and financial well-being • Systems for financing care that reward professionals for the timeintensive nature of patient and family support and communication in palliative care As has been mentioned more than once in this chapter, the disruptive power of death makes it impossible for even the best systems and most dedicated individuals to ensure that every person dies according to his or her ideals and hopes for meaning, dignity, and comfort. And the physician 696

is only one actor—albeit a very significant one—in the universal human process of coming to terms with life’s ending. Families, faith communities, neighborhoods, civic groups, employers, professional caregivers, and many others have the opportunity and responsibility to help a person die in ways that affirm the values and qualities that made his or her life itself worthwhile. The best social policies, laws, and regulations for the care of the dying will be those that make the efforts of all of these people easier rather than harder. References 1. Hinton J. The dying and the doctor. In: Toynbee A, ed. Man’s Concern with Death. St. Louis, MO: McGraw-Hill; 1969:36–45. 2. Burt RA. Death Is That Man Taking Names: Intersections of American Medicine, Law, and Culture. Berkeley: University of California Press; 2002. 3. McIntyre A. After Virtue. Notre Dame, IN: Notre Dame University Press; 1981. 4. Engelhardt HT Jr. The Foundations of Bioethics. 2nd ed. New York: Oxford University Press; 1996. 5. Meisel A. The legal consensus about forgoing life-sustaining treatment: its status and its prospects. Kennedy Inst Ethics J 1993:2(4):309–345. 6. Oken D. What to tell cancer patients. A study of medical attitudes. JAMA 1961;175:1120– 1128. 7. Novack DH, Plumer R, Smith RL, et al. Changes in physicians’ attitudes toward telling the cancer patient. JAMA 1979;241:897–900. 8. Baile WF, Buckman R, Lenzi R, et al. SPIKES—a six-step protocol for delivering bad news: application to the patient with cancer. Oncologist 2000;5:302–311. 9. Benbassat J, Pilpel D, Tidhar M. Patients’ preferences for participation in clinical decisionmaking: a review of published surveys. Behav Med 1998;24:81–88. 10. Ford S, Fallowfield L, Lewis S. Can oncologists detect distress in their out-patients and how satisfied are they with their performance during bad news consultations? Br J of Cancer 1994;70:767–770. 11. Ford S, Fallowfield L, Lewis S. Doctor-patient interactions in oncology. Soc Sci Med 1996;42:1511–1519. 12. World Health Organization. Cancer Pain Relief and Palliative Care. Geneva, Switzerland: World Health Organization; 1990. Technical report series 804. 13. Billings JA. What is palliative care? J Palliat Med 1998;1(1):73–81. 14. Billings JA. On being a reluctant physician—strains and rewards in caring for the dying at home. In: Billings JA, ed. Outpatient Management of Advanced Cancer. Philadelphia: Lippincott; 1985:309–318. 15. Berg JW, Appelbaum PS, Lidz CW, et al. Informed Consent: Legal Theory and Clinical Practice. 2nd ed. New York: Oxford University Press; 2001. 16. Hauser CA, Stockler MR, Tattersall MH. Prognostic factors in patients with recently diagnosed incurable cancer: a systematic review. Support Care Cancer 2006;14:999–1011. 17. Levy WC, Mozaffarian D, Linker DT, et al. The Seattle Heart Failure Model: prediction of survival in heart failure. Circulation 2006;113:1424–1433. 18. Childers JW, Arnold RM, Curtis JR. Prognosis in end-stage chronic obstructive pulmonary

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disease #141. J Palliat Med 2007;10(3):806–807. Mitchell SL, Kiely DK, Hamel MB, et al. Estimating prognosis for nursing home residents with advanced dementia. JAMA 2004;291:2734–2740. D’Amico G, Garcia-Tsao G, Pagliaro L, et al. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 188 studies. J Hepatol 2006;44:217–231. Wijdicks EF, Hijdra A, Young GB, et al. Practice parameters: prediction of outcome in comatose survivors after cardiopulmonary resuscitation (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006;67:203–210. Christakis NA, Lamont EB. Extent and determinants of error in doctors’ prognoses in terminally ill patients: prospective cohort study. BMJ 2000;320:469–472. Lamont EB, Christakis NA. Complexities in prognostication in advanced cancer: “to help them live their lives the way they want to.” JAMA 2003;290(1):98–104. Callahan D. The Troubled Dream of Life: Living with Mortality. New York: Simon & Schuster; 1993. Herth K. Fostering hope in terminally-ill people. J Adv Nurs 1990;15:1250–1259. Schofield P, Carey M, Love A, et al. ‘Would you like to talk about your future treatment options’? Discussing the transition from curative cancer treatment to palliative care. Palliat Med 2006;20:397–406. Appelbaum PS, Grisso T. Assessing patients’ capacities to consent to treatment. N Engl J Med 1988;319(25):1635–1638. Institute of Medicine. Dying in America: Improving Quality and Honoring Individual Preferences Near the End of Life. Washington, DC: National Academies Press; 2014. Hickman SE, Hammes BJ, Moss AH, et al. Hope for the future: achieving the original intent of advanced directives. Hastings Cent Rep 2005;35:S26–S30. Brett AS. Limitations of listing specific medical interventions in advanced directives. JAMA 1991;266(6):825–828. Tversky A, Kahneman D. The framing of decisions and the psychology of choice. Science 1981;211:453–458. Barnard D. Advance care planning is not about “getting it right.” J Palliat Med 2002;5:475– 481. National POLST Paradigm. Available at: http://polst.org. Accessed April 10, 2017. Meisel A. The Right to Die. 2nd ed. New York: Aspen; 1985. Helft PR, Siegler M, Lantos J. The rise and fall of the futility movement. N Engl J Med 2000;343:293–296. Clouser KD. Allowing or causing: another look. Ann Intern Med 1977;87:622–624. Back AL, Arnold RM. Dealing with conflict in caring for the seriously ill: “it was just out of the question.” JAMA 2005;293(11):1374–1381. Oregon Public Health Division. Death with Dignity Act annual reports. Available at: https://public.health.oregon.gov/ProviderPartnerResources/EvaluationResearch/DeathwithDignityAct/Pages/ar index.aspx. Accessed April 17, 2017. Oregon Public Health Division. Oregon death data. Available at: https://public.health.oregon.gov/BirthDeathCertificates/VitalStatistics/death/Pages/index.aspx. Accessed April 12, 2017. Emanuel EJ, Onwuteaka-Philipsen BD, Urwin JW, et al. Attitudes and practices of euthanasia and physician-assisted suicide in the United States, Canada, and Europe. JAMA 2016;316:79– 90. Battin MP, Rhodes R, Silvers A, eds. Physician-assisted Suicide: Expanding the Debate. New York: Routledge; 1998.

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42. American Public Health Association. Patients’ rights to self-determination at the end of life. Available at: https://www.apha.org/policies-and-advocacy/public-health-policystatements/policy-database/2014/07/29/13/28/patients-rights-to-self-determination-at-the-endof-life. Accessed April 10, 2017. 43. American Academy of Hospice and Palliative Medicine. Statement on physician-assisted dying. Available at: http://aahpm.org/positions/pad. Accessed April 10, 2017. 44. Quill TE, Lee BC, Nunn S. Palliative treatments of last resort: choosing the least harmful alternative. University of Pennsylvania Center for Bioethics Assisted Suicide Consensus Panel. Ann Intern Med 2000;132:488–493. 45. Quill TE, Lo B, Brock DW. Palliative options of last resort: a comparison of voluntarily stopping eating and drinking, terminal sedation, physician-assisted suicide, and voluntary active euthanasia. JAMA 1997;278(23):2099–2104. 46. Quill TE, Dresser R, Brock DW. The rule of double effect—a critique of its role in end-of-life decision making. N Engl J Med 1997;337:1768–1771. 47. Sulmasy DP, Pellegrino ED. The rule of double effect: clearing up the double talk. Arch Intern Med 1999;159:545–550. 48. Fohr SA. The double effect of pain medication: separating myth from reality. J Palliat Med 1998;1:315–328. 49. Billings JA, Block SD. Slow euthanasia. J Palliat Care 1996;12(4):21–30. 50. Pellegrino ED. Doctors must not kill. J Clin Ethics 1992;3:95–102. 51. Quill TE. Doctor, I want to die, will you help me? JAMA 1993;270:870–873. 52. Magnusson RS. Angels of Death: Exploring the Euthanasia Underground. New Haven, CT: Yale University Press; 2002. 53. Quill TE, Arnold R. Fast fact and concept #156: evaluating requests for hastened death. Available at: https://www.mypcnow.org/fast-facts. Accessed April 10, 2017. 54. Arras JD. Physician-assisted suicide: a tragic view. In: Battin MP, Rhodes R, Silvers A, eds. Physician-Assisted Suicide: Expanding the Debate. New York: Routledge; 1998:63–72. 55. Randall F, Downie RS. Palliative Care Ethics: A Companion for All Specialties. 2nd ed. Oxford: Oxford University Press; 1999.

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CHAPTER 14 Laws and Policies Affecting Pain Management in the United States AARON M. GILSON and JAMES F. CLEARY

Introduction PREVALENCE OF UNRELIEVED PAIN IS A PUBLIC HEALTH PROBLEM In The Mystery of Pain, poet Emily Dickinson wrote, Pain has an element of blank; It cannot recollect When it began, or if there were A day when it was not. It has no future but itself, Its infinite realms contain Its past, enlightened to perceive New periods of pain.1(p650) Dickinson’s description personifies pain and reveals that the pain experience, conversely, depersonalizes the sufferer. As intense and prolonged pain becomes a defining trait of someone’s life, pain and that person’s existence become intertwined—defining not only the present and future but also the past. This loss of self, coupled with constant suffering, sheds light onto why some people feel hopelessness because of unremitting pain.2,3 Pain is, in fact, one of the most common physical complaints on a person’s admission into the health care system, and moderate to severe pain is frequently reported to be experienced throughout hospitalization, during treatment, and even after discharge. The Institute of Medicine (IOM) estimates that “at least 100 million Americans” live with chronic pain, including pain associated with the 700

disease of cancer,4 and recent research suggests that the prevalence of pain in people with cancer can vary considerably, depending on chronicity, severity, and site of the disease.5 In addition, the national prevalence of chronic pain (defined as pain every day for the past 3 months) is estimated at approximately 11%, whereas around 16% reported a lot of pain or the most severe level of pain.6 The costs of pain, both emotional and financial, can be enormous.4 Untreated or undertreated severe pain from any condition or any stage of disease can limit a person’s functioning, productivity, and ability to interact socially; sometimes, pain destroys the will to live.2 A recent study from the Johns Hopkins Center for Health Disparities Solutions and Department of Health Policy and Management indicated that cumulative US health care costs associated with pain exceeded $560 billion in 2010 and calculated an estimate ranging between $299 and $335 billion per year in lost productivity and wages.7 These estimates suggest that the financial cost of chronic pain has surpassed that of cancer, cardiovascular disease, or diabetes.7 Increasingly, unrelieved pain has been recognized as a significant public health problem in the United States.4,8,9 Issues of public health demand a public health approach to develop informed and organized responses to these health problems.10 A public health approach is intended to protect the community and enhance the health and quality of life of this population by making available effective and economical interventions.11 Utilizing a social systems perspective, which incorporates input from various levels of the government (including administrative agencies), health care, education, and welfare systems, often is necessary to guide effective interventions.12 As inadequate pain management becomes accepted as an important public health issue, efforts to rectify this situation will necessarily involve the systematic utilization of methods to measure outcomes of improved treatment. Some of the most frequent outcome measures, including reduction in pain scores and indicators of quality of life enhancement, must be considered alongside more long-term objectives that denote optimal levels of health status.13 Before such approaches and outcomes can be conceptualized and achieved, however, the numerous factors that can combine to result in unrelieved pain for patients with chronic diseases or conditions must be 701

understood.

BARRIERS TO THE SAFE AND EFFECTIVE USE OF OPIOID ANALGESICS FOR PAIN MANAGEMENT Unlike most countries in the world, the problem of unrelieved pain in the United States is not a function of needed medications being unavailable (see Chapter 16 for more detail about global medication unavailability). Patients who experience chronic severe pain still often do not have access to prescription opioid analgesics, which are considered essential medications for treating this level of pain.14 Of course, this does not mean that prescription opioid medications are to be considered the first-choice treatment option for every patient, a position that is apparent throughout this text, but rather one to be initiated and monitored when the clinical circumstances warrant.13,15,16 Access to effective pain management requiring prescription opioids is a direct function of the equity of health care services, and the reasons for inequity relate to a variety of issues. Health care organizations and national experts suggest that a number of diverse factors can interfere with the legitimate medical use of opioid analgesics for the treatment of pain and can negatively affect patients’ access to safe and effective pain relief. Most studies have focused on issues in the patient or clinical domains, such as (1) patients’ and family perceptions about the use of opioids for pain relief17–26; (2) patients’ characteristics such as race or ethnicity, substance use history, or the community in which they live27–34; and (3) knowledge and attitudes of health care professionals about the legitimate use of opioids.35–43 When considering whether to treat pain with opioid analgesics, health care practitioners must determine how to maximize benefit and minimize harm,15 which they have generally not been trained to do.44–47 Such inadequate preparation contributes to an unfamiliarity with pain management in general and with relevant treatment modalities in particular, as well as inconsistent use of risk mitigation strategies for patients48 and perceptions about regulatory or criminal sanctions resulting from prescribing the medications.49 As a result, there remains an urgent need to enhance clinicians’ skills and confidence and to explore the motivations and challenges to get both practitioners and patients involved 702

in activities promoting pain management services. Many of the clinical and patient factors previously mentioned can contribute to the high prevalence of unrelieved pain in the United States, including characteristics of the health care system and health care professionals.50 Restrictive federal and state policies relating to drug control and health care practice (often referred to as regulatory barriers) also are recognized as potential impediments to pain management, especially considering the extent that practitioners know of and adhere to such policies. Since the early 1990s, national health care organizations have frequently voiced concern about the possible detrimental effects of regulatory barriers. In 1994, the Agency for Health Care Policy and Research (AHCPR) (now the Agency for Healthcare Research and Quality) published a clinical practice guideline on cancer pain relief, which recognized the existence of regulatory barriers, and recommended that laws and regulations aimed at preventing the abuse and diversion of opioids should not hamper their appropriate use in the treatment of cancer pain51; these messages were retained a decade later when the American Pain Society updated the guideline.52 Around the time of the AHCPR guideline dissemination, the National Cancer Institute sponsored a workshop to define priorities in cancer pain–related research that included policy and regulatory issues.53 The American Cancer Society (ACS) later convened a Cancer Pain Management Policy Review Group to discuss regulatory challenges facing cancer pain management, with an emphasis on ensuring access to appropriate treatment given the national attention on the nonmedical use of pain medications. The Review Group developed several policy statements about various aspects of cancer pain management,54–56 including a description of regulatory barriers affecting quality pain treatment.55 Calls for studies to improve pain management and identify the legal and regulatory impediments to appropriately using opioids for pain relief have come from the ACS54 as well as the IOM57 and the National Institutes of Health (NIH).58 For the United States, this involves an understanding and examination of both federal and state laws.

POLICIES GOVERNING THE USE OF OPIOID ANALGESICS FOR PAIN MANAGEMENT 703

Governments, at both the federal and state levels, can create and change public policies that influence the health of the population. Laws reflect governmental decisions that are largely influenced by social values but provide the legal basis for actions that affect public health, including pain management. For example, given the increasing recognition of pain relief as a basic human right,9,59 health care facility licensing regulatory standards (e.g., for hospitals, nursing homes, residential care units, and hospices) have even emphasized the pain care of their patients.60 The World Health Organization (WHO) embraces the incorporation of human rights principles, acknowledging the need to “balance effective responses to disease risks” with respect for fundamental individual freedoms.61 However, a patient receiving effective pain relief currently is viewed more as a right in the moral sense but generally not in the sense of law or regulatory content.62 Legislative bodies typically create laws (i.e., statutes) that are broad and general and depend on the relevant regulatory agency to interpret and implement the laws through regulations. In fact, legislatures that avoid making considerably detailed law would likely require less frequent amendments to such laws because the accompanying regulations contain the professional or technical details that would need to be revised periodically to keep pace with changing practice standards. For medicine, for example, the legislature grants authority to the state medical board to define and implement its laws through regulation (or administrative rules); regulations must be consistent with legislative provisions. Even given this structured process, pain-related law has not kept pace with advances in medical and scientific understanding. Although professional boards may revise their pain management policies in reaction to updated professional standards, legislation has been slow to change. This has particular implication for pain management, including opioid prescribing, where such legislation tends to have extensive detail and may not reflect current medical standards (see “State Pain Policy Development: An Emerging Trend” section for examples). In late 2016, Pain Medicine published Daniel Carr’s President’s Message to the American Academy of Pain Medicine readership, entitled “Patients with Pain Need Less Stigma, Not More.”63 According to Dr. 704

Carr, who is the founding director of the Tufts Program on Pain Research, Education and Policy, the ubiquitous clinical scenario surrounding the treatment of patients with chronic pain (especially noncancer pain) is characterized by, among other things: • “Stigma—shaming and shunning—continues to befall patients with chronic pain, as do inequities in access to care.”63(p1391) • “[The] most damaging barrier now facing patients with chronic pain [is] the unprecedented rise in illegal diversion and abuse of opioids, often involving prescription painkillers, with pervasive societal consequences from addiction, crime, overdose, and death . . . [despite the] general agreement that most patients prescribed opioids for chronic noncancer pain are not these problematic outliers.”63(p1392) • “Practice guidelines put forth or proposed by different governmental agencies are not uniform, leaving prescribers uneasy that by prescribing opioids at any dose, to any patient, they place themselves in harm’s way . . . unleashing a torrent of blame and stigma directed towards all opioid prescriptions, prescribers, and patients.”63(p1392) • “Increasing numbers of legitimate patients are voicing personal narratives of long-term benefit from a chronic modest dose of an opioid, now finding such care terminated by policies based upon administrators’ interpretations of group statistics never meant to guide individual care.”63(pp1392–1393) Within these statements, Dr. Carr recognizes that health care professionals must practice in an environment of legal and regulatory influences, one that can seem particularly ambiguous when it comes to chronic pain, opioid therapy, and risk of addiction or other serious harms. In such an environment, understanding current practice policy requirements is critical. Although practitioners generally do not receive training in legal and regulatory issues related to prescribing of opioid analgesics and can be unfamiliar with the federal and state laws that govern their practice, there has been an increasing call for clinicians to acquire knowledge about the policies under which they practice.13,16,64,65 This chapter attempts to create a resource to address this need by describing the three layers of laws in the United States that create the policy framework for both the diversion and 705

legitimate medical use of opioid analgesics: (1) international treaties governing drug control; (2) federal laws and regulations governing drug control, which includes the legal parameters for prescribing controlled substances; and (3) state laws and regulations governing drug control and health care practice, including prescribing controlled substances. The chapter also discusses other policy considerations related to prescribing practices, highlights the need for communication and implementation as a means to improve practitioners’ understanding of policy requirements, and suggests the influence that diversion of medications can have on opioidrelated harms.

International Treaties: Establishing Balance between Drug Control and Medical Use Treaties form the basic legal framework to control international and domestic production and distribution of drugs—including medications— that have a recognized abuse liability. The drugs subject to these more rigorous controls are therefore referred to as controlled substances and include, but are not limited to, opioid analgesics. The principal treaty establishing controls for prescription opioids used to treat pain is the Single Convention on Narcotic Drugs of 1961 (Single Convention).66,67 It should be understood that the term narcotic, which includes opioid analgesics, is now primarily used in legal contexts, such as in reference to the international drug control treaty or relevant laws; narcotic, which generally is defined as an agent that produces stupor or insensibility, is not considered “useful in a pharmacological context” when describing opioid medications.68(p486) The Single Convention establishes a number of basic requirements for a country’s laws and regulations to create effective measures against drug abuse and diversion. Many of these measures relate directly to the health care setting, including: • A country’s government must duly authorize everyone involved in the medical distribution of narcotic drugs (Article 30). • Opioid medicines are to be possessed with only legal authority—that is, a valid prescription issued to a patient by a properly licensed practitioner for a legitimate medical purpose in the usual course of 706

professional practice (Articles 30 and 33). • All licensees are qualified and adhere to their obligation to prescribe and dispense controlled medicines in full and faithful execution of the law, as well as maintain records for medication manufacture, acquisition, and disposal (Article 34).67 Although established as international law aimed at preventing drug abuse, this treaty also recognizes that many controlled substances are indispensable to public health and that there is a need to ensure their availability for legitimate medical and scientific purposes (United Nations,67 Preamble). Becoming a party to this treaty obligates a government to take steps to make controlled substances available in adequate amounts to effectively treat medical conditions. Most, but not all, of the world governments are parties to the Single Convention, including the United States, which means that they formally accept the obligation to develop a legislative and administrative framework to implement the treaty’s objectives.69 The long-standing dual obligation of country governments to (1) establish a system of controls to prevent abuse, trafficking, and diversion of controlled substances and (2) simultaneously assure their medical availability, is referred to as Balance.70 Balance maintains that opioid analgesics, although designated as controlled drugs, also are essential medicines, are absolutely necessary for adequate pain relief, and must be accessible to patients who need them for medical purposes. Within this framework, the status of these medications as “controlled substances” is not meant to diminish their medical usefulness or create the perception that practitioners should avoid their use when there is a clear clinical indication. Moreover, the principle of Balance does not sanction medication use outside an established system of control, recognizing that only properly licensed health care practitioners can use opioid analgesics for legitimate medical purposes in the course of professional practice.67 Governments that achieve and implement balanced policy continue to maintain an opioids supply sufficient to meet medical demand and empower practitioners to rationally prescribe, dispense, and administer opioids in the course of professional practice and in response to individual patient needs. With these efforts, it is clear that medication availability is 707

supposed to be limited exclusively to medical and scientific purposes.67 The International Narcotics Control Board (INCB), a United Nations– affiliated agency responsible for monitoring governments’ implementation of the Single Convention, has historically observed, and continues to note that the global medical need for opioid analgesics is not being fully met.71–73 Opioids remain insufficiently available to meet medical needs throughout the world for many reasons, including severely restrictive drug control policies74–79; the real and overriding concern about drug abuse and addiction also has motivated the creation of laws that when put into practice hamper the appropriate medical use of opioids, including for the treatment of cancer pain74,77,80,81: . . . the reaction of some legislators and administrators to the fear of drug abuse developing or spreading has led to the enactment of laws and regulations that may, in some cases, unduly impede the availability of opiates. The problem may also arise as a result of the manner in which drug control laws and regulations are interpreted or implemented.71(p1) More recently, such international organizations as the Council of Europe,82 the World Medical Association,83 the WHO,79 WHO HIV/AIDS,84 the INCB,75,85 the United Nations Commission on Narcotic Drugs,86 and the United Nations Economic and Social Council87,88 have called for governments to identify and address regulatory barriers in their narcotics control policies. For example, a common requirement found in international drug control policies has been and continues to be the use of multiple-copy prescription forms (also commonly called “serialized forms”), which the Single Convention encourages when a country’s government considers such a control measure necessary or desirable (United Nations,67 Article 30(2)(b) (ii)). This requirement typically involves the need for physicians to issue prescriptions using a special form so that a designated regulatory or enforcement agency can monitor the prescribing and dispensing of certain drugs. These forms are designed and enacted primarily to prevent forgery of narcotic prescriptions and can vary in type, from the use of prescription pads with counterfoil or carbon pages to an extreme where the physician 708

must complete the same required prescription information repeatedly on a number of separate forms. Serialized prescription forms are governmentissued, but they may be difficult to obtain and can increase the health care and social stigma associated with prescribing opioid medications.89–93 As early as 1990, the WHO Expert Committee on Cancer Pain Relief and Active Supportive Care addressed how special government-issued prescription forms can influence prescribing: Record-keeping and authorization requirements should not be such that, for all practical purposes, they eliminate the availability of opioids for medical purposes. Multiple-copy prescription programmes are cited as means of reducing careless prescribing and “multiple doctoring” (patients registering with several medical practitioners in order to obtain several prescriptions for the same, or similar drugs). There is some justification for [this], but the extent to which these programmes restrict or inhibit the prescribing of opioids to patients who need them should also be questioned.94(p39) Some governments have concluded that multiple-copy prescription forms create burdens to physicians’ practice that can unduly limit access to covered medications, and have changed the requirements of these forms to respond to these problems—this has occurred in such countries as Austria,95 Italy,96 and Mexico97 and in numerous states in the United States.98,99 These positive programmatic changes are not meant to undermine the drug control capacities inherent in the serialized forms but rather to make it less likely that they hinder patient care. Other ways that countries have established overly restrictive drug monitoring and control systems include establishing extremely short medication supply limits (e.g., 3 days)90,100–104 and only allowing physicians with certain specialties to prescribe.100–103,105,106 Again, countries’ governments are addressing these potential barriers in law, which is described in detail in Chapter 16. It is apparent that the international narcotics treaty is intended for drug control and to maintain drug availability for medical purposes, which the World Health Assembly59,107–109 has historically reaffirmed. However, some countries have implemented the treaty too strictly, resulting in 709

abuse/diversion mitigation while making the use of opioid medications for pain management difficult if not impossible.110 Given this reality, it may help to understand the current status of national laws and regulations. The next section describes the extent that the United States is meeting its obligation to prevent medication diversion and abuse while continuing its responsibility to ensure the appropriate medical use of opioid analgesics.

US Federal Law: Preserving Balance between Drug Control and Medical Use THE FEDERAL FOOD, DRUG, AND COSMETIC ACT Under the authority of the Federal Food, Drug, and Cosmetic Act of 1962 (FFDCA), the U.S. Food and Drug Administration (FDA), which is part of the U.S. Department of Health and Human Services, is responsible for promoting public health by ensuring that all medications, including opioids and other controlled substances, are safe and effective for human use.111 The FDA’s approval decisions for marketing a particular drug always involve an assessment of the benefits and risks,112 including its abuse liability. The drug manufacturer must provide to the FDA all relevant data related to safety by the time a new drug application is submitted.113 When the benefits of a drug are considered to outweigh its risks, and when the labeling instructions allow for safe and effective use, only then does the FDA consider the drug safe for approval and marketing.114 To further reduce opportunities for adverse events, patients also are expected to use the medications according to the prescriber’s instructions.115 Of course, use of any medication outside of the prescriber’s instructions, for nonmedical purposes, or absent medical supervision, undermines the safety profile of that medication and increases the likelihood of harms. When reviewing a new drug application, or after the FDA approves a medication, a determination can be made that the manufacturer also must submit plans for a risk evaluation and mitigation strategy (REMS) to ensure that the benefits of the medication outweigh its risks.116 In the context of pain management, the FDA approved a shared class-wide REMS for long-acting (LA) and extended-release (ER) opioid analgesics in mid-2012, which has been updated with new products every year 710

since117; as of this writing, this REMS program encompasses 65 separate generic or branded LA/ER products.117 In addition, a REMS for transmucosal immediate-release fentanyl (TIRF) products was begun in 2011 and subsequently has been applied to additional products, at this time covering a total of ten TIRF medications.118 Within the primary objective of REMS programs to enhance medication safety, there remains an explicit commitment to “enable patients to have continued access to such medicines by managing their safe use” (webinar statement).116 A REMS program contains steps to address morbidity and mortality and, according to law, requires a timetable to assess the strategy at 18 months, 3 years, and 7 years after the strategy is approved,119 whereas the LA/ER REMS specifically mandates that assessments be submitted to the FDA at 6 months and 12 months and then every year thereafter.120 Again, the goal of the REMS relates to reducing serious adverse outcomes from the misuse and abuse of, as well as to ensure appropriate access to, the covered medications.120 Two components comprise the adopted REMS: (1) a medication guide and (2) elements to assure safe use. A one-page medication guide is designed for each covered opioid product, either generic or branded,121 and are to be provided through the pharmacy when an LA/ER opioid is dispensed outside of a hospital setting. Elements to assure safe use are satisfied through voluntary REMS-compliant training for prescribers, with the training content conforming to learning objectives outlined in the FDA Blueprint.122 The learning objectives relate broadly to the consideration of medication-related risks and benefits throughout treatment, including during initial patient assessment; initiating, maintaining, or discontinuing opioid therapy; and counseling patients and their caregivers.122 In addition, the training is designed to improve practitioners’ general and specific understanding of LA/ER opioid medications.122 Various methods are being used to enhance prescribers’ awareness of available REMS training opportunities, as a means to achieve explicitly defined performance goals.120 Such methods include developing and maintaining a REMS-related Web site, sending letters to all practitioners registered to prescribe relevant medications, and requesting that informational letters be disseminated through state health care licensing 711

and disciplinary boards (i.e., boards of medicine, nursing, and dentistry) as well as their national associations (i.e., the Federation of State Medical Boards of the United States [the Federation], the National Council of State Boards of Nursing, and the American Association of Dental Boards) and professional societies and associations.120 Another important resource included in these methods is the availability of a one-page counseling document, which health care practitioners are expected to give to patients when treatment involves LA/ER opioids. It is clear that these LA/ER REMS characteristics conform to general programmatic elements defined in law to include a communications plan to health care practitioners about the medications, such as (1) sending letters, (2) disseminating information about the REMS to explain certain safety protocols or to encourage implementation by health care practitioners of applicable components of the REMS, and (3) using professional societies to disseminate information about serious drug risks and protocols to enhance safety.123 Available research suggests, cumulatively, that implementation of REMS-compliant prescriber training contributes to increases in practitioner knowledge; better patient awareness of mediation risks; and lower occurrence of abuse, overdose, and death while not creating a barrier to appropriate medication access.36,124,125 When searched on March 22, 2017, almost 80 REMS-compliant continuing education (CE) training courses were available either at no cost or for a nominal fee, some extending into 2018 (https://search.er-laopioidrems.com/Guest/GuestPageExternal.aspx), whereas Cepeda et al.125 indicated that more than 500 such courses were offered in 2013 and 2014. Despite these opportunities, proportionally few prescribers have completed REMS-compliant training.125 Many reasons account for this low completion rate, including the voluntary nature of the training, participation in non–REMS-compliant CE training (which does not cover all of the content outlined in the FDA Blueprint), and incomplete documentation such as failure to submit a posttest evaluation and the prescribing of an LA/ER opioid in the last year.125 The FDA is responsible for reviewing and sanctioning product labeling,126 with the purpose of providing information for the patients’ safe and effective use of the medication.114 The FDA also has an 712

obligation to ensure that postmarketing promotional materials are consistent with the approved labeling information.127 Historically, the FDA’s statutory authority applied primarily to the evaluation of premarketing testing and, after drug approval, the agency’s role was limited. However, in September 2007, the FFDCA was expanded to comprise active postmarket risk identification for approved drugs.128 Activities under this mandate include ongoing analysis of drug safety data from disparate data sources as well as adverse event surveillance using electronic data from the federal government (e.g., the FDA Adverse Event Reporting System) and the private sector (e.g., the Researched Abuse, Diversion and Addiction-Related Surveillance [RADARS] system).114 Information from these sources can lead to safety-related label changes to address new safety data. For example, in 2013, LA/ER opioid medications underwent an indication revision. As a result, LA/ER opioids are no longer indicated for the treatment of moderate to severe pain but rather “for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.”129 This change has the benefit of characterizing a more explicit clinical circumstance warranting opioid therapy and implicitly reinforces the standard that these medications are to be initiated only after other modalities have been at least considered and ruled out as unsatisfactory. Overall, the collaborative process engendered through the 2007 legislative change is designed to improve the quality and efficiency of postmarketing drug safety risk–benefit analysis and to allow for the public disclosure of safety and effectiveness data in a timely, systematic, and transparent manner.114 A potentially important contribution to the FDA regulatory process comes from a 2017 report from the National Academies of Sciences, Engineering, and Medicine on opioid medications and pain management.130 The report contains a series of recommendations that, among other things, advises the FDA to conduct a full review of currently marketed and approved opioid products to further ensure the benefit and safety of those modifications both on patients and to public health.130 Accomplishing this objective is further enhanced when the review is conducted within a framework of what is called a “comprehensive systems 713

approach,” in which the following factors are urged to be considered: • “Benefits and risks to individual patients, including pain relief, functional improvement, the impact of off-label use, incident opioid use disorder (OUD), respiratory depression, and death; • Benefits and risks to members of a patient’s household, as well as community health and welfare, such as effects on family well-being, crime, and unemployment; • Effects on the overall market for legal opioids and, to the extent possible, impacts on illicit opioid markets; • Risks associated with existing and potential levels of diversion of all prescription opioids; • Risks associated with the transition to illicit opioids (e.g., heroin), including unsafe routes of administration, injection-related harms (e.g., HIV and hepatitis C virus), and OUD; and • Specific subpopulations or geographic areas that may present distinct benefit-risk profiles.”130(pp6–26) To the extent that this recommended approach is informed by available evidence that considers the benefit/risk profiles with those for whom the medications are indicated and prescribed, as well as those for whom the medications are not prescribed (e.g., use for nonmedical purposes), this would be a highly valuable and illustrative decision-making process. Another important consideration for an FDA review will be to ascertain whether the prescribing conforms to current practice standards, including patient risk stratification and ongoing treatment monitoring as well as whether patients were compliant with practitioner instructions or product labeling directions. Along with additional attention to illegal drug markets and diversion activity (see the “Taking Diversion into Account” section), there can be a more complete understanding of the degree to which demonstrated harms result from legitimate medical, compared to nonmedical, use. Of course, prescribing decisions are part of medical practice. The FFDCA is intended neither to regulate medical practice131 nor to interfere with the authority of a licensed health care practitioner to use controlled substances for a legitimate medical purpose.132 It is the responsibility of the states, and not the US federal government to regulate professional 714

health care practice. However, both the state and the federal government share drug control responsibilities.

US FEDERAL CONTROLLED SUBSTANCES LAW Controlled substances laws provide an additional layer of control over the distribution of prescription drugs that have an abuse liability (i.e., using criteria related to the potential to produce psychological or physical dependence), establishing a closed distribution system to minimize their abuse, trafficking, and diversion. The federal Controlled Substances Act (CSA)133 is part of the Comprehensive Drug Abuse Prevention and Control Act of 1970,134 and is the principal drug control law in the United States and conforms to the international treaties—it establishes criminal penalties for the illicit possession, manufacture, and trafficking of controlled substances and prohibits their nonmedical use while, at the same time, recognizing that they are necessary for public health and that their medical availability must be ensured. The CSA creates a comprehensive regulatory framework designed to ensure that controlled substances are only produced and distributed through proper channels and for proper medical purposes. In fact, the CSA is a culmination of more than 50 pieces of federal legislation adopted since 1914 relating to drug control and diversion.134 The CSA specifies five classification schedules for controlled substances, each carrying different penalties for unlawful uses. A drug’s medical usefulness and abuse liability form the basis for the decision to assign it to a particular schedule.135 Schedule I drugs have no currently accepted medical use, no accepted safety for use under medical supervision, and a high potential for abuse (e.g., ecstasy; heroin, LSD, marijuana, methaqualone, and peyote) and are available only for scientific research. Drugs that have an FDA-approved medical use are placed in Schedules II through V according to potential for abuse in the following manner: • Schedule II medications have the highest potential for abuse and include such opioids as codeine, fentanyl, hydrocodone (including combination products since 2014),136 hydromorphone, meperidine, methadone, morphine, and oxycodone (including combination 715

products) as well as nonopioids such as short-acting barbiturates (e.g., pentobarbital), amphetamine, methamphetamine, methylphenidate, and cocaine. • Schedule III medications have a lower abuse potential than Schedule II drugs and include opioids such as dihydrocodeine and codeine combinations with aspirin or acetaminophen as well as nonopioids such as buprenorphine, intermediate-acting barbiturates (e.g., butalbital), and the synthetic cannabinoid dronabinol. • Schedule IV medications have a lower abuse potential relative to drugs in Schedule III and include opioids such as dextropropoxyphene, pentazocine, and tramadol as well as nonopioids such as benzodiazepines (e.g., alprazolam and diazepam), LA barbiturates (e.g., phenobarbital), and certain nonamphetamine stimulants (e.g., pemoline). • Schedule V medications have a lower abuse potential compared to drugs in Schedule IV and include compounds or preparations containing limited quantities of opioids such as codeine or opium, which may be used for over-the-counter preparations to treat cough or diarrhea, respectively, as well as antidiarrheals containing diphenoxylate and difenoxin, and pregabalin. Under federal law, the Drug Enforcement Administration (DEA) is the primary federal agency responsible for enforcing the CSA and, thus, has regulatory authority over controlled substances. The DEA is an agency of the federal Department of Justice, headed by the attorney general of the United States. To conduct research with, or manufacture, distribute, handle, dispense, administer, or prescribe, controlled substances, a person or business must be registered with the DEA (and, in some cases, also with the relevant state agencies).137,138 Licensed and registered practitioners can prescribe, dispense, or administer controlled substances only for legitimate medical purposes and in the usual course of professional practice139,140; the DEA and federal courts have interpreted this to mean that prescriptions must be issued “in accordance with a standard of medical practice generally recognized and accepted in the United States.”141(p139) Registrants’ distribution of Schedule I and II controlled substances are made using a 716

special order form (DEA Form 222) to monitor all transfers of these controlled substances within the “closed” system.142,143 A number of federal standards are relevant to pain treatment involving controlled medications. For example, prescriptions for Schedule II medications must be written and may not be refilled,144,145 whereas five refills are permitted for drugs in Schedules III and IV.146,147 The requirement for a written prescription is additionally fulfilled through federal law’s allowance of prescribers to issue electronic prescriptions for Schedule II controlled substances148; electronic prescriptions remain an option that is not designed to completely supplant written paper prescriptions. For this reason, pharmacists and health care facilities are required to have the technologic infrastructure to process eprescriptions as a means to create a transparent environment that is auditable and DEA-compliant.149 Regulatory requirements governing this process are quite elaborate. Every aspect of the technology requires certification by the DEA, such as supervised pre-enrollment, maintaining records, the cryptographic signing module, the authentication software and hardware, and the routing of the prescription to the pharmacies (with those pharmacies needing a certified technology platform).148 Generally, many practitioner obligations involve maintaining information and transmission security, including the need to promptly report security breaches.150 The same legal responsibilities exist when issuing electronic prescriptions as with hard-copy prescription forms for controlled substances, especially the need to issue for a legitimate medical purpose and in the course of professional practice. Clearly, electronic prescriptions must be issued in conformity to applicable laws, as with any other prescription. All states have modified their laws to accommodate this federal authorization,151 and as of January 1, 2015, about 70% of pharmacies and 4% of practitioners have the ability to issue electronic prescriptions for controlled substances (Rick Camp, marketing director of Surescripts, as a comment to HealthIT Buzz’s “The Electronic Prescribing of Controlled Substances Is on the Rise,” https://www.healthit.gov/buzz-blog/health-information-exchange2/electronic-prescribing-controlled-substances-rise/). Federal law also allows oral or faxed (but not electronic) transmission of prescriptions for Schedule II controlled substances in medical emergencies 717

under specific circumstances,152 as well as for the partial dispensing and faxing (but not oral or electronic data transmission) of prescriptions under certain specific clinical circumstances.153 There are penalties, both criminal and civil, for violating federal requirements. Although prescriptions for certain controlled substances must be in writing, and refills are limited, the fact that a drug has been approved for medical use does not change when it becomes a controlled substance. This principle is conveyed by the CSA statement that many of the drugs included within this title have a useful and legitimate medical purpose and are necessary to maintain the health and general welfare of the American people.154 Overall, the legislative history, as well as language contained in the CSA itself (and its related regulations), makes it clear that efforts to prevent drug abuse and diversion are not to interfere with legitimate medical practice and appropriate patient care.155

The Controlled Substances Act Ensures Availability of Controlled Substances for Medical Purposes The CSA authorizes the DEA to establish production quotas for a number of opioids and other controlled substances as a means to stem diversion resulting from excessive unused supplies.156 Such quotas also must maintain sufficient supplies to accommodate all medical and scientific needs as well as to establish and maintain reserve stock.140 Despite this apparent standard, however, insufficiently low quotas have occurred for various controlled substances. For example, 30 years ago, the DEA set a very low quota for methylphenidate to restrict its production in an effort to control diversion.157 As a result, the methylphenidate supply was inadequate to treat patients with attention-deficit/hyperactivity disorder and narcolepsy, which are legitimate medical uses. An official statement was promulgated in response to this action, establishing the principle of an “undisputed proposition” of drug availability: The CSA requirement for a determination of legitimate medical need is based on the undisputed proposition that patients and pharmacies should be able to obtain sufficient quantities of methylphenidate, or 718

of any Schedule II drug, to fill prescriptions. A therapeutic drug should be available to patients when they need it. To accomplish this, a smooth flow of distribution is required . . . the harshest impact of actual or threatened shortages falls on the patients who must take methylphenidate, not on the manufacturers to whom the quotas directly apply. Actual drug shortages, or even threatened ones, can seriously interfere with patients’ lives and those of their families.157(pp50593–50594) Following this statement, the DEA recalculated the methylphenidate quotas to accommodate its demand for medical purposes. The same situation later occurred for amphetamines as a treatment for attentiondeficit/hyperactivity disorder.158 The DEA has, over time, expressed a willingness to grant additional quotas for controlled substances necessary to treat medical conditions, including prescription opioids for pain.159–161 In fact, in response to concerns about natural disasters or other unanticipated situations resulting in prolonged interruption of medication availability: DEA included in all schedule II aggregate production quotas, and certain schedule I aggregate production quotas, an additional 25% of the estimated medical, scientific, and research needs as part of the amount necessary to ensure the establishment and maintenance of reserve stocks. The established aggregate production quotas reflect these included amounts.1(p59980) However, the most recent proposed quotas have removed the 25% buffer that were in effect over the last few years, an action that some have interpreted to exemplify a potentially problematic supply reduction (see Anson162 for example). It is possible, though, that activities such as increased sales to meet prescription demand or product development will prompt the DEA to revise the quotas. Such quota revisions are indeed permissible under federal law.163

The Controlled Substances Act Does Not Regulate Medical Practice The CSA’s legislative history demonstrates health care professionals’ 719

overriding concern that the drug control law ultimately would give law enforcement inappropriate authority over medical and scientific decisions155; abundant professional testimony resulted in Congress establishing a procedure in which the federal health agency (now the U.S. Department of Health and Human Services) makes medical determinations under the CSA. This history makes it apparent that the federal government is obligated to create criteria for drug control, including the legal parameters for prescribing controlled substances and to investigate intentional criminal conduct (e.g., issuing prescriptions not for a legitimate medical purpose and in the usual course of professional practice). That is, cases involving questionable prescribing are to be evaluated to determine whether the relevant practice is intentional criminal conduct or substandard professional practice.64,164–166 Such a distinction historically has helped assure proper jurisdiction: Good faith professional practice, even if poor, can insulate a practitioner from criminal prosecution167; both state and federal case law supports this differentiation.168 If a practitioner’s conduct is intentionally outside legitimate professional practice, law enforcement interventions from federal, state, or local agencies seem warranted.165 That is, a prescription issued or dispensed other than in good faith (i.e., the practitioner knew, or intended, that the prescription would not be used for a legitimate medical purpose) could form the basis for criminal sanctions.165,169 By extension, unwarranted criminal charges against practitioners may become less frequent, at least in part, to the extent that investigations clearly and consistently consider criminal behavior as distinct from unprofessional conduct. Chapter 16 of this text provides much more descriptive detail about this legal foundation through a discussion of legal cases involving pain management within four primary domains of law: administrative proceedings, civil litigation, criminal litigation, and constitutional cases. Given this context, the federal government clearly does not have the statutory authority to regulate medical practice. This authority belongs to the states and is based on the police power in state constitutions and underlies the medical practice acts that are designed to protect the public health and safety.170 The CSA is not intended to supersede the authority of the FFDCA and provides no authority for the DEA to define or regulate 720

medical practice,133 including the treatment of pain or the indications for which a drug may be prescribed. The DEA’s enforcement authority is intended to relate to clinicians involved in unlawful distribution of controlled substances that is outside legitimate health care practice (i.e., behaviors that are clearly criminal in nature). To this end, a prescription for a controlled substance is only lawful when issued for a legitimate medical purpose and in the usual course of professional practice.139 David Brushwood, a pharmacist and attorney and now professor emeritus from the College of Pharmacy at the University of Florida, Gainesville, has interpreted a useful distinction between the phrases “legitimate medical purpose” and “course of professional practice,” which define the boundaries of practitioner investigations and prosecutions for the DEA: “Legitimate medical purpose” has no meaning unless “illegitimate medical purpose” has meaning. Yet medicine is inherently legitimate; there is no such thing as “illegitimate medicine.” A practice that is not medical is neither legitimate nor legal under the DEA regulation. A practice that is medical is legitimate and is legal under the DEA regulation. DEA does not regulate within medical practice but simply discerns whether a practice is medical or nonmedical. . . . The DEA regulation has nothing to do with the credentials or qualifications of a health care provider. It has everything to do with the activities of the health care provider. If those activities are not professional health care activities, then they are illegal under the DEA regulations; if they are professional health care activities, they are legal. DEA has no authority to pass judgment on the merits of a professional practice. Its role is limited to determining whether a practice is a professional practice.171(p307) This critical distinction remains relevant today. Further evidence that the CSA was not intended to interfere with legitimate medical practice is found when Congress enacted a law in 1978 to implement another international treaty (i.e., the Convention on Psychotropic Substances of 1971).172 Consequently, the control of psychotropic substances such as benzodiazepines became a responsibility 721

within the CSA to: insure that the availability of psychotropic substances to manufacturers, distributors, dispensers, and researchers for useful and legitimate medical and scientific purposes will not be unduly restricted . . . and nothing in the Convention [on psychotropic substances] will interfere with ethical medical practice in this country as determined by the secretary of Health and Human Services on the basis of a consensus of the American medical and scientific community.173

The Controlled Substances Act Distinguishes Treatment of Addiction from Treatment of Pain, but Legal Definitions Create Confusion Under the CSA, a separate registration by the federal government as an opioid treatment program (OTP) is required for the purpose of maintenance or detoxification of opioid addiction with certain opioid medications.174 The use of medications approved for the purpose of addiction treatment, such as methadone and buprenorphine, must comply with federal and state regulations. Methadone and some buprenorphine products, however, are indicated for analgesic purposes according to the same laws for prescribing any other Schedule II or Schedule III opioids. The accurate application of terminology is central to shaping a balanced policy on drug control and professional practice, especially in the United States where extended opioid therapy to maintain addiction (without a separate registration) is illegal. Addiction often is perceived as being based solely on the development of physical dependence or tolerance, both of which are expected physiologic consequences of using opioids for a prolonged period, which runs counter to current diagnostic nomenclature.175 Practitioners who consider these related, but separate, phenomena as synonymous can inappropriately label a patient with pain who is receiving opioid therapy as an “addict,” which can influence care decisions and inflate determinations about iatrogenic addiction. Given this situation, one must carefully differentiate between treating a patient’s pain and maintaining or detoxifying a person with an addictive disease and to understand and use terms correctly. 722

The CSA defines addict as an individual who habitually uses any narcotic drug so as to endanger the public morals, health, safety, or who is so far addicted to the use of narcotic drugs as to have lost power of self-control with reference to his addiction.176 This definition is characterized by the use of circular, imprecise, and outdated language and is not comparable to the WHO’s current International Classification of Diseases [ICD10] concept of dependence syndrome,177 the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM) classification of substance use disorder,175 or the American Society of Addiction Medicine’s definition of addiction.178 Given its inconsistency with more recent nomenclature, the CSA could indeed be updated to conform more completely to current terminology and standards. Although not contained in the CSA, in 1970, a definition of drugdependent person was added to the federal Public Health Service Act (now the Public Health and Welfare Act).179 The Interstate and Foreign Commerce Committee of the House of Representatives180 considered the adopted definition as similar to the WHO’s terminology of the time. Drugdependent person was defined as a person who is using a controlled substance . . . and who is in a state of psychic or physical dependence, or both, arising from the use of that substance on a continuous basis. Drug dependence is characterized by behavioral and other responses which include a strong compulsion to take the substance on a continuous basis in order to experience its psychic effects or to avoid the discomfort caused by its absence [italics added].179 Although indeed similar, there is a critical interpretive distinction between the resulting US legal term and the WHO term from which it was adopted. Unlike the US definition, the WHO conceptualization did not provide the opportunity for physical dependence alone to characterize drug dependence. In 1998, the WHO reaffirmed this conceptualization when it replaced the term drug dependence with dependence syndrome and further

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emphasized the biopsychosocial nature of compulsive drug seeking.181 Even given the medical and scientific evolution of addiction-related terminology that has occurred in the last 50 years, the 1970 Public Health and Welfare definition continues to have the potential to legally codify as “drug dependent” a patient with pain who has been taking opioids for a prolonged period. Despite the inconsistent and incorrect use of addiction-related terminology in federal law, it remains lawful under federal law to use opioids to treat pain in patients, even when they have a history of substance use or current addictive disease. For example, in 1993, the DEA initiated action to revoke an Ohio physician’s prescribing authority because prescriptions were issued to patients who were “known” drug abusers and drug traffickers. A DEA administrative law judge ruled, however, that the physician’s controlled substances prescriptions were lawful because they were issued for legitimate medical purposes (e.g., pain relief, muscle spasm, and anxiety).182 This ruling represented the critical distinction between a practitioner’s ability to prescribe controlled substances to treat pain, even though the patient has an addictive disease, and clearly criminal behavior in which controlled substances are distributed without regard to their purposes or ultimate use. Such a judgment upholds the fundamental principle that, when considering the legality of a particular prescribing practice, the determination must be based, at least in part, on the purpose of the prescribing and not the type of patient being treated.

The Controlled Substances Act and Regulations Do Not Limit Prescription Amount or Duration As stated previously, federal law establishes requirements for what constitutes a lawful controlled substances prescription.139 At this time, neither the CSA nor the Code of Federal Regulations (CFR) sets limits on the amount or duration of medication for which a practitioner can prescribe, administer, or dispense at one time. This still holds true after the DEA amended the CFR in late 2007 to allow practitioners to issue multiple prescriptions of a Schedule II controlled substance, each issued on the same date and filled sequentially (called a “prescription series”).183 724

A prescription series is a method for a practitioner to provide a patient with a large enough amount of a Schedule II medication, for example, for a 3-month supply, without using a single prescription. Rather, the practitioner can now issue several prescriptions, each for one-third of the total amount needed. These prescriptions, each issued on the same day and containing written instructions for the date on which they are to be dispensed, would be delivered to the pharmacist and then dispensed sequentially on the dates indicated on the prescriptions. This procedure allows patients access to the medications they need and results in fewer doses dispensed at a time, thereby reducing the potential for diversion. A practitioner’s ability to specifically issue a prescription series for Schedule II controlled substances was not previously authorized within the CSA; the CSA, when adopted in 1970, did not address this practice because continual pain treatment was uncommon at that time.184 The DEA said it wanted to reassure health care professionals and patients that it is legal for practitioners to provide a prescription series to individual patients during a single office visit,184,185 and authorized multiple prescriptions for “a total of up to a 90-day supply of a Schedule II controlled substance.”183 The DEA clarified that allowing a 90-day prescription series did not alter the fact that the CSA and the CFR do not limit the quantity or number of days for which a single prescription for a Schedule II controlled substance can be written: The [Final] rule in no way changes longstanding federal law governing the issuance of prescription for controlled substances . . . the CSA and DEA regulations contain no specific limit on the number of days worth of a schedule II controlled substance that a physician may authorize per prescription.183(pp64923–64924) In addition, the DEA verified that the new prescription series rule did not preclude additional practice standards to which health care professionals must conform, especially in relation to a practitioner’s responsibility to minimize the potential for medication abuse and diversion186: Under this Final Rule, practitioners who prescribe controlled substances are subject to the same standard in preventing diversion as 725

they always have been under the CSA and DEA regulations. Section 1306.12(b)(iii) of this Final Rule is intended to make clear that a practitioner may not simply comply with the other requirements of this Final Rule while turning a blind eye to circumstances that might be indicative of diversion. Thus, section 1306.12(b)(iii) merely underscores that the longstanding requirement of providing effective controls against diversion remains in effective when issuing multiple schedule II prescriptions in accordance with this Final Rule.183(p64926) The intent of the CFR amendment is commendable, with the DEA wanting to reaffirm a practitioner’s legal authority to issue a prescription series for Schedule II medications.183,184,187 Multiple prescriptions for sequential dispensing permit health care professionals to better manage chronic pain in stable patients while exercising improved control over potential medication abuse and diversion, which is consistent with the principle of Balance.188 The DEA also recognizes the need to maintain balanced policy: . . . DEA, through its enforcement of the CSA and its implementing regulations, must prevent the diversion and abuse of controlled substances while ensuring that there is an adequate supply for legitimate medical purposes. DEA supports the intent of this Final Rule to address patients’ needs for schedule II controlled substances while preventing the diversion of those substances.183(p64929) Indeed, the federal prescription series regulation was an important step to improve the regulatory environment for both diversion control and providing pain management and palliative care.

Regulations Implementing the Controlled Substances Act Now Authorize a Greater Variety of Secure Disposal Opportunities for Controlled Substances An even more recent change to the CFR, effective on October 9, 2014, relates specifically to reducing the public health threats inherent in large volumes of unused medications.189 Under federal law, certain entities who have a DEA registration to handle controlled substances now can volunteer to become a collector of controlled medications for the purpose of 726

destruction using a variety of prescribed methods.190,191 The DEA registrants permitted to become collectors are manufacturers, distributors, reverse distributors, OTPs, hospitals or clinics with an on-site pharmacy, and retail pharmacies.190 These registrants can accept back the controlled substances using either mail-back programs or collection receptacles (also called “drop boxes”), or both.192 In addition, authorized hospitals and clinics and retail pharmacies now have broader authority for maintaining drop boxes at long-term care facilities, when so authorized.193,194 Finally, a reverse distributor can also acquire these drugs from law enforcement and from other collectors.195 Of course, the new rule requires additional registration, security, methods of controlled substances destruction, and record-keeping procedures.191 Given the introduction into federal law of these disposal standards, now more than ever before there is an acknowledged need for ultimate users (i.e., patients or their caregivers) to have additional ways in which their controlled medications can be collected and destroyed. Although this new law does not give prescribers (e.g., physicians, osteopathic physicians, nurses, and physician assistances) the option to become a collector, there could be a way that these practitioners could help achieve the purpose for which these regulations were developed. If up-to-date resources were easily available that identified local collection opportunities, practitioners could at least advise their patients about the variety of disposal options within the vicinity. Such information could motivate patients to take advantage of the more widespread secure disposal system that may be present in their community. However, the authors are unaware of whether such data are available or even if data exist about the overall proportion of relevant registrants who have chosen to become authorized as collectors.

US State Laws: Striving for Balance between Drug Control and Medical Use Both federal and state laws regulate the prescribing, dispensing, and administering of controlled medications as well as establish controls to mitigate the unlawful distribution and use of all controlled substances. Federal and state laws prohibit the nonmedical use of controlled 727

substances; set potential penalties and sanctions for violations; and are enforced by local, state, or federal law enforcement. In addition, states are solely responsible for regulating health care practice, including medical, pharmacy, and nursing practice. State licensing boards establish minimum expectations (or standards) for health care practice and the use of controlled substances to treat pain and can discipline practitioners for unprofessional conduct. Given this reality, it is important for practitioners to understand the legal and regulatory framework for the treatment of pain, including when it involves the use of opioid analgesics or other controlled substances. State policies, historically, have not consistently supported the availability of needed medications to the extent of international treaties and federal law.196 For example, most state laws do not specifically recognize the appropriate medical use of controlled medications as important to public health, which is a concept inherent in federal law.154 Some state policies also establish more requirements on the prescribing and dispensing of opioids, compared to federal law, which can ultimately interfere with medical decision making, decision making that should be based both on the expertise of the practitioner and the individual patient needs.197 Policy impediments at the state level have been known to contribute to inadequate pain management.52,198–206 In response to this knowledge, both international organizations74,94,207,208 and national organizations55,57,58 have called for studies to improve pain management by identifying and addressing the legal and regulatory impediments to using opioids for pain relief. A number of governmental and national authorities, such as Congress,133 the National Conference of Commissioners on Uniform State Laws,201,202,209 and the Federation,210,211 have recommended controlled substances or medical practice policy that permits medication access to patients when needed while restricting nonmedical use by either patients or people to whom the medications are not prescribed.

STATE PAIN POLICY DEVELOPMENT: AN EMERGING TREND Since the late 1980s, there have been an increasing number of state painspecific policies, including legislatively issued statutes and health care 728

regulatory board regulations and guidelines or policy statements. Such policy adoption typically promoted the safe and appropriate use of controlled substances when clinically warranted and recommended ways to reduce abuse or diversion of those medications. In some cases, however, these policies led to additional restrictions and requirements with the potential to create barriers to the effective treatment of pain. As an early example of this occurrence, intractable pain treatment acts (IPTAs) were statutes that created immunity from regulatory sanctions for physicians who prescribe opioids to patients with intractable pain, and thus were intended to improve access to pain management; however, many IPTAs imposed additional requirements and restrictions on prescribing opioids to such patients.196,212–215 IPTAs often implied that opioid use for “intractable pain” was outside of ordinary medical practice, which produced greater rather than less government regulation when treating pain with controlled substances. For physicians who prescribe to patients whose pain did not satisfy the definition of “intractable pain,” there was question about whether an IPTA provides immunity and created ambiguity for the clinician. Many IPTAs did not contain clear statements supporting enhanced pain management or instructing practitioners about how to provide safe and appropriate access and maintenance to such care. Some advocates have recently recognized the potential negative impact of these characteristics on patient care and have worked with the legislature to remove ambiguities and restrictions from their state’s IPTA. Iowa and Michigan became the first states, in 2002, to delete the term intractable pain from law. More recently, Arizona, California, North Dakota, Oregon, Rhode Island, Tennessee, and Texas repealed a number of restrictive provisions from their IPTAs, including removing the term and definition of intractable pain; the resulting laws now govern treatment for all types of pain. Indeed, IPTAs were the first instance of legislation created specifically for the treatment of chronic pain (i.e., “intractable pain”), which differed from the approach commonly taken by regulatory boards at the time to address the issues related to pain management in general. As an alternative approach to creating legislation, which often is difficult to modify to keep pace with evolutions in medical and scientific 729

understanding, many states chose to develop health care regulatory board guidelines or regulations to encourage better pain management and to address physicians’ expressed anxiety surrounding investigation and sanction.196,216 Early reports suggested that concerns about regulatory scrutiny were prevalent and could hinder the availability of opioids for patients who may clinically benefit from these medications.203,217–220 Apprehension about disciplinary action for opioid prescribing221–224 has been documented for a variety of health care practitioners, including primary care physicians,225–228 oncologists,229 pain specialists,230,231 medical residents,232 pharmacists,225,233 and nurses.225,234–236 To address these concerns directly, for more than 30 years, health care regulatory boards have promulgated regulations, guidelines, and policy statements perpetuating the message that pain management, including the appropriate use of controlled substances, is an accepted part of professional practice; a typical goal of such policies was to reassure clinicians that they had nothing to fear from their licensing agency if reasonable professional practices are followed when using controlled substances for appropriate patient care. State medical boards’ issuance of recommendations for pain management was aided considerably when, in 1998, the Federation adopted a policy template to promote consistency in state medical board policy, entitled Model Guidelines for the Use of Controlled Substances for the Treatment of Pain (Model Guideline).210 In May 2004, the Federation revised the Model Guideline as the Model Policy for the Use of Controlled Substances for the Treatment of Pain (Model Policy).211 The 2004 Model Policy is substantially the same as the 1998 guideline but encouraged state boards to consider the failure to treat pain as worthy of disciplinary sanction; undertreated pain previously had been identified as an important clinical topic to address in state policy.237 These models were later supplanted by the Model Policy on the Use of Opioid Analgesics for the Treatment of Chronic Pain16 in 2013 and then, most recently, the 2017 Guidelines for the Chronic Use of Opioid Analgesics.13 Interestingly, these newer templates relate specifically to the treatment of chronic pain related to noncancer conditions (i.e., excluding “acute pain, acute pain management in the perioperative setting, emergency care, cancer-related 730

pain, palliative care, or end-of-life care”13[p2]) rather than offering guidance for pain management in general as was done in the previous versions. They do, however, offer a benefit by providing more descriptive recommendations than older templates about altering or discontinuing opioid treatment when clinical evidence supports such an approach. According to the Federation, most state medical and osteopathic boards have adopted policies based, at least in part, on these model templates (see https://www.fsmb.org/Media/Default/PDF/FSMB/Advocacy/GRPOL_Pain_Manageme

EVALUATING THE QUALITY OF STATE PAIN POLICY Since the early 2000s, a criteria-based policy research methodology has existed to evaluate federal and state drug control and health care regulatory policies related to pain management, palliative care, and end-of-life care (issued in a report called an Evaluation Guide).98,188,238–242 The basis for this policy evaluation was the aforementioned principle called Balance, which is a fundamental and long-standing national and international principle of drug regulation and medical ethics. Balanced state policies maintain drug controls and avoid undue restrictions to appropriate health care practice and patient care and support pain treatment, including the use of controlled substances when warranted, as a component of quality medical practice.98 Although additional efforts are necessary to assess the presence and effectiveness of current state-level drug control frameworks to minimize abuse and diversion, the purpose of this evaluation has been to characterize pain-related issues covered in state policies. The principle of Balance was used to derive 16 evaluation criteria. Each criterion relates to one of two categories: (1) positive provisions—policy language that can enhance pain relief and (2) negative provisions— language that can impede pain relief. A complete description of the criteria, the evaluation methodology, and the policy language from all states (including the District of Columbia) that satisfies each criterion, can be found at http://www.painpolicy.wisc.edu.

Policy Evaluation Findings Policy language was identified that promotes appropriate pain management; such language is common in the policies from state 731

regulatory agencies rather than from legislative statutes. The frequency with which states’ policies contained such language in 201560 is as follows: • A statement that recognizes medical use of opioid as legitimate professional practice (in all states) • A statement that recognizes pain management as part of general medical practice (in 45 states) • A statement that encourages pain management (in 40 states) • A statement that addresses practitioners’ concerns about regulatory scrutiny (in 39 states) • A definition or statement in which addiction is different from physical dependence or analgesic tolerance (in 38 states) • A statement that recognizes medication amount or duration as insufficient to determine legitimacy of a prescription (in 32 states) Policy language that appears less frequently than the earlier concepts, but that also promotes effective pain control and patient care, was identified and relates to three broad domains: (1) health care professional issues (e.g., encourages patient evaluation and discussion relating to potential benefits and risks of opioid treatment, recognizes that the goals of pain treatment should include improvements in patient functioning and quality of life, and recognizes the need for a multidisciplinary approach to pain management [integrative pain care]), (2) patient characteristics (e.g., assures that no person will be considered an “addict” based solely on taking a medication pursuant to a lawful prescription issued by a physician in the course of professional treatment for legitimate medical purposes and exempts certain patient populations from undue prescription requirements), and (3) regulatory or policy issues (e.g., encourages health care professionals to understand and follow federal and state laws governing their practice and specifically acknowledges that drug control policies should not interfere with legitimate medical use of controlled substances). A state’s drug control laws, appropriately, focus on the abuse potential of controlled medications but often to the exclusion of recognizing their public health and medical benefit when used as directed for legitimate purposes unlike more positive provisions contained in federal law (see, for example, CSA154; Federal Food Drug and Cosmetic 732

Act243). It has been, and continues to be, possible to adopt state policies designed to prevent drug abuse and the transfer of medications to an illicit distribution system without creating ambiguity for health care decision making that conform to and do not conflict with current standards of professional practice, and that eschew imposing excessive burdens on patients. In 2015, however, the frequency with which states’ policies contained such language is as follows: • A definition or statement in which addiction is synonymous with physical dependence or analgesic tolerance (in 13 states) • A statement that seems to require a specialist consultation for every patient who is prescribed Schedule II controlled substances (in 7 states) • A statement that seems to completely prohibit prescribing of controlled substances to certain patients (in 5 states) • A requirement that limits the amount of time that a Schedule II prescription is valid to less than 2 weeks (in 2 states) (see Table 14.1 for specific restrictions for each state) • A requirement that limits the number of dosage units of pain medications that can be prescribed and dispensed at one time (in 1 state) (see Table 14.2 for the specific restriction) TABLE 14.1 States with Laws Restricting Schedule II Prescription Validity Period (in days) Delaware Hawaii

7 7

TABLE 14.2 State with a Law Restricting Schedule II Prescription Quantity or Duration Utah

A Schedule II controlled substance may not be filled in a quantity to exceed a one-month’s supply, as directed on the daily dosage rate of the prescriptions . . . (i) A practitioner licensed under this chapter may not prescribe or administer dosages of a controlled substance in excess of medically recognized quantities necessary to treat the ailment, malady, or condition of the ultimate user. (Utah Code Ann. § 58-37-6(B))

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These evaluations also consider, at least to a limited extent, laws that create and implement prescription monitoring program (PMP), which are primary diversion control mechanisms in the United States, specifically at the state level. PMPs historically were characterized as multiple-copy prescription programs (MCPPs), which use multiple-copy governmentissued serialized prescription forms (usually required in triplicate or duplicate). The prescription forms were required for Schedule II medications only (i.e., the only medications indicated for severe pain) and the programs were administered by state law enforcement, such as the state Department of Justice. The purpose of early PMPs was to provide law enforcement and prescribers and dispensers with information on “doctor shoppers,” “scammers,” and dishonest physicians. Unfortunately, prescription information collected through MCPPs was not real-time and often took a considerable time to compile, which severely undermined their ability to actively monitor diversion or abuse activity. MCPPs also focused exclusively on Schedule II medications and used unique forms that practitioners had to order from the government to prescribe only those medications. Research suggested that linking the government-issued prescription form only to those medications in Schedule II often motivated practitioners to prescribe lower scheduled medications to avoid being monitored244–248; this phenomenon has come to be known as the substitution effect.248 Of course, practices influenced by concerns about governmental oversight, rather than solely by patient needs and clinical circumstances, usually characterized the substitution effect as the potential for inappropriately treated pain. It is also true that decreased prescribing of Schedule II medications often has been interpreted, by itself, as evidence that the program was effective in reducing diversion,249,250 rather than considering outcomes more descriptive of diversion. MCPPs have been replaced by electronic data transfer (EDT) programs that collect prescription information about more than Schedule II controlled substances (usually Schedules II, III, and IV).251–253 Monitoring multiple schedules minimizes a potential substitution effect because there are few other medications with which they could be replaced. EDT programs tend to be administered by state health agencies, such as the pharmacy board, and the policies that implement the programs generally 734

emphasize that this effort to reduce abuse and diversion is not meant to interfere with appropriate patient care. The information from these programs is collected in a more timely fashion, although it is usually not real-time. However, there is still limited evidence to demonstrate the programs’ effects either on practitioner prescribing or on incidents of medication abuse and diversion. As of this writing, all but one state and the District of Columbia have a functional PMP that is an EDT system for a variety of medication schedules. Over half of these programs were created since the early 2000s, primarily as a result of the Harold Rogers Prescription Drug Monitoring Program grant program through the U.S. Department of Justice.254 Requirements for states to apply for such grants has been described as “relatively simple.”255(p509) At around the same time, an additional funding mechanism was introduced through the National All Schedules Prescription Electronic Reporting Act of 2005 (NASPER)256 and administered through the U.S. Department of Health and Human Services. NASPER also provides grants to states to develop PMPs only if the programs are EDTs that apply to medications in at least Schedules II to IV; states can create programs with different characteristics, but they are not fundable under NASPER. Federal law mandates that the Secretary of Health and Human Services evaluates the safety and efficacy of the programs established through NASPER. In this context, “safety” refers to the extent that the programs avoid creating barriers to prescribing to patients for legitimate medical purposes, such as for pain management. “Efficacy” means the ability of the program to validly identify instances of abuse and diversion. Although there seems to be less chance for EDTs to restrict patient care, especially when compared to MCPPs, empirical documentation remains mixed about either the safety or efficacy of these programs.257 In addition to the discrete occurrences of policy language that can either enhance or impede the appropriate treatment of pain, including with opioid analgesics, some state policies contain requirements or concepts that are contradictory and can create ambiguous practice expectations. For example, as identified previously, policies in 38 states define addiction as a psychological/behavioral disorder that is not synonymous with either 735

physical dependence or tolerance. Laws in 13 states also have a definition that could legally classify patients being treated chronically with opioids as “addicts” only because they are physically dependent. As a result, 8 states have at least one policy that defines addiction according to current official standards and another that defines the concept differently (see Table 14.3 for a listing of the discrepant definitions). There is no clear guidance for practitioners in these states about how patients with pain who are being treated with opioids are to be viewed, given the inconsistencies among the legal, regulatory, and health care classification. Achieving positive uniform policy often depends on potentially discrepant practice standards being identified and corrected. TABLE 14.3 States with Laws Containing Conflicting Definitions of Addiction-Related Terminology Definitions in Which Physical Dependence or Analgesic Tolerance Are Not Confused with “Addiction”

Definitions in Which Physical Dependence or Analgesic Tolerance Are Confused with “Addiction”

Arizona

As discussed, physical dependence and tolerance are expected physiological consequences of extended opioid therapy for pain and in this context do not indicate the presence of addiction. (Medical Board: Reference for Physicians on the Use of Opioid Analgesics in the Treatment of Chronic Pain, in the Office Setting)

Hawaii

Addiction—Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include the following: impaired control over drug use, craving, compulsive use, and continued use despite

“Drug-dependent person” means a person who is using a controlled substance and who is in a state of psychic or physical dependence, or both, arising from the use of that substance on a continuous basis. Drug dependence is characterized by behavioral and other responses which include a strong compulsion to take the substance on a continuing basis in order to experience its psychic effects or to avoid the discomfort caused by its absence. (A.R.S. § 36-2501(A)(5)) The term narcotic-dependent person as used in this section means an individual who physiologically needs heroin or a morphine-like drug to prevent the onset of signs of withdrawal. (HRS § 329-40)

State

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Louisiana

harm. Physical dependence and tolerance are normal physiologic consequences of extended opioid therapy for pain and are not the same as addiction. (Medical Board: Pain Management Guidelines) “Substance abuse” or “addiction” means a compulsive disorder in which an individual becomes preoccupied with obtaining and using a substance, despite adverse social, psychological, or physical consequences, the continued use of which results in a decreased quality of life. The development of controlled dangerous substance tolerance or physical dependence does not equate with substance abuse or addiction. (La. R.S. 40:961(38))

Maryland

It is important to realize that habituation and tolerance to drugs are not the same as addiction. These are expected consequences of long-term analgesic therapy and do not have the characteristics of sociopathy and psychological dependence associated with addiction. (Medical Board: Prescribing Controlled Substances)

Nebraska

Physicians should recognize that tolerance and physical dependence are normal consequences of sustained use of opioid analgesics and are not the

737

“Drug-dependent person” means a person who is using a controlled dangerous substance and who is in a state of psychic or physical dependence, or both, arising from administration of that controlled dangerous substance on a continuous basis. Drug dependence is characterized by behavioral and other responses which include a strong compulsion to take the substance on a continuous basis in order to experience its psychic effects or to avoid the discomfort of its absence. (La. R.S. 40:961(18)) Drug-dependent person—“Drugdependent person” means a person who (1) is using a controlled dangerous substance and (2) is in a state of psychological or physical dependence, or both, that (i) arises from administration of that controlled dangerous substance on a continuous basis and (ii) is characterized by behavioral and other responses that include a strong compulsion to take the substance on a continuous basis in order to experience its psychological effects or to avoid the discomfort of its absence. (Md. CRIMINAL LAW Code Ann. § 5-101(o)) Active addiction means current physical or psychological dependence on alcohol or a substance, which develops following the use of alcohol or a

Nevada

North Carolina

Oklahoma

same as addiction. (Medical Board: Guidelines for the Use of Controlled Substances for the Treatment of Pain) Physicians should recognize that tolerance and physical dependence are normal consequences of sustained use of opioid analgesics and are not synonymous with addiction. (NAC 630.187) Addiction: A primary, chronic, neurobiologic disease with genetic, psychosocial, and environmental factors influencing its development and manifestations. Addiction is characterized by behaviors that include the following: impaired control over drug use, craving, compulsive use, and continued use despite harm. Physical dependence and tolerance are normal physiologic consequences of extended opioid therapy for pain and are not the same as addiction. (Medical Board: Policy for the Use of Opiates for the Treatment of Pain) Physicians should recognize that tolerance and physical dependence are normal consequences of sustained use of opioid analgesics and are not the same as addiction. (Medical Board: Use of Controlled Substances for the Treatment of Pain)

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substance on a periodic or continuing basis. (Nebraska Admin. Code Title 172, Ch. 88, 88-002) “Narcotic addiction” means compulsion to continue taking or psychic or physical dependence on the effects of a narcotic drug. (Nev. Rev. Stat. Ann. § 453.099)

“Drug-dependent person” means a person who is using a controlled substance and who is in a state of psychic or physical dependence, or both, arising from use of that controlled substance on a continuous basis. Drug dependence is characterized by behavioral and other responses which include a strong compulsion to take the substance on a continuous basis in order to experience its psychic effects or to avoid the discomfort of its absence. (N.C. Gen. Stat. § 90-87(13))

“Drug-dependent person” means a person who is using a controlled dangerous substance and who is in a state of psychic or physical dependence, or both, arising from administration of that controlled dangerous substance on a continuous basis. Drug dependence is characterized by behavioral and other responses which include a strong compulsion to take the substance on a continuous basis in order to experience its psychic effects or to avoid the discomfort of its absence. (63 Okl. St. § 2-101(15)

A PROGRESS REPORT CARD TO MEASURE CHANGES IN THE QUALITY OF STATE PAIN POLICIES

The criteria-based evaluation of state pain policy also serves as the basis for a methodology to quantify a state’s policy based on its quality, creating a single metric that can then be used to compare all states and track policy changes over time.60,188,258–262 This metric, along with the content of the Evaluation Guide, has helped states identify policy provisions that could be considered for modification.263 In the latest report using cumulative policy data from the state profiles, grades were calculated for the state policies in effect in 2015.60 The grades, and the methodology used to calculate the grades, are contained in the most recent report, entitled “Achieving Balance in State Pain Policy: A Progress Report Card” (Progress Report Card), and is available at https://www.acscan.org/sites/default/files/National%20Documents/Achieving%20Balan Grades can range from A to F, using midpoint grades (e.g., B+, C+, D+) to characterize more precisely each state’s overall combination of positive and negative provisions. A higher grade means a state’s policies have many positives and few negatives and are, therefore, more balanced in relation to appropriate pain management. An A is achieved only if a state has a high number of positive provisions and no instances of unduly restrictive or ambiguous language. A lower grade is associated with the presence of provisions that contradict current medical knowledge; are inconsistent with policy guidance recommendations from authoritative sources; or fail to communicate the appropriate messages about pain management to professionals, patients, and the public. An F results when a state has abundant negative provisions and no positive language.

Progress Report Card Findings Results show that the quality of pain policies continues to vary across states as of December 31, 2015, which were reported in the most recent Progress Report Card60 (see Table 14.4 for a list of each state’s grade). In the aggregate, 13 states achieved an A. An A means that there is prevalent language in laws or regulatory policies, or both, that promote safe and effective pain management as well as there being no language that can create inflexible barriers or ambiguities for clinical decision making. 739

Eighteen states had a B+, 13 states had a B, 6 states had a C+, and only 1 state had a grade of C. In terms of population coverage, the 13 states achieving an A comprise 19% of the total US population, and states with a B or B+ make up almost 65% of the US population. Another 16% of the US population live in the 7 states that have grade of C or C+. TABLE 14.4 States’ Pain Policy Grades for 2015 Alabama Alaska Arizona Arkansas California Colorado Connecticut Delaware District of Columbia Florida Georgia Hawaii Idaho Illinois Indiana Iowa Kansas

A B+ B+ B B+ B B+ B+ B

Kentucky Louisiana Maine Maryland Massachusetts Michigan Minnesota Mississippi Missouri

B+ C+ A B+ B A B+ B+ C

North Dakota Ohio Oklahoma Oregon Pennsylvania Rhode Island South Carolina South Dakota Tennessee

B B+ C+ A B+ A B+ B C+

B A B A B B+ A A

Montana Nebraska Nevada New Hampshire New Jersey New Mexico New York North Carolina

C+ B C+ B+ B B B B+

Texas Utah Vermont Virginia Washington West Virginia Wisconsin Wyoming

C+ B+ A A A B+ A B+

A variety of policy changes contributed to these current grades. Within the past few years, a total of 11 states had adopted legislation or regulations mandating CE about prescribing controlled substances or opioid medications, pain management, or palliative care for licensees or for those who prescribe as staff of pain clinics. Eight states either adopted, adopted by reference or adopted based on, or updated to the Federation’s 2013 Model Policy on the Use of Opioid Analgesics in the Treatment of Chronic Pain16 (the most recent version of the Federation’s models that was current at the time of the evaluation), whereas another 10 states added or updated other statutes or regulatory policies governing pain management, and an additional 2 states now require the development of rules governing prescribing for pain. Four states adopted legislative or regulatory language initiating or expanding their pain management, 740

hospice, or palliative care standards in various health care facilities. Importantly, two states also added a law containing a statement that directly supports the principle of Balance. Further improvements were made through the following policy adoptions: • A regulation for offering addiction treatment services in the office that provides a definition of “addiction” that not only distinguishes it from physical dependence or tolerance but also explicitly acknowledges that physical dependence occurring with a “patient on long-term opioid analgesics for pain” is distinct from ICD10 or DSM diagnostic classification systems. • A statute governing a state PMP will now offer educational information to the program Web site and will regularly send updates of such information to registered program users, whereas another state’s PMP regulations now offer training to practitioners and pharmacists and their delegates, as well as to other users, about how to use program information. • A statute that appears to allow pharmacists to dispense up to a 10-day supply of a Schedule II or Schedule III opioid medication from a prescription issued by an out-of-state practitioner (while needing to notify the practitioner of the partial dispensing), rather than prohibiting any such prescriptions. • A statute that initiated an interdisciplinary advisory council within the Department of Health as a mechanism to create, maintain, and evaluate state palliative care initiatives. In addition to adopting policy language that promotes safe and effective pain management, a number of states further improved policy quality by repealing restrictive or ambiguous provisions from statutes or regulatory policy. Such recent abrogations involved a 1-week prescription validity period; the requirement that the standard for “unprofessional conduct” be met by a failure to strictly adhere to a clinical practice guideline, which does not allow for treatment flexibility based on reasonable cause; a prescription filling standard with broad interpretive latitude for pharmacists; an entire IPTA, along with the various requirements and ambiguities typically contained in such policies (see “State Pain Policy Development: An Emerging Trend” section); an immutable requirement 741

for patients to undergo other treatment modalities before being prescribed opioids and other controlled substances, regardless of the clinical circumstances; and definitions of drug-dependent person, chemical dependency, and dependence that could be established by the presence of physical dependence only and, thus, could legally apply to a person who is being treated with opioid pain medications. As with previous evaluations, only a very few states adopted any type of policy containing restrictive or ambiguous policy language. As such, states have generally avoided adopting new policies that could impede pain management and the medical use of controlled substances. Considering current policy content, states wanting to achieve an A can be classified into four domains. First, three states currently have no restrictive or ambiguous language in their state’s pain policies and can change to an A simply by adopting additional positive language. Second, 32 states (84%) of the remaining 38 states that do not have an A can improve their grade only by repealing restrictive or ambiguous policy language. Of these states, six continue to not only have a considerable number of beneficial provisions but also have many potentially problematic provisions, which represent a noteworthy challenge. These particular states must undertake a continued focus on reducing the number of restrictive or ambiguous provisions for any grade improvement to occur. Third, as of December 31, 2015, four states have neither medical nor pharmacy board policies addressing the treatment of pain (including the use of controlled substances), palliative care, or end-of-life care. In these states, clinicians are not provided guidance from their licensing agency about what is considered acceptable approaches related to patient pain care. Finally, when striving for an A, two states now face the challenge not only of adopting positive policies but also of removing restrictive or ambiguous language from legislation or regulations. Even for those 13 states that currently have an A, a potential remains for additional policy activity (however well-intentioned) to introduce policy provisions that ultimately can lower the state’s grade. Continued state policy efforts to improve patient pain care, including through activities to address clinical and societal harms related to prescription opioids, can seek to maintain grade improvements. 742

THE IMPORTANCE OF IMPROVING STATE PAIN POLICY In the aggregate, the last decade witnessed notable improvement in the quality of many states’ drug control and professional practice laws and regulatory policies. This policy advancement was in response to continuing national and state acknowledgment that adopting positive policies governing health care practice and patient care is part of improving safe and effective pain treatments for patients with cancer, HIV/AIDS, and other chronic diseases or conditions. States typically have avoided adopting new policies that could inadvertently impede pain management, including treatment involving the medical use of controlled substances when clinically justified. Members of government and regulatory agencies, as well as health care professionals, are in a position to continue seeking policy approaches that eschew requirements that could confound medical decision making or lead to unintentional consequences on pain treatment. Such improvements, as evidenced by higher state policy grades, are a necessary part of an overall multifaceted plan to enhance pain and symptom management while stemming prescription medication abuse and diversion.60,98 Much of the positive content inherent in state pain policies has resulted historically from individual health care regulatory boards taking advantage of the Federation’s policy templates to promote consistency in state medical board policy.16,210,211 Throughout the templates, the importance of documenting various aspects of treatment is mentioned. These templates also have, at various points in time, encouraged safe and effective pain relief, perpetuated the message that pain management and the appropriate use of controlled substances was an accepted part of professional practice, and reassured clinicians that they should not be concerned about disciplinary action from their licensing agency if reasonable professional practices are followed when using controlled substances for patient care. In addition, the policies promote assessment of both potential benefits and risks when considering opioid treatment, especially for patients with more chronic conditions. Patient risk assessment, as well as the periodic monitoring for adverse events and the manifestation of abuse-, addiction-, and diversion-related behaviors, have been an explicit component of the 743

Federation’s templates since their first inception264,265; in fact, the clinical need for risk stratification strategies was emphasized even more in the most recent policies issued in 201316 and 2017.13 Importantly, health care regulatory boards (e.g., medical, osteopathic, pharmacy, and nursing) in many states have worked together to adopt joint guidelines for pain management, palliative care, or end-of-life care.60 Such policies tend to emphasize the value of an integrative multidisciplinary approach to treating pain; recognize that the goal of pain treatment should include improvements in patient functioning and quality of life; and assure that a broader variety of health care practitioners can engage in practice that generally conforms to adopted treatment standards without being apprehensive about regulatory sanctions from their licensing board. Given this notable regulatory progress, most states now can focus on maintaining policy improvement and consider efforts to remove longoutdated restrictive or ambiguous language from law, some of which has been present for over 30 years. This is especially the case with drug control laws that contain outdated definitions of “drug-dependent person” (or “addict”) that are based on the concept of physical dependence and developing a withdrawal syndrome. Such definitions can, when interpreted strictly, legally classify as an addict any patient who is taking an opioid for analgesia (see Table 14.3 for examples of these types of definitions).98 Repeal from law of decades-old restrictive language has received less attention compared to the work of professional licensing boards to adopt positive policy.60 Avoiding such language ensures that patient care decisions requiring medical judgment are not overly limited by governmental laws.

The Need to Implement and Communicate Policy Inadequately treated pain is a multifactorial phenomenon. As such, focusing solely on changing state policy is likely insufficient to guarantee better patient access to appropriate pain relief and symptom control.266 Addressing this single factor, however, often remains a necessary activity to attain a supportive professional practice and regulatory environment for the appropriate treatment of pain. Adoption of such policies also requires broad dissemination and communication to relevant practitioners to help 744

enhance compliance to the policy recommendations or requirements,266 because an evaluation of practice should always involve a determination regarding adherence to applicable policy.267 Improving state policies covering pain-related issues requires a strategic approach, often beginning simply by determining the types of policies in need of improvement. For example, the revision of statutory law requires legislative activity, whereas a change in regulatory policy involves engaging with the relevant health care administrative agency such as the medical, pharmacy, or nursing board. Health care practitioners increasingly have assumed a leadership role in collaborating with legislators or members of administrative agencies to help construct state policy that avoids interfering with appropriate decision making or creating ambiguities, recognizes the professional obligation to treat pain, and promotes effective patient pain care.266 This activity has been accomplished when practitioners have acted alone, in conjunction with a state pain initiative or other organization, or as a member of a legislatively created advisory committee.263,268

Considering Additional US Policies The aforementioned policy evaluation reports synthesize the content of numerous state-level statutes and regulatory policies governing drug control and medical, pharmacy, and nursing practice. Because this evaluation was policy-specific, it did not consider reports or projects from federal or state agencies that related directly to pain, such as the IOM’s Relieving Pain in America,4 the U.S. Department of Health and Human Service’s National Pain Strategy,50 and the NIH’s Federal Pain Research Strategy (https://iprcc.nih.gov/FPRS/FPRS.htm). The finalized methodology also was never meant to imply that the reviewed policies are the only policies relevant to pain management. In fact, various other policy types may affect patient pain care but ultimately fall outside the scope of the evaluation process. Examples of unevaluated policies include, but are not necessarily limited to, physician assistant’s practice, controlled substances scheduling, advance directives or living wills, workers’ compensation, institutional (including chain pharmacies) policies, and 745

program grants to state agencies. Another unconsidered, but especially important, influence on treatment considerations is the multitude of federal and state laws establishing standards for reimbursement of therapeutic interventions, covering such areas as prior authorization, drug formularies, medication synchronization, and abuse-deterrent formulations for opioid medications. Efforts to understand the beneficial or potentially problematic ramifications of these policies, as well as the impact of such policy requirements on professional practice and patient care, are warranted. It also is important to keep informed about the content of proposed statutes being introduced in the state legislature but which have not yet been signed into law (i.e., bills). Some recent bills, including some that have been drafted with the objective of improving public health and safety by reducing prescription medication abuse and diversion, may inadvertently create barriers to the availability of medications to people who use them therapeutically for pain relief and to maintain quality of life (see http://sppan.aapainmanage.org/legislation). Coordinated reactions to both draft and introduced legislative bills, and also to proposed regulatory policies whenever possible, can create opportunities to make policymakers aware of potential unintended consequences and recommendations for language modifications. Engagement with legislators and regulators during policy development can effectively reduce the prospect of future policy impediments and can even strengthen the policy’s ability to achieve its stated objectives. One of the most prevalently considered policies, which has been recently promoted to improve patients’ pain care and reduce opioid-related overdoses and other harmful consequences, is dosing thresholds based on cumulative morphine equivalent daily dose (MEDD) milligram amounts. At this time, these thresholds typically are limited only to the treatment of patients with chronic noncancer pain and exempts patients with the disease of cancer and those undergoing palliative care or end-of-life care. These MEDD thresholds have been described as “a precautionary signal to get the prescriber to press pause before moving forward with dose escalation.”269(p1851) Meeting or exceeding the dosage threshold is often coupled with a recommendation for the prescriber to obtain an expert consultation (see Paice and Von Roenn270 for example). Washington was 746

the first state (in 2007) to establish a recommended MEDD threshold, at 120 mg, in a clinical practice guideline.271 Since that time, some states (including Washington) eventually established such amounts in law (see, for example, Washington Administrative Code272). Measures even were put into place to evaluate outcomes from codifying the Washington MEDD, with the goal of: [making] sure any interventions to prevent problematic use don’t adversely affect the vast majority who are appropriately using their medications.273(p2) An inherent by-product of codifying these dosage amounts into law is that this now establishes a legal liability for practitioners who fail to comply with the requirements. This concern was especially important for a state like Maine, which in 2016 adopted a 100-mg MEDD amount for treating chronic pain that generally could not be exceeded274 but has since been modified to allow for therapeutic exceptions through a documentation of medical necessity.275 In addition to the MEDD threshold itself, the American Academy of Pain Management276 (now the Academy of Integrative Pain Management) issued a statement reviewing requirements contained in the Washington law, and consequently also contained in similar policies adopted subsequently by other states, which could create uncertainty for practitioners attempting to comply to this distinctive regulation. Such provisions included (1) use of a written prescriber–patient agreement for those judged to be at a high risk of substance abuse, have a history of substance abuse, or have psychiatric comorbidities; (2) requiring certain prescribers to obtain a consultation with a “pain management specialist” under certain circumstances, including exceeding the dosing threshold; and (3) establishing qualifications for prescribers who can serve as adequately prepared specialist consultants.276 Within this statement, though, the possibility was raised that any practitioner reluctance surrounding this law may relate more to perceptions based on an inaccurate understanding of the legal requirements, rather than being founded on a direct reaction to the mandatory conditions themselves.276 That is, it is acknowledged that policy barriers to practice can occur as much from misinterpretations about 747

policy requirements than from perceptions about legal liability based on actual policy content. A more recent commentary by Ziegler269 has identified additional substantive concerns related to policies establishing MEDD dosage thresholds. These potentially problematic issues include the implied emphasis on potential harms only at higher dosage levels (although risks are heightened at any dosage level,277 especially without proper treatment monitoring); neglect of other, separate, factors that could contribute to clinical harms; nonstandard and erroneous conversion formulas for morphine equivalence; and an insufficient number of pain management specialists available for required consultations.269 These considerations, as well as those mentioned earlier, support the need to thoroughly assess the various reasons for practitioners’ reactions to such laws to help formulate ideas about addressing health care professionals’ perceptions. This is especially feasible now because some of these policies have been in effect for a few years, so practitioner awareness should be higher than it would have been closer to the policy adoption. Ultimately, it can be determined whether any identified practitioner concerns are more likely remedied through modifying (to any degree) the requirements or recommendations contained in the laws or other regulatory policies, increasing resources to aid more broad and consistent implementation, or improving practitioners’ understanding about the policy standards and promoting their clinical utility, or through a combination of approaches.

Taking Diversion into Account In addition to efforts to promulgate pain policies that enhance benefits and minimize harms from treatments for patients with pain, drug control measures must be established, through both the same and separate policies, to reduce the potential for transferring prescription medications into illicit channels. Even given the numerous and varied legislative and regulatory requirements that have been implemented over time in the United States to govern the closed distribution of controlled medications, opioid analgesics can still be diverted from all levels of the distribution system.278 Diverted opioid medications often become illegally available for illicit distribution 748

and nonmedical use, which can contribute to harmful outcomes such as overdose and death. It should come as no surprise that using controlled medications obtained through means other than a valid prescription issued by a properly licensed practitioner for a legitimate medical purpose, or in ways that do not conform to practitioner instructions, compounds the risk of harmful consequences. Given the risks inherent in all controlled substances, health care professionals who provide treatment with opioid medications have a responsibility to protect patient and public safety by taking actions to avoid contributing to abuse and diversion. Prescribing or dispensing more dosage units than medically necessary is potentially problematic because these medications may go unused, accumulate in volume, and become susceptible to theft or perhaps accidental use by others.279,280 When a practitioner’s issuance of prescriptions reaches a level or pattern considered “excessive,” in some states, it can fulfill the criteria for “unprofessional conduct” in which the practitioner is subject to license revocation or other civil penalties under law (see New Mexico Medical Board281 as an example). Patients receiving prescription-only controlled medications for pain treatment also share responsibilities under law, which has only recently begun receiving attention in earnest. Warnings on prescription labeling denote that it is a violation of law for patients to transfer the medications prescribed for them to any other person.282 More generally, any person who possess controlled substances, including opioid analgesics, without a valid prescription, as well as someone who acquires these medications by theft, fraud, or misrepresentation, is in violation of federal and state laws. Opioids may even be prescribed legitimately but, when they are not stored securely in the patient’s home, they are vulnerable to diversion through loss or theft. These scenarios reinforce the reality that learning whether a person acquired an opioid from peers or family, or even through a dispensed prescription, is often not enough information to inform a sufficient response—it is necessary to additionally consider the circumstances leading up to how the opioid was obtained initially. There is a potential for opioid medications to be diverted from throughout the entire medication distribution system, including before they 749

are prescribed. Consequently, there are many potential sources that feed the use of prescription opioids for illicit purposes. Examples of such activities, from each level of the distribution chain, include the following: • From the wholesale level: Criminal diversions of large quantities are reported by manufacturers and distributors. • From the retail level: Criminal activities by organizations and individuals, including some patients, to obtain opioid analgesics unlawfully Armed robberies and night break-ins from pharmacies Thefts, including employee pilferage, occurring from pharmacy supplies in nursing homes and hospitals Fraud and misrepresentation, such as “doctor shopping” or prescription form theft, forgery, or alteration “Script doctors” and “pill mills,” which are illegal activities by rogue physicians who still have the necessary authority to prescribe, or to purchase and dispense, controlled substances Misuse of Medicare and Medicaid drug coverage • From the ultimate user level: Intentional or unintentional behaviors Patient sharing with friends or family members Patient selling to strangers Caregiver stealing directly from patient Stealing from unsecured amounts Such a variety of diversion opportunities makes it clear that efforts to reduce nonmedical drug use should include, but must be more comprehensive than, focusing on prescribing and dispensing practices and patient access. Although potential diversion sources can be identified through knowledge of the medication distribution system, little empirical evidence exists about the degree to which these numerous conceivable diversion activities are involved in prescription medication–related abuse, addiction, overdose, and death. However, understanding the multiple ways that diversion can occur substantiates use of a broad multifaceted approach for effectively addressing nonmedical use of prescription opioids. Such an approach is exemplified at a federal level by the Office of National Drug Control Policy’s (ONDCP’s) Prescription Drug Abuse Prevention Plan,283 750

which was unveiled in April 2011 and then updated each year as part of the US national drug control strategy (see ONDCP284 for example). Under the ONDCP’s Plan, multiple federal, state, and local regulatory and enforcement agencies are collaborating to address four distinct domains: (1) Education—to enhance practitioner and public awareness about the risks and benefits of prescription medications, to investigate the production of analgesics with less or no abuse liability, and to promote research to demonstrate changes in abuse trends; (2) Tracking and monitoring—to support the funding, breadth, and use of PMPs, to promote electronic prescribing of controlled substances and other treatment technologies, and to evaluate the utility of federal database for epidemiologic purposes; (3) Proper medication disposal—to reduce the volume of unused medications through enhanced disposal opportunities; (4) Enforcement—to train laws enforcement members and others to address pill mills and other drugtrafficking activities and to focus on doctor shopping or pharmacy hopping.283 This collaborative and systematic strategy has the benefit of seeking to more comprehensively address the multiple means by which prescription medications can become available for illicit use, including through the practitioner–patient relationship. Such an approach, as well as detailed multiagency policy initiatives now underway in some states, symbolizes an apt appreciation for the intricate nature of the national public health problem of nonmedical drug use.285–287

Conclusions In the United States, destructive consequences related to the use, misuse, and abuse of, as well as addiction to, prescription opioid analgesics have been increasing for more than a decade. These occurrences can create a potential to put at odds, and even conflate, the needs of those who are being harmed through the often-illicit use of prescription medications with patients who may benefit from their therapeutic use.288 It is beneficial to contemplate, however, how current US legislative and regulatory policies can provide a critical reference point for considering the needs of these two separate, but sometimes overlapping, populations. As has been described throughout this chapter, both US federal and state 751

governmental and regulatory policies can contain language that establishes an effective drug control system that reduces the likelihood that these medications become available for inappropriate or unlawful use while also promoting medication access to patients when clinically warranted (i.e., Balance).110 These dual objectives are promoted by many national and international entities and sanctioned by international treaty and federal law. Even given the substantial progress in reducing legal and regulatory barriers, there is a need to maintain ongoing vigilance to new or changing policy content. For this, the principle of Balance remains an unassailable conceptual framework to guide the continuing development of state policies governing health care practice and controlled substances prescribing. Importantly, improved policy does not guarantee that the ideal outcomes of safe and effective pain management and reducing deaths and harm associated with the nonmedical use of controlled medications will be achieved. For example, it certainly is feasible that nonconformity to the recommendations inherent in a state-issued regulatory guideline could adversely affect the benefit/risk determinations necessary to best reach treatment decisions, as well as undermine the strategies offered in the policy to identify and address potential abuse or diversion behaviors. This scenario does not even account for the numerous factors within the health care system that can work against policies with balanced content, including a lack of understanding or misperceptions about a policy or poor or nonexistent implementation of a policy. Because of such influences, any policy improvement that is accomplished may not produce results that reflect its inherent Balance. Realizing true Balance requires an understanding of not only the actual policy content but also the extent of practice adherence to that policy content and then effectuating interventions based on this knowledge. Although Balance is a principle conceived in, and intended for, policy development in an effort to maintain patient care with controlled medications during implementation of a broader abuse/diversion mitigation regulatory infrastructure, it has even been applied to activities outside of policy. This principle is useful for delineating the appropriate roles and responsibilities of health care professionals, members of 752

regulatory agencies, and law enforcement officials regarding the issues of pain treatment and stemming the nonmedical use and prescription opioid– related harms. A practitioner’s responsibility, of course, is patient health care—when providing pain treatment using opioid therapy, that practitioner is also expected to monitor for the abuse and diversion of the prescribed medications and to identify possible comorbidities and other patient factors that may have treatment implications; such an outcome represents Balance. Conversely, drug control is chiefly a responsibility of certain regulatory agencies and law enforcement—when planning efforts to curb abuse and diversion, these efforts can avoid interfering in legitimate medication availability, health care practice, or patient care; this, too, represents Balance. From this national and international medicolegal concept, it is clear that the actions of members of health care, regulation, and law enforcement often overlap in the obligations related to medication availability and efforts to minimize abuse and diversion. In addition, recent national efforts to curb harms involving prescription medications, such as practitioner educational initiatives,122 clinical practice guidelines,15,289 and a Surgeon General’s report,290 have acknowledged the value of maintaining appropriate pain treatment. Clearly, these examples demonstrate a widespread belief in, as well as a commitment to, the ability to contemporaneously address the dual public health problems of undertreated pain and prescription medication abuse/diversion without sacrificing either. Attaining either objective at the expense of the other represents a failure of the drug control or health care regulatory systems, or both, that demands immediate corrective action. The laudable goals expressed through these activities will, hopefully, be demonstrated through the routine collection, assessment, and consideration of relevant outcomes to document whether implementation of any adopted approach effectively reduces harms and eschews deleterious unintended consequences for health care practitioners who provide pain management services using opioids. Given these considerations, it is time to move beyond the call to evaluate policies. The increased research focus on degree of opioid prescribing concordance with clinical practice guidelines291–296 establishes the precedent that attention must now turn toward determining the effect of 753

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258. Pain & Policy Studies Group. Achieving Balance in State Pain Policy: A Progress Report Card. Madison, WI: University of Wisconsin Paul P. Carbone Comprehensive Cancer Center; 2003. 259. Pain & Policy Studies Group. Achieving Balance in State Pain Policy: A Progress Report Card. 2nd ed. Madison, WI: University of Wisconsin Paul P. Carbone Comprehensive Cancer Center; 2006. 260. Pain & Policy Studies Group. Achieving Balance in State Pain Policy: A Progress Report Card. 3rd ed. Madison, WI: University of Wisconsin Paul P. Carbone Comprehensive Cancer Center; 2007. 261. Pain & Policy Studies Group. Achieving Balance in Federal and State Pain Policy: A Progress Report Card (CY 2012). Madison, WI: University of Wisconsin Paul P. Carbone Comprehensive Cancer Center; 2013. 262. Pain & Policy Studies Group. Achieving Balance in State Pain Policy: A Progress Report Card (CY 2013). Madison, WI: University of Wisconsin Paul P. Carbone Comprehensive Cancer Center; 2014. 263. Twillman RK, Kirch R, Gilson A. Efforts to control prescription drug abuse: why clinicians should be concerned and take action as essential advocates for rational policy. CA Cancer J Clin 2014;64:369–376. 264. Fishman SM. Responsible Opioid Prescribing: A Physician’s Guide. Washington, DC: Waterford Life Sciences; 2007. 265. Fishman SM. Responsible Opioid Prescribing: A Clinician’s Guide. 2nd ed. Washington, DC: Waterford Life Sciences; 2012. 266. Gilson AM. Good state policy may not mean good pain care, but policy improvement offers hope for further progress: response to the Wahowiak article. J Pain Palliat Care Pharmacother 2015;29:169–172. 267. Brushwood DB, Rich BA, Coleman JJ, et al. Legal liability perspectives on abuse-deterrent opioids in the treatment of chronic pain. J Pain Palliat Care Pharmacother 2010;24:333–348. 268. Gilson AM, Joranson DE, Maurer MA. Improving state pain policies: recent progress and continuing opportunities. CA Cancer J Clin 2007;57:341–353. 269. Ziegler SJ. The proliferation of dosage thresholds in opioid prescribing policies and their potential to increase pain and opioid-related mortality. Pain Med 2015;16:1851–1856. 270. Paice JA, Von Roenn JH. Under- or overtreatment of pain in the patient with cancer: how to achieve the proper balance. J Clin Oncol 2014;32:1721–1726. 271. Agency Medical Director’s Group. Washington State’s draft guidelines for opioids for chronic non-cancer pain: frequently asked questions. Available at: http://www.agencymeddirectors.wa.gov/Files/2006FAQV8.pdf. Accessed April 12, 2018. 272. Washington State Legislature, Pain Management—Intent. Olympia, WA: WAC 246-919-850. 273. Magill-Lewis J. Washington State weighs limiting narcotic doses. Drug Topics. January 8, 2007. 274. Maine Revised Statutes. 32 M.R.S. §3300-F. 275. Maine Legislature. An Act to establish reasonable and clinically appropriate exceptions to opioid medication prescribing limits. SP0338 LD 1031, 128th Session, 2017. 276. American Academy of Pain Management. State of Washington Pain Management Rules Opinions of the American Academy of Pain Management. Chicago, IL: American Academy of Pain Management; 2011. 277. Bohnert AS, Logan JE, Ganoczy D, et al. A detail exploration into the association of prescribed opioid dosage and overdose deaths among patients with chronic pain. Med Care 2016;54:435–441. 278. Coleman JJ. The supply chain of medicinal controlled substances: addressing the Achilles heel

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CHAPTER 15 Litigation Involving Pain Management BEN A. RICH In recent decades, issues arising in the context of pain management have increasingly been raised in the context of law and public policy. Indeed, one of the major professional journals, Pain Medicine, now has an entire section devoted to this area of activity (i.e., forensic pain medicine). Although technically, forensic pain medicine encompasses all instances in which pain medicine and the law converge, this chapter focuses on the area of convergence that is most often associated with the term forensic— litigation. Other aspects of law and public policy affecting pain management are covered in the pain policy chapter of this book (Chapter 14). American jurisprudence is divided into two broad categories of jurisdiction—state and federal—and four distinct domains within both categories: administrative, civil, criminal, and constitutional. Cases involving pain management have arisen in all four domains, and in this chapter, we will consider representative cases in each and identify the important lessons for practitioners. We will begin with administrative proceedings, all of which involve disciplinary actions by state medical licensing boards against physicians. In reviewing these cases, it will become clear how the pendulum has been swinging over the last 20 to 25 years. Beginning in the early 1990s, the long-standing concern about “overprescribing” of opioid analgesics was disrupted by several cases in which health care institutions and professionals were charged with substandard practice for their failure to provide seriously ill or dying patients with adequate management of pain and/or symptom distress. These proceedings reflect an emerging policy trend among licensing boards to emphasize the important role of pain management in patient 768

care. With the ever-increasing evidence in the last 10 years that opioid overdose deaths have reached epidemic levels in some parts of the country, state boards and federal regulators have begun to revise policies and guidelines to reflect the current level of risk posed by the indiscriminate prescribing of opioids. These policy permutations are more fully discussed in the pain policy chapter (Chapter 14). The aspect of civil litigation that most often involves health care professionals is medical malpractice. Such claims are a species of tort claim in which an injured party, the plaintiff, asserts that they have sustained compensable injury as a result of the negligence of the other party, the defendant. In order to be successful, medical malpractice claimants must establish four essential elements. The first element is the existence of a duty owed by the defendant to the plaintiff. The generic characterization of such a duty is “due care.”1 In professional liability cases, this translates to compliance with the prevailing standard of care. However, a health care professional–patient relationship must exist before such a duty may be deemed to have arisen. The second element is breach of the duty owed, hence in medical malpractice litigation, a material departure from the standard of care. A dispute as to what constitutes the relevant standard of care by which the defendant professional’s conduct is to be evaluated is usually the critical issue in a medical malpractice case, and the outcome often depends on whose expert witness or witnesses are deemed by the jury to be most convincing. Consequently, medical malpractice cases have come to be characterized as little more than a “battle of the experts.” Traditionally, the usual custom and practice of physicians in the same or similar situations to the defendant has set the standard of care. Evidence of compliance by the defendant physician with the custom tended to create an irrefutable presumption that the applicable standard of care had been met. Over the last several decades, there has been a gradual trend by the courts toward a recognition of instances in which the custom and practice of clinicians has lagged noticeably far behind advances in medical science and technology, or physicians have failed to adopt safer or more effective clinical practices such as those advocated by national clinical guidelines. In such situations, the courts have acknowledged that rigid and unreflective adherence to the 769

customary practice might demonstrate a failure to exercise appropriate clinical judgment. We will consider that issue further in the section of the chapter pertaining to civil litigation. The third element of a tort claim is damage or injury. The breach of a duty of due care that fails to produce an injury or other harm is, from a strictly legal perspective, of no consequence. It is characterized in the law as damnum absque injuria (a wrong without injury). Such circumstances may be of interest to risk managers and quality improvement personnel, but they do not give rise to tort liability. The intriguing aspect of harm in the context of pain management is whether subjecting patients to unnecessary pain through substandard care would be deemed by juries as on the same level as medical errors that produce demonstrable physical injury or even death. The cases we will examine confirm that this is indeed the case, at least for patients who were at the end of life. Finally, the plaintiff must establish that the breach of the duty of care by the defendant was the proximate (direct and immediate) cause of the damage or injury he or she sustained. In the cases we will be considering, the plaintiff must persuade the jury that pain management consistent with the standard of care would have, to a reasonable degree of medical probability, ensured that the patient did not suffer to the same extent as she did. In the fourth section of the chapter, we will review criminal prosecutions by both the state and federal governments that concern the prescribing of opioid analgesics for terminal or chronic noncancer pain patients. Finally, in “Constitutional Cases” section, we will consider three US Supreme Court cases in which constitutional issues are raised in the context of cases related to pain management and/or end-of-life care.

Administrative Proceedings Until recently, disciplinary actions by state medical licensing boards involving the prescribing of opioid analgesics targeted the phenomenon of “overprescribing,” and it was the leading cause of both investigations and disciplinary actions.2 Some of these actions were well-founded efforts to punish physicians who prescribed controlled substances inappropriately or

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without a legitimate medical purpose, thereby endangering their patients and/or society. Others, however, sought to punish physicians who were engaged in a good faith effort to manage chronic noncancer pain and demonstrated either a dismissal by the boards of the plight of chronic pain patients or an ignorance of the risks, side effects, and benefits of opioid analgesia.3 We will consider two cases from the second group in which the practices of the accused physicians were ultimately vindicated by state appellate court decisions.

IN THE MATTER OF DILEO Dr. Lucas DiLeo, a general practitioner, prescribed opioid analgesics for some of his patients with significant chronic nonmalignant pain. One of these patients, for example, was an ironworker who had fallen over 40 ft onto concrete and sustained 153 fractures, 93 in the face, as well as shattering his knees, ankles, and left femur. He underwent 10 operations, and continued thereafter to suffer with chronic pain. In 1992, the Louisiana Board of Medical Examiners filed an administrative complaint against Dr. DiLeo alleging that his prescribing of opioids to seven patients (an eighth patient was treated for obesity with a combination of benzphetamine [Didrex] and alprazolam [Xanax]) was not for a legitimate medical purpose, demonstrated incompetence, and fell outside acceptable standards of medical practice. The board’s expert witness, Dr. Linda Stuart, a board-certified family practitioner and addiction specialist, did not question that the seven patients receiving opioids had serious pain problems nor did she challenge the doses prescribed as excessive. However, she did testify that in her opinion, opioid analgesia was provided for too long a period of time, thereby posing an unacceptable risk of addiction and withdrawal symptoms. She acknowledged, however, that there were different schools of thought on this issue in the medical profession. As for the obesity patient, Dr. Stuart questioned the prescribing of Didrex and Xanax at the same time because she considered the former to be a stimulant, whereas the latter was a depressant. Five of Dr. DiLeo’s patients testified on his behalf, as did a physician whose specialty was internal medicine/endocrinology. The medical board 771

ruled against Dr. DiLeo, and that ruling was affirmed by a trial court. The Louisiana Court of Appeals reversed and dismissed all charges against him after finding that no evidence had been presented by the board to support Dr. Stuart’s assertion that the duration of Dr. DiLeo’s prescriptions was excessive. Indeed, the Court of Appeals held that the board had failed to present any evidence as to what the relevant standard of medical practice was for prescribing opioids for chronic pain. In the absence of such evidence, the unsupported assertions of Dr. Stuart were insufficient to justify the disciplinary measures imposed on Dr. DiLeo, and the charges against him were deemed by the court to be arbitrary, capricious, and an abuse of the board’s discretion.4

HOOVER V AGENCY FOR HEALTH CARE ADMINISTRATION Katherine Hoover, MD, was a board-certified internist who had a number of chronic pain patients in her practice. For some of them, she elected to prescribe opioid analgesics for an extended period of time. The state medical board took a dim view of this and initiated disciplinary proceedings for “inappropriately and excessively” prescribing Schedule II drugs to seven patients. The board’s case against Dr. Hoover consisted of two physicians who had reviewed pharmacy computer printouts documenting the prescriptions written for these patients by Dr. Hoover, and their opinions that the dosages she had prescribed were “excessive, perhaps lethal.” None of these patients had, in fact, suffered any adverse effects from the prescriptions written by Dr. Hoover. Rather, they rallied to her support because she had diligently and successfully worked to manage their pain and restore their ability to function, whereas other physicians had either discounted their reports of pain or refused to prescribe opioids. The board’s experts did not review the medical records for any of these patients. Also, on cross-examination, these “experts” acknowledged that they did not treat chronic pain patients in their practice. Indeed, under the more stringent standards for expert testimony that have developed in the last 10 years, one could reasonably argue that the medical board’s experts were not really experts in pain management. The hearing officer in the case may have taken the same view because she ultimately ruled that the 772

evidence presented at the hearing supported a conclusion that Dr. Hoover’s care of these patients was entirely appropriate. Nevertheless, the Board of Medicine took the remarkable step of disregarding the hearing officer’s findings and conclusions and imposed sanctions that included an administrative fine of $4,000, continuing medical education (CME) on the prescribing of “abusable drugs,” and 2 years of probation. Dr. Hoover appealed, and in a scathing opinion by a three-judge panel of the Florida Court of Appeals, the ruling of the medical board was reversed. Noting a disturbing pattern and practice by the medical board, the opinion declared, “The board has once again engaged in the uniformly rejected practice of overzealously supplanting a hearing officer’s valid findings of fact regarding a doctor’s prescription practices with its own opinion in a case founded on a woefully inadequate quantum of evidence.”5 Elsewhere in the opinion, the court referred to the board’s “draconian policy of policing pain prescription practice.” Similar to the decision by the Louisiana Court of Appeals in DiLeo, the Florida Court of Appeals noted that the medical board had failed to introduce competent, credible evidence of the standard of care by which Dr. Hoover’s prescribing practices could be evaluated. One very important implication of the DiLeo and Hoover cases is that the courts will not simply sit back and allow medical boards to declare what the standard of care is in any particular clinical situation. Rather, the board must present persuasive evidence in support of the prevailing standard of care. Moreover, such cases as these appear to represent an “ethic of underprescribing” on the part of state medical boards that persisted for decades.6 It was the deeply engrained and pervasive nature of this ethic that prompted some state legislatures to adopt the intractable pain treatment acts (IPTAs) that are discussed in Chapter 14. The thrust of such legislation was to send a message that the public policy of the state should not be to discourage physicians from providing effective pain management to patients with chronic nonmalignant pain, even if in some cases, that would involve the extended use of opioid analgesics. The Hoover case suggests how difficult it was to surmount the prevailing ethic in some boards because that case was brought shortly after the State of Florida had enacted an IPTA. The medical board rationalized its attempt to 773

discipline Dr. Hoover by arguing that she had treated the patients in question prior to the effective date of the Florida law. The Florida Court of Appeals critiqued the cramped and legalistic way in which the board attempted to flaunt the statute, noting that what the board failed or refused to recognize was that the public policy of the state did not support its approach to punishing physicians who dared to prescribe opioids to patients with chronic noncancer pain. As noted earlier, beginning in the mid-1990s, a few state medical boards adopted policies on pain management that were intended to reassure physicians that the board was not, in fact, hostile to good pain management practice and sought to outline how physicians could care for such patients in a manner that was consistent with good medical practice. Then, in 1998, the Federation of State Medical Boards (FSMB) promulgated model guidelines for the use of controlled substances for the treatment of pain.7 The gradual dissemination of medical board policies promoting effective pain relief as an essential component of quality patient care signaled the beginning of a paradigm shift. Heretofore, the idea that if there could be such a thing as overprescribing of opioids, then as a matter of logic and consistency, there must be an opposite side to the coin (i.e., underprescribing of opioids) seemed to be unintelligible to many medical boards. The inconsistency between perception and reality was truly remarkable. Whereas the medical literature in the 1980s and 1990s was replete with data indicating that pain was significantly undertreated in almost all patient care settings, no medical board had ever encountered a case in which underprescribing was deemed to constitute incompetent or unprofessional conduct.8

OREGON BOARD OF MEDICAL EXAMINERS V BILDER Paul A. Bilder is a pulmonary specialist who in the late 1990s was practicing in a small Oregon community. In 1999, the Oregon Board of Medical Examiners (OBME) initiated disciplinary action against Bilder following an investigation of complaints concerning his alleged failure to properly manage the pain and other distressing symptoms of six patients over a period of 5 years. The disciplinary action ultimately led to a 774

stipulated order in which Bilder agreed to certain remedial measures.9 Two of the six were elderly patients with metastatic cancer who were enrolled in hospice. In each instance, the hospice nurse requested an increase in the dosage of pain medication in what turned out to be the last hours of the patient’s life which Dr. Bilder refused to provide because he considered the amount requested excessive. In the other three cases, he refused to provide morphine or similar pain medication to a patient with congestive heart failure (CHF) who was do not resuscitate (DNR) and gasping for breath. The other three cases involved patients who were ventilatordependent because of chronic obstructive pulmonary disease (COPD) or pneumonia. Dr. Bilder ordered paralytic agents but refused to order antianxiolytics or pain medication. By the terms of the stipulated order, Dr. Bilder agreed to a 10-year probation, a formal reprimand, successful completion of the board’s Physician’s Evaluation Education Renewal Program, and an approved course in physician–patient communication as well as continuing psychiatric treatment with regular reports from the treating psychiatrist to the board. The Oregon Board once again found it necessary to take disciplinary action against Dr. Bilder 2 years later for similar instances of failure or refusal to appropriately respond to clear indications of patient suffering.10

ACCUSATION OF EUGENE WHITNEY, MD In 2003, California became the second state to take disciplinary action against a physician for failure to provide appropriate pain relief. The patient in question was an 85-year-old man with advanced mesothelioma. The care of Lester Tomlinson in the last weeks of his life was the subject of both civil litigation and medical board disciplinary action. The civil litigation will be discussed in the next section of this chapter. Mr. Tomlinson spent 5 days in a local hospital receiving treatment for pneumonia and pleural effusion. He was then transferred to a skilled nursing facility (SNF) and came under the care of Eugene B. Whitney, MD, for the duration of his stay, which ended with his death approximately 3 weeks later.11 The care of Mr. Tomlinson at the SNF generated a great deal of contention between the members of his family 775

(wife and daughter) and the caregivers. Each administration of pain medication, which began on the fourth day following his transfer from the hospital, was precipitated by a complaint from the family that he was in pain. Medication orders progressed from remazepam (Restoril) to hydrocodone/paracetamol (Vicodin) to various strengths of fentanyl transdermal (Duragesic) patch. Only after the family specifically requested morphine for Mr. Tomlinson’s increasing pain did Dr. Whitney discontinue the hydrocodone/paracetamol (Vicodin) and ordered morphine (Roxanol) 20 mg, 10 mg orally every 6 hours. Dr. Whitney saw Mr. Tomlinson only once during that period of time, 2 days after the first administration of Roxanol. He found the patient to be in pain and ordered morphine sulfate controlled-release (MS Contin) oral solution 10 mg every 4 hours as needed. As noted in the medical board charges against Dr. Whitney, MS Contin comes in tablet form only and should be provided on a regular schedule and not on an “as needed” basis. Dr. Whitney discontinued the prior order 2 days later and instead ordered MS Contin 5 mg every 2 hours for breakthrough pain. As further noted in the medical board accusation, halving the dose of an opioid analgesic and doubling the frequency of administration will not increase the analgesic potency. Nursing notes at the SNF in the subsequent 2 days until Mr. Tomlinson’s death indicate uncontrolled pain and anxiety. The Medical Board of California charged Dr. Whitney with unprofessional conduct and incompetence for his failure “to understand the unique properties of Roxanol solution and MS Contin tablets and to prescribe the medications properly.”11 The board and Dr. Whitney entered into a stipulation for public reprimand, the terms and conditions of which require that he obtain CME in pain management, the prescribing of opioid analgesics, and communication with patients and families.12 At this point, it is still too early to conclude that the medical board actions against Drs. Bilder and Whitney represent any sort of lasting paradigm shift in philosophy and practice of medical boards generally in regard to opioid prescribing by their licensees. Two cases do not constitute a trend. The FSMB Model Policy concerning controlled substances for pain relief has undergone a number of periodic updates, expansions, and revisions over the last two decades. In the most recent iteration (2013), it 776

states that “evidence for the risk associated with opioids has surged, while the evidence for benefits has remained controversial and insufficient.”13 The current document admonishes prescribing professionals to recognize that appropriate pain management includes an ongoing risk–benefit assessment of opioid analgesia versus nonpharmacologic measures. A majority of state medical boards had adopted the model policies or promulgated policies that emphasize the need to incorporate sound pain management practices into patient care.14 To some extent, the shift in attitudes about the role of pain management in patient care, and the influence of those new attitudes in the formulation of medical practice guidelines and policies, can be traced to a few dramatic legal cases. We turn now to these cases and their role in informing public attitudes and policies about pain and its management.

Civil Litigation Despite growing evidence in the clinical literature that pain is often undertreated, and a medical malpractice crisis purportedly arising out of a plethora of malpractice claims yielding significant monetary damage awards, prior to 1990, there had never been a malpractice suit seeking damages for failure to provide appropriate pain relief. Although somewhat speculative, there are several possible explanations of this curious state of affairs. First, the phenomenon of widespread undertreated pain was not well known outside of the health professions. It had yet to become a featured topic in the print or electronic media. Moreover, laypersons held the erroneous belief that pain was the inevitable result of traumatic injury, serious illness, or a major surgical procedure. Finally, the generally high repute in which health care professionals were held presupposed that they would most certainly not allow a patient to experience unnecessary pain or suffering. The pervasiveness of pain in the clinical setting must, on this view, result from the sheer intractability of the pain associated with major illness and most certainly with the process of dying. From this perspective, the case we now consider is all that more remarkable in its outcome.

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ESTATE OF HENRY JAMES V HILLHAVEN CORPORATION Henry James was a 75-year-old man who carried the diagnosis of stage III adenocarcinoma of the prostate with metastasis to the lumbar sacral spine and left femur. In December of 1986 and January of 1987, he spent nearly 2 months in a local hospital receiving treatment for a pathologic hip fracture. During that hospitalization, in addition to bone debridement and radiation therapy, Mr. James was evaluated by hospice and received Roxanol 150 mg every 3 to 4 hours around the clock for his pain. Progress notes indicate that his pain was well controlled on this regimen. After a very short stay at home, he was admitted to an SNF owned and operated by the Hillhaven Corporation. The continuing orders for pain medication included 150 mg per day of Roxanol, along with two tablets of acetaminophen (Tylenol) every 4 hours as needed and propoxyphene napsylate and acetaminophen (Darvocet-N) 100 mg. His family had ensured that he received the medication when he was at home and made certain that the nursing home staff was aware of it on his admission.15 In preparation of the SNF admission documents, a nurse offered the opinion that Mr. James was addicted to morphine and on that basis declared her intent to significantly reduce the amount of opioid analgesia and replace it with a tranquilizing agent. Remarkably, she was able to effectuate this change in the pain management regimen without the review and approval of the patient’s physician. His family learned about the change only after he had been discharged from the facility and was interviewed by investigators for the North Carolina Department of Human Resources, the licensing agency for the facility. Their investigation revealed that at no time during his 23-day stay did he receive pain medication as ordered.15 Thereafter, the family consulted an attorney and suit was filed against the nurse and the facility for failure to properly treat Mr. James’s pain.16 In order to prevail in such a case, the plaintiff (Mr. James’s estate) had to establish by a preponderance of the evidence that (1) a recognized standard of care for the management of his pain existed, (2) the standard was violated by the defendants, and (3) the departure from the standard of care caused him to experience pain to an extent that he would not had the 778

standard been met. If the jury answered each of those questions in the affirmative, then it must proceed to determine what several weeks of unnecessary pain should be worth in monetary damages. During the course of the trial, expert witnesses called by the plaintiff challenged the position taken by the nurse at the Hillhaven facility that the dose of morphine prescribed for Mr. James was excessive and not necessary to control his pain.17 The jury answered each of the questions in the affirmative and awarded the plaintiff compensatory damages of $7.5 million. However, the jury did not stop with that award. In a civil action, when a defendant’s conduct is sufficiently egregious to meet certain criteria, punitive damages may be awarded. The purpose of such damages, as the term suggests, is not to compensate the plaintiff, but rather to make a negative example of and punish the defendant. The jury in this case assessed another $7.5 million in punitive damages. Apparently, the jurors were convinced that there is or ought to be something like a right to effective pain relief, at least for patients in the circumstances of Mr. James, and that the defendant corporation and/or its agent consciously disregarded that right and in the process subjected an elderly, dying patient to unnecessary pain and suffering. In a subsequent section of this chapter, we will consider two cases in which the US Supreme Court appears to adopt a similar position as a matter of constitutional law. Several years after the verdict and subsequent out-of-court (and confidential) settlement of the Estate of Henry James v Hillhaven Corporation case, North Carolina joined a number of other states in enacting tort reform legislation. Consequently, the same result could not be achieved today even in the same or a very similar case. Punitive damages are now capped at 3 times the amount of compensatory damages or $250,000, whichever is greater. Furthermore, punitive damages cannot even be sought unless the plaintiff can prove by clear and convincing evidence (a higher burden of proof than a preponderance of the evidence) one of the following aggravating factors: (1) the defendant acted out of malice, (2) fraudulently, or (3) in willful and wanton disregard of the rights or safety of the defendant. Punitive damages could not be recovered from a corporation (such as Hillhaven) unless the officers, managers, or directors 779

participated in or condoned the conduct that constituted the aggravating factors.18

BERGMAN V CHIN, MD, AND EDEN MEDICAL CENTER William Bergman was an 85-year-old man in severe pain when he arrived at the emergency department (ED) of Eden Medical Center. He had been taking the Vicodin prescribed by his physician but without receiving adequate relief. He was given morphine by the ED physician and experienced significant relief. In order to do a more extensive workup, he was admitted to the hospital and came under the care of a hospitalist, Wing Chin, MD. Out of concerns about the side effects of morphine, in particular respiratory depression, Dr. Chin discontinued it and wrote a standing order for meperidine (Demerol), 25 to 50 mg every 4 hours “as needed.” This order remained in place throughout the 5-day hospital stay, during which the nurses charted pain levels in the range of 7 to 10 on the standard 10-point scale. On the date of Mr. Bergman’s discharge, his numerical pain score was noted to be a 10; nevertheless, Dr. Chin planned to send him home with a prescription for Vicodin. When Mr. Bergman’s daughter protested, Dr. Chin ordered another administration of Demerol and a fentanyl patch. During the hospitalization, the medical workup was strongly suggestive of lung cancer, although Mr. Bergman refused to consent to a lung biopsy that Dr. Chin believed was indicated in order to make a definitive diagnosis. Despite a diagnosis Dr. Chin deemed less than definitive, shortly following his discharge, Mr. Bergman came under the care of a hospice nurse, who prevailed on another physician in the community to write a prescription for morphine after she found the fentanyl patch to be inadequate to manage Mr. Bergman’s pain. He died 3 days following discharge. No autopsy was performed. The cause of death was considered to be complications from lung cancer.19 The children of William Bergman became convinced that the last days of their father’s life were severely compromised by a clinical failure to provide effective pain relief. Their conviction resulted in part from a review of his medical record by an expert secured through the assistance of 780

the organization Compassion in Dying (now Compassion and Choices). The family initially filed a complaint against Dr. Chin with the Medical Board of California. In an interesting approach to the case, the board’s own investigation and independent expert review confirmed that the pain relief Dr. Chin provided to Mr. Bergman was inadequate. Nevertheless, the board notified the family that it would not take any adverse disciplinary action against Dr. Chin based on only one episode of inadequate patient care. Displeased by this response, and with continuing support from Compassion in Dying, the Bergman family secured legal counsel and filed a civil action against Dr. Chin and Eden Medical Center. The medical center settled with the plaintiffs prior to trial. The complaint against Dr. Chin that was tried to a jury was unusual in that it was not a straightforward medical malpractice claim. Such a claim could not have any chance of success in California because, as a result of tort reform legislation, damages for pain and suffering resulting from medical malpractice can only be recovered by the patient; they are not deemed to “survive” such that they can be recovered following the patient’s death by the personal representative. The only challenge to the medical care provided by Dr. Chin related to his alleged failure to properly manage Mr. Bergman’s pain; hence, the only damages that could be awarded would be for unnecessary pain and suffering. However, if the pain and suffering can be proven to have resulted from acts or omissions that constitute “elder abuse,” under California law, the personal representative of the “victim” of the abuse can recover damages. Consequently, the Bergman family’s suit against Dr. Chin and the hospital alleged elder abuse. Another complicating factor about an elder abuse claim in California is that it carries an elevated burden of proof. Rather than a mere preponderance of the evidence, the plaintiff must establish by “clear and convincing evidence” that the defendant was guilty of recklessness, fraud, or malice in perpetrating physical, financial, or fiduciary abuse or neglect.20 Prior to this case, no physician had ever been accused of elder abuse, and the claim that failure of a health care professional to provide effective pain management might constitute a violation of the statute was an even further stretch. From all appearances, the trial of the case 781

proceeded as would a typical medical malpractice claim. The plaintiffs offered the testimony of two physician expert witnesses, both of whom testified that there were serious problems with the type, dose, and schedule of administration of analgesia to Mr. Bergman while a patient at Eden Medical Center. In rebuttal, Dr. Chin called two physician expert witnesses who testified that in their opinion, the measures he employed in an effort to manage Mr. Bergman’s pain did not constitute a material departure from the custom and practice of similar physicians caring for patients like Mr. Bergman.21 During the course of the trial, despite Dr. Chin’s contention that there was no conclusive evidence that Mr. Bergman had lung cancer, the judge allowed the plaintiffs to introduce into evidence the Agency for Health Care Policy and Research Clinical Practice Guideline Managing Cancer Pain. That evidence tended to bolster the testimony of the plaintiff’s experts that Dr. Chin’s pain management strategy was deficient in significant ways. The guideline provides, for example: • Treatment of persistent or moderate to severe pain should be based on increasing the opioid potency or dose. • Medications for persistent cancer-related pain should be administered on an around-the-clock basis with additional “as needed” doses, because regularly scheduled dosing maintains a constant level of drug in the body and helps prevent recurrence of the pain. • Meperidine (Demerol) should not be used if continued opioid use is anticipated.22 Dr. Chin testified that he had no familiarity with these or with the Medical Board of California’s 1994 guidelines and policy on pain management. He also stated that he did not take the nurses’ notes on Mr. Bergman’s pain levels into account because he did not have any confidence in that form of pain assessment. The nurses involved in the care of Mr. Bergman testified on behalf of Dr. Chin that whenever Mr. Bergman reported pain in the moderate to severe range, they administered another 25-mg dose of Demerol consistent with the standing order. Interestingly, however, they testified that the reason the medical record did not reflect what they insisted to have been consistent achievement of pain relief in response to these administrations 782

was that at Eden Medical Center, pain was charted “by exception.” In other words, pain was only noted when it was outside of normal limits. Such an approach begs the question of what constitutes an authoritative source for the “normal limits” of pain for any particular patient. This charting anomaly worked against the defendant because the medical record was replete with pain levels in the moderate to severe range each day but not in the mild to nonexistent range that would have supported their claim that the opioids administered to Mr. Bergman during his hospitalization were sufficient to meet his needs. Ultimately, the jury reached a verdict in favor of the plaintiffs and awarded $1.5 million in damages. They came within one vote of awarding an additional amount in punitive damages. The trial judge reduced the award to $250,000 on the theory that the statutory cap on monetary damage awards for medical malpractice claims applied even though this claim was filed pursuant to the elder abuse statute. The judge awarded nearly $1 million in attorney fees and litigation costs to the plaintiffs as well. Outstanding posttrial issues were resolved by confidential agreement between the parties; hence, no appeal was taken by either side. News of the verdict in the Bergman v Chin case shook the medical community. The stark contrast between the reaction of the Medical Board of California to the allegations in the case and that of the lay jury seemed to support an observation by the physician Eric Cassell nearly 20 years earlier: “The relief of suffering, it would appear, is considered one of the primary ends of medicine by patients and lay persons, but not by the medical profession.”23 Because the verdict came in the context of an elder abuse claim against Dr. Chin, it seemed particularly punitive in nature and raised the issue of how to most appropriately and effectively “rehabilitate” physicians whose knowledge, skills, and/or attitudes were not conducive to the effective assessment and management of pain. We will revisit this issue after the discussion of the Tomlinson case that follows.

TOMLINSON V BAYBERRY CARE CENTER, ET AL. We have previously discussed the Tomlinson case in the context of the elder abuse claims filed against both the acute and long-term care facilities in which the patient received care in the last month of his life as well as the 783

physicians who were responsible for that care in both clinical settings. The claims in that case bore a striking resemblance to the claims in the Bergman v Chin case.24 Perhaps, because of the jury verdict in the prior case, as noted, all of the defendants in Tomlinson settled prior to trial. Interestingly, as alluded to previously, the Medical Board of California took a much different position in dealing with the complaint by the Tomlinson family against Dr. Eugene Whitney, who was the responsible physician when Mr. Tomlinson was in the SNF (Bayberry Care Center) than it did with regard to the complaint filed by the Bergman family against Dr. Chin. The Medical Board of California sanctioned Dr. Whitney for his failure “to understand the unique properties of Roxanol solution and MS Contin tablets and to prescribe the medications properly” pursuant to a stipulated disciplinary order he entered into with the board. He was required to undergo an extensive evaluation of his professional knowledge and skills and work with the board in developing a detailed remediation plan.25 Also, the California Department of Health Services issued a notice of deficiency against Bayberry Care Center based on the many problems with the care Mr. Tomlinson received at that facility.26 Just as one can speculate that the defendants in the elder abuse claims by the Tomlinson family were motivated to settle prior to trial because of the earlier jury verdict against Dr. Chin, it is also tempting to suggest that the decision of the Medical Board of California to take disciplinary action against Dr. Whitney in response to the complaint filed against him by the Tomlinson family was influenced by the highly negative public response to the board’s refusal to take similar action against Dr. Chin, particularly when a lay jury deemed the same conduct not just malpractice but elder abuse and the California legislature was motivated to pass a law mandating CME in pain management for California physicians. It is certainly possible that one influenced the other, but there is no way to authoritatively establish that proposition. More contemporaneously, some patients who have developed addiction to prescription opioids have initiated legal actions against their physicians. In a recent West Virginia Supreme Court ruling, a number of patients sued several physicians and a clinic alleging negligence in the prescribing of opioid analgesics. What is remarkable about the cases consolidated for 784

review of questions submitted by the trial court was that the plaintiffs admitted not only that they had abused controlled substances before they sought treatment from the defendant physicians but also that they had engaged in criminal conduct involving opioids such as obtaining them through fraud. The West Virginia Supreme Court ruled that the plaintiffs criminal misconduct would not, under its interpretation of state law, act as a complete bar to their claims of negligence against the defendants.27 Dissenting opinions in the case noted that in many other jurisdictions such wrongful conduct by a plaintiff would preclude the action from going forward. One of the physician defendants in this case was Kathrine Hoover, whose ultimate legal victory over the Florida medical board was discussed earlier. She was alleged to be the number one prescriber of opioids in the state. The clinic where she practiced was raided by law enforcement, but she was never criminally charged.

Criminal Litigation Criminal prosecutions of health care professionals for acts or omissions resulting in death or grave harm to patients are exceedingly rare.28 By far, the most common means of imposing sanctions on health professionals for negligent or even reckless patient care are those we have already considered—disciplinary action by state licensing boards or professional liability (malpractice) claims. The exceptional case that prompts a criminal prosecution is almost invariably one involving the death of the patient and conduct by the professional that is considered egregious in nature or in the extent to which it departs from a consensus view of what constitutes the parameters of responsible professional conduct. Because our focus is necessarily on pain management and palliative care, we will consider several instances in which physicians have been prosecuted in either state or federal court. Some of the more high-profile state prosecutions have involved the care of dying patients, whereas those in federal court have been pursuant to the Controlled Substances Act (CSA) and involved prescribing opioids for chronic noncancer pain patients. We begin with a highly instructive state prosecution. 785

STATE V NARAMORE In 1994, the attorney general of Kansas filed a two-count criminal complaint against L. Stanley Naramore, D.O. Both counts related to his care of patients almost 2 years before who were facing terminal conditions. Early in 1996, a jury returned guilty verdicts related to each count and the court sentenced Dr. Naramore to concurrent terms of 5 to 20 years. We will focus on the case that gave rise to the first count and on the subsequent reversal of both convictions by the Kansas Court of Appeals. The patient, Ruth Leach, was a 78-year-old woman suffering from advanced breast cancer that had metastasized to her bones, lungs, and brain. She had been hospitalized and her condition deteriorating. The fentanyl patches no longer controlled her pain, and she was restless and agitated. A nurse suggested to the family that Dr. Naramore be called and asked to prescribe stronger pain medication. Upon arriving at the hospital, he examined Ruth Leach and spoke with her two adult children. Together, they reached a decision to increase her pain medication. Dr. Naramore explained that there was a risk of depressed respiration. He then administered 4 mg of midazolam (Versed) and 100 micromilligrams of fentanyl. Thereafter, the nursing notes indicate that the patient’s respiration slowed and grew irregular. From this point on, the accounts of what transpired take on a curious, disjointed quality. To the extent they are accurate, it is not difficult to understand why there was a failure to maintain a consensus among the family and caregivers concerning the goals of care and how each subsequent action would be consistent with the reasonable pursuit of those goals. The patient’s son, who had training as an emergency medical technician, is reported to have asked Dr. Naramore if his mother was dying, and Naramore was said to have observed that she was but that the effects of the fentanyl could be reversed by the administration of Narcan. This statement suggested to the patient’s son and the nurse on duty that an overdose of pain medication must have been given. Thereafter, when Dr. Naramore began to prepare for continuing IV infusion of analgesics, the son insisted that he not administer any more and was quoted as saying, “I’d rather have my mother lay there and suffer for 10 more days than you do anything to 786

speed up her death.” In an effort to dissuade the son, Dr. Naramore told him that “it just gets terrible from here on out . . . the next few days are going to be absolutely terrible.”29 When the son remained intransigent and assured Dr. Naramore that he would hold the doctor accountable for anything that happened, Dr. Naramore withdrew from the case. The next day, Ruth Leach was transported to another hospital, where she was given morphine for her pain and died 3 days later of her underlying terminal illness.29 The patient’s family became convinced, and they in turn persuaded the Kansas Attorney General that Dr. Naramore had intended to hasten her death through administration of excessive doses of analgesics. Dr. Naramore was charged with attempted first-degree murder. He was also charged with second-degree murder of another patient from about the same time period, Chris Willt. In order to convict a defendant of attempted first-degree murder, the jury must find that the prosecution has proven beyond a reasonable doubt that the defendant (1) performed an overt act toward the commission of the crime, (2) did so with the intent to commit the crime of first-degree murder, and (3) failed to complete the commission of that crime. The elements of murder in the first degree include intent to kill a person, the intentional performance of an overt act toward that end that is both deliberate and premeditated. The prosecution presented several medical experts. The director of Emergency Medicine at the University of Kansas Medical Center testified that in his opinion, Ruth Leach was near death after the administration of Versed and fentanyl and that she would have died if the morphine Dr. Naramore had ordered had in fact been administered. This view was similarly expressed by a specialist in anesthesiology and critical care medicine at the University of Vermont College of Medicine who had previously practiced in Kansas. He testified that a dose of Versed combined with that of the fentanyl were excessive and in short order would have caused the patient to stop breathing. An additional respiratory depressant such as morphine would simply have added to the certainty of her death. In his defense, Dr. Naramore called several expert witnesses. One, a 787

physician who had cared for Ruth Leach for 5 years prior to her death, noted that she had received a variety of medications for her pain, none of which had brought it under control. He found it to be “phenomenal” that anyone would accuse Dr. Naramore of trying to kill her under these circumstances. A family physician from another small Kansas community said that if Dr. Naramore had actually intended to kill Ruth Leach, he would have used 10 times the dosage administered. He characterized the care provided as “concerned and compassionate.” Another witness for Dr. Naramore, the president of the Kansas Association of Osteopathic Medicine and a family medicine practitioner, characterized Dr. Naramore’s efforts to control Ruth Leach’s pain and distress as exemplary. Finally, another family physician who served on the peer-review committee for Blue Cross/Blue Shield of Kansas testified that given her significant history of opioid analgesia and the extent of her distress at the time, the dosages of Versed and fentanyl were reasonable and in no sense an overdose. The convictions of Dr. Naramore for the attempted murder of Ruth Leach and for the second-degree murder of the other patient were reviewed and reversed by the Kansas Court of Appeals. In its opinion, the Court of Appeals made numerous references not only to the expert witness testimony on his behalf at trial but also to amicus curiae (friend of the court) briefs filed on behalf of Dr. Naramore by the Kansas Association of Osteopathic Medicine, the American Osteopathic Association, and the Kansas Medical Society. The court also noted that it had done its own substantial research on the subject of palliative care. Moreover, its review of the case law revealed “no criminal conviction of a physician for the attempted murder or murder of a patient which has ever been sustained on appeal based upon evidence of the kind presented here.”29 In articulating the rationale for its decision that the criminal convictions must be reversed, the Court of Appeals declared, We have made a thorough review of the record [of the trial court proceedings], which contains a wealth of undisputed evidence and expert medical testimony. We find that no rational jury could find criminal intent and guilt beyond a reasonable doubt based on the record here. When the issue is whether there is reasonable doubt, a 788

jury is not free to disbelieve undisputed facts. What occurred here is generally known. The jury was not free to disbelieve that there was substantial competent medical opinion in support of the proposition that Dr. Naramore’s actions were not only noncriminal, but were medically appropriate. . . . When there is such strong evidence supporting a reasonable, noncriminal explanation for the doctor’s actions, it cannot be said that there is no reasonable doubt of criminal guilt . . . All three amicus briefs . . . note that if criminal responsibility can be assessed based solely on opinions of a portion of the medical community which are strongly challenged by an opposing and authoritative medical consensus, we have criminalized malpractice, and even the possibility of malpractice. The instant case is a very good example of this.29 The quoted language of the court mentioned and subsequent statements in the court’s decision regarding the absence of any jury instructions “relating to the medical and moral responsibilities of care givers for the critically or terminally ill patient” are of considerable consequence because of their implications for a wide range of criminal prosecutions of physicians for care provided in an effort to manage the pain and adverse symptoms associated with terminal or serious chronic conditions. Although physician fears persist concerning the risk of potential criminal prosecution for actions taken to relieve the distress of dying patients, such prosecutions are quite rare.30 Despite his ultimate vindication in these proceedings, Dr. Naramore’s legal travails did not end. After relocating to Ohio, in late 2009, he plead guilty to conspiracy to distribute methadone to over 100 patients whom he acknowledged were likely distributing the pills, thereby promoting drug trafficking. He was sentenced to 48 months in prison.31 Several more recent cases reflect the mixed results of state criminal prosecutions of physicians for based on their prescribing of controlled substances. In October of 2015, southern California physician Hsiu-Ying “Lisa” Tseng was convicted of second-degree murder after three of her patients died as a result of drug overdoses. According to the prosecutor, this is the first time a physician has been convicted of murder for 789

prescribing practices leading to overdose death. Dr. Tseng’s defense was that at worst her conduct amounted to negligence, not criminal homicide. The prosecutor and the jury disagreed.32 In February of 2016, Dr. Tseng was sentenced to 30 years to life in prison. In issuing the sentence, the trial judge criticized Dr. Tseng for blaming the patients, pharmacists, and even other physicians rather than accepting any responsibility. The prosecution had argued to the jury that despite having been notified by medical examiners or law enforcement of the death of a patient, Dr. Tseng did not change her prescribing practices.33 At about the same time, Florida physician Gerald Klein was acquitted of first-degree murder and other serious drug charges by a Palm Beach County jury. Although one of his patients died of a drug overdose, the jury did not find sufficient evidence to hold the prescribing physician responsible for it. Only one charge, “sale of alprazolam,” resulted in a conviction. Interestingly, the patient in that transaction was at the time a chef for billionaire Donald Trump.34 Before concluding this discussion of civil and criminal cases against physicians at the local and state level, we should also note the multiplicity of ongoing litigation against major pharmaceutical companies concerning their marketing of prescription pain medications. The most frequent target of these cases is Purdue Pharma LP and its aggressive marketing of oxycodone HCl (OxyContin). In late December of 2015, the company settled a case filed by the State of Kentucky in 2007 charging it with misleading marketing of the drug to induce physicians and patients to discount its potential to lead to addiction. According to the terms of the settlement, Purdue Pharma will pay $24 million over a period of 8 years.35 In July of 2016, Pfizer entered into an agreement with the City of Chicago to adhere to a written code of conduct for marketing opioids. The code calls for disclosure that opioid analgesics may pose a serious risk of addiction in some patients even when used properly as well as an assurance that it will not promote opioids for “off-label” uses. The City of Chicago filed a lawsuit against Pfizer, Purdue Pharma, and several other pharmaceutical companies alleging misleading marketing of this type of medication.36

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Federal Criminal Prosecutions Recent federal criminal prosecutions of physicians pursuant to the federal CSA for prescribing practices in the care of chronic noncancer pain patients are not entirely aberrational. They follow in the history and tradition of earlier cases, and the appellate courts reviewing these cases cite the earlier decisions profusely as correctly interpreting and applying the intent of the Congress when enacting the CSA. It therefore behooves us to review key elements of one such precedent-setting case before taking up the contemporary examples.

UNITED STATES V ROSEN (1978) Although Dr. Isadore Rosen was prosecuted under the CSA for prescribing controlled substances to patients for weight loss as part of an “obesity practice,” and not for pain management, the language of the appellate court decision and its analysis of the CSA are often cited in later cases involving the prescribing of controlled substances for pain. Also, the prosecution of Dr. Rosen was based in large measure on the testimony of undercover law enforcement agents who came to him posing as patients seeking to lose weight. The use of such tactics generally gives rise to a claim of “entrapment” by the defendant; that is, that the government agents induced him to engage in one or more unlawful acts that he was not otherwise contemplating and in which he never would have engaged but for their inducement. As often happens, the court in United States v Rosen easily disposed of this defense by noting, “When a person is shown to be ready and willing to violate the law, the providing of an opportunity therefore by undercover agents or police officers is not entrapment.”37 In order to convict Dr. Rosen of the 25 counts of distributing controlled substances in violation of the CSA with which he was charged, the government had to prove the following three elements of the offense beyond a reasonable doubt: 1. That he distributed or dispensed a controlled substance 2. That he acted knowingly and intentionally 3. That he did so other than for a legitimate medical purpose and in the usual course of his professional practice Dr. Rosen conceded the first two elements but asserted as to the third 791

that each of the agents who came to him posing as patients presented symptoms for which the drugs he prescribed or dispensed were medically appropriate. It is important to note that although the prescribing of certain types of medications for the purpose of weight reduction is subject to some controversy, for purposes of this decision, the court noted that all of the drugs prescribed by Dr. Rosen have legitimate therapeutic uses. The crux of Dr. Rosen’s argument on appeal of his criminal conviction was that the trial court relied on what it considered to be evidence of substandard medical practice as a basis for finding criminal intent. This point is critical as it will arise in the discussion of more recent prosecutions under the CSA. If the third element listed earlier is deemed to have been established beyond a reasonable doubt by the evidence, then the courts treat the physician not simply as a negligent, or even in some instances a reckless physician, but simply as a drug dealer. The court in United States v Rosen reviewed a number of earlier convictions under the CSA and identified the following list of “red flags” suggesting that a physician may be acting illegitimately or outside the course of professional practice. 1. An inordinately large quantity of controlled substances was prescribed. 2. Large numbers of prescriptions were issued. 3. No physical exam was given. 4. The physician warned the patient to fill the prescriptions at different pharmacies. 5. The physician issued prescriptions to a patient known to be delivering the drugs to others. 6. The physician prescribed controlled substances at intervals inconsistent with legitimate medical treatment. 7. The physician used street slang rather than medical terminology for the drugs prescribed. 8. There was no logical relationship between the drugs prescribed and treatment of the condition allegedly existing. 9. The physician wrote more than one prescription on occasions in order to spread them out.37 The routine followed by Dr. Rosen’s weight loss “clinic” included many 792

of these red flag elements according to the testimony of the government agents who posed as patients seeking to lose weight. In particular, Dr. Rosen did not take a medical history or perform a physical exam other than to have the patients weighed and their blood pressure taken on the first visit by a staff member who was not a nurse. He provided no instructions on how to take the medications or warnings of risks or side effects to be concerned about, nor did he schedule follow-up appointments. Based on this and other evidence at trial, the court of appeals ruled that the government had met its burden of proof that Dr. Rosen’s prescribing or dispensing of controlled substances to the undercover agents was not in good faith for legitimate medical purposes in the course of his professional practice.

UNITED STATES V HURWITZ Dr. William Hurwitz was a medical doctor who operated a pain medicine practice in McLean, Virginia. So widespread was his reputation as a liberal prescriber of opioids that many of his patients came from great distances— 39 states—seeking medications from him that other physicians would not prescribe. In 1992, he was reprimanded by the District of Columbia medical board because of his “liberal” prescribing practices, and in 1996, the Virginia board revoked his license and subsequently reinstated it with ongoing monitoring of his prescribing practices. Ostensibly, that monitoring was still taking place when, in 2004, a federal grand jury indicted him on 62 counts, including drug trafficking resulting in death and serious bodily injuries, health care fraud, and criminal forfeiture. He was subsequently convicted on 50 of those counts and sentenced to 25 years in prison.38 Throughout the criminal process, Dr. Hurwitz was portrayed by the federal prosecutor and officials of the U.S. Drug Enforcement Administration (DEA) as “no different from a cocaine or heroin dealer peddling poison on the street corner.”39 At the trial, however, several nationally prominent experts in pain medicine testified on behalf of Dr. Hurwitz. During the trial, immediately following the testimony of the government’s chief expert witness, six former presidents of the American Pain Society (APS) took the unprecedented step of sending a letter to the trial judge expressing their deep concerns about “serious 793

misrepresentations” that had been made by the government’s expert, who was also a past president of the APS. When Dr. Hurwitz appealed his convictions to the Fourth Circuit Federal Court of Appeals, the American Academy of Pain Medicine, the American Pain Foundation, and a group of nationally prominent experts in pain management, among others, filed amicus curiae (friend of the court) briefs in support of his appeal. These briefs asserted, among other points, that “seriously erroneous rules of law and scientific theories [were] relied upon to convict [Dr. Hurwitz].”40 It is important to understand the significance one can reasonably attach to the willingness of these prominent organizations and individual members of the pain medicine community to go on record in this case. The government’s position was that Dr. Hurwitz’s prescribing of controlled substances had absolutely nothing to do with pain management. It was drug trafficking, pure and simple. The persons to whom he dispensed or prescribed these drugs were not patients but rather drug seekers who sought either to feed their addiction or further disseminate them in the illicit market for prescription drugs. The thrust of the argument on the other side was not that Dr. Hurwitz was practicing exemplary medicine, or in some instances, even prescribing within the minimal standard of acceptable care for chronic pain patients but rather that however far out of the mainstream his prescribing practices were, he was nevertheless a physician and not a drug dealer. The appropriate societal sanctions for physicians who practice negligently are medical malpractice liability claims or disciplinary action by licensing boards. In egregious circumstances, appropriate sanctions might include the permanent revocation of licensure. Nevertheless, physicians who practice substandard medicine are nonetheless physicians, and their patients remain patients in need of medical care, even if in some instances, the care they require is for addiction. The Fourth Circuit Court of Appeals reversed the Hurwitz conviction and remanded the case to the District Court for a new trial. In doing so, it sought to make clear where the trial judge had erred and how the retrial should be conducted to provide Dr. Hurwitz with a fair trial. At the end of the new trial, he was convicted of 16 counts of drug trafficking and 794

sentenced to 57 months in prison.

UNITED STATES V MCIVER Dr. Ronald McIver had approximately 1,000 patients in his South Carolina practice, most of whom saw him because of problems with chronic noncancer pain. In response to reports from the Columbia, South Carolina, police department about Dr. McIver’s prescribing practices, the DEA initiated an investigation of his practice in 2002. Based on investigatory findings that among McIver’s patients, there were those who regularly received prescriptions for what were characterized as “massive quantities” of oxycodone, hydromorphone hydrochloride (Dilaudid), OxyContin, methadone, and morphine; he was indicted on 15 counts of drug trafficking related to his treatment of 10 patients, 9 of whom testified for the government at his trial. The remaining patient was deceased, the cause of death having been characterized as an “oxycodone overdose.”41 The major thrust of the prosecution’s case at trial was based on the expert testimony of a Dr. Steven Storick, an anesthesiologist who the court deemed to be duly qualified as an expert in pain management. After reviewing the medical records of the patients in question, he concluded that Dr. McIver’s treatment of several of them fell outside the parameters of legitimate medical practice. For example, in the case of a patient with a history of substance abuse, Dr. Storick asserted that prescribing opioids to such a patient was “like pouring gasoline on a fire.” A Medicaid patient who sought treatment from Dr. McIver for fibromyalgia traveled almost 3 hours to see him, paid for his services in cash, and filled prescriptions for methadone, OxyContin, oxycodone, and morphine costing thousands of dollars. The patient testified that she sold the methadone and morphine and was addicted to oxycodone. With regard to her treatment, Dr. Storick testified that Dr. McIver’s conduct was “way outside the course of legitimate medical treatment.”41 The jury convicted Dr. McIver of multiple counts of unlawful distribution of a controlled substance and one that resulted in death. He was sentenced to 30 years in prison. On appeal to the Fourth Circuit Court of Appeals, the same court that granted Dr. Hurwitz a new trial, Dr. McIver’s counsel attacked Dr. Storick’s testimony as reflective of a hostile 795

and suspicious approach to the care of chronic noncancer pain patients in that he insisted on objective signs of tissue damage before prescribing opioids, and he refused to acknowledge that physicians could be deceived by some patients’ reports of pain and yet still be legitimately prescribing opioids for them based on a reasonable belief that they had significant pain. The appeal also challenged the jury instructions, which Dr. McIver claimed suggested to the jury that he could be convicted if he “deviated drastically from accepted medical practice.” The Court of Appeals, in affirming the conviction, disagreed, noting that the jury was instructed that the prosecution must prove not only that the defendant acted “outside the course of professional practice” but also that he acted “for other than a legitimate medical purpose.”42 Federal criminal prosecutions of physicians concerning pain management do not always result in convictions. As part of the initiative to aggressively pursue “pill mill” operations in the state of Florida, a federal prosecutor indicted Debra Roggow, MD, who was board-certified in physical medicine and rehabilitation, on 10 counts of drug trafficking based on allegations that she was inappropriately prescribing opioids to some of her patients.43 However, based on significant part on her meticulous patient records carefully documenting the justification for the prescribing of opioids in the case of each patient, the jury acquitted her of all charges.44 Before concluding the discussion of these federal prosecutions of physicians who were at the far liberal end of the prescribing continuum, it may be helpful to delineate the parameters of that entire continuum, and perhaps even to suggest where, as a matter of law and public policy, the line should be drawn between “the bounds of medicine” and the realm of drug dealing and trafficking by health care professionals. The thrust of the argument goes something like this: Just as we do not criminally prosecute clinicians whose failure or refusal to provide pain relief subjects some of their patients to physical and mental anguish, neither ought we to criminally prosecute clinicians whose excessive prescribing creates or exacerbates some of their patients’ addiction disorders or propensity to engage in drug dealing under the guise of being a pain patient. In the most 796

egregious instances at both ends of the continuum, the appropriate public policy stance is to suspend or permanently revoke their professional licensure. Currently, however, at least clinicians at the far liberal end of the prescribing continuum, such as Hurwitz and McIver, prosecutors, and judges (through approved jury instructions) invite juries to act as though no real physician–patient relationship existed. As suggested by the Kansas Court of Appeals in the Naramore case, whenever the criminally charged clinician is able to present expert testimony that what he or she did was within the “bounds of medicine,” the mere fact that the prosecution can offer expert testimony maintaining that it was not should never be sufficient for a conviction. Such a conflict of testimony should necessarily create the reasonable doubt that precludes a jury verdict against a criminal defendant.

Constitutional Cases Several decisions by the Supreme Court of the United States in the last two decades have addressed issues related to the treatment of pain. Each case also involved highly controversial ethical and political issues: physicianassisted suicide and medical marijuana. As is typical of the Supreme Court, the rulings in each case were not an effort to decide which side was correct on the ethics or the politics but rather to determine what was consistent with the Constitution and a reasonable interpretation and application of federal statutes. The first of these, the companion cases of Washington v Glucksberg45 and Vacco v Quill46 decided in 1997 directly involved the question of whether there was a constitutional right on the part of dying patients to be able to acquire lethal doses of medication from willing physicians for purposes of hastening their death. In the process of unanimously ruling that there was no such constitutional right, five of the nine justices joined in two concurring opinions that have been interpreted as a recognition by a majority of the court of a constitutional right on the part of terminal patients to receive palliative care.46 The language from these companion cases most consistently cited for this proposition include the following 797

passage from the concurring opinion by Justice O’Connor: The parties and amici agree that in these states [Washington and New York] a patient who is suffering from a terminal illness and who is experiencing great pain has no legal barriers to obtaining medication from qualified physicians, to alleviate that suffering, even to the point of causing unconsciousness and hastening death. Combined with language from a separate opinion by Justice Breyer: Were the legal circumstances different [than in Washington and New York]—for example were state law to prevent the provision of palliative care, including the provision of drugs as needed to avoid pain at the end of life—then the law’s impact upon serious and otherwise unavoidable physical pain (accompanying death) would be more directly at issue. And as Justice O’Connor suggests, the Court might have to revisit its conclusions in these cases.46 The focus on pain and suffering at the end of life by the concurring justices may simply be a consequence of the fact that a right to lethal medication was asserted by the plaintiffs in these cases only as to patients with terminal illness. However, a right to appropriately aggressive palliative care as opposed to a lethal prescription, especially if defined quite broadly as the relief of pain and suffering, might be of even greater significance for a patient with severe chronic noncancer pain than for a terminally ill patient because it could persist for years or decades rather than merely weeks or months. Only future cases will illuminate whether there might be constitutional protection from unreasonable governmental barriers to pain relief for such patients. The constitutionality of the Oregon Death with Dignity Act (ODWDA), pursuant to which the state of Oregon legalized and regulated physicianassisted suicide (referred to by its proponents as physician aid in dying) was not directly at issue in either Washington v Glucksberg or Vacco v Quill. However, those decisions by implication upheld the ODWDA because they determined that there is neither a constitutional right to nor a constitutional prohibition of such a practice. Consequently, it is a matter for each individual state to determine as part of its authority to regulate the practice of health care professionals.47 798

In 2001, Attorney General John Ashcroft issued an interpretive rule (IR) of the federal CSA, maintaining that prescribing a controlled substance for the purpose of assisting a patient in ending his or her life, even pursuant to a state statutory scheme such as the ODWDA, contravened the CSA and rendered the prescriber vulnerable to federal prosecution. Because all lethal prescriptions written pursuant to the ODWDA were federally controlled substances, the Ashcroft IR would essentially nullify the Oregon law. The State of Oregon immediately challenged the IR in federal court and obtained first a temporary restraining order and subsequently an injunction prohibiting enforcement of the IR pending resolution by the courts. When Ashcroft resigned as attorney general, his successor Alberto Gonzales decided to continue the legislation. By then, review of adverse rulings by the federal district and Ninth Circuit Court of Appeals had been sought and the case was pending before the US Supreme Court. The central issue decided by the Supreme Court in Gonzales v Oregon was “who decides whether a particular activity is ‘in the course of medical practice’ or done for a ‘legitimate medical purpose.’”48 The attorney general claimed authority under the CSA to define standards of medical practice at least insofar as the prescribing of scheduled drugs. Taking into consideration the legislative history of the CSA, the Supreme Court majority ruled that the intent of Congress was to combat a national problem of recreational drug abuse by ensuring that scheduled narcotics were secured within the health care setting through the prescribing by licensed practitioners for legitimate medical purposes. Nothing in the language or the legislative history of the CSA suggests that Congress intended to confer on the attorney general, in his capacity of law enforcement, to usurp the usual authority of the individual states in regulating the practice of medicine, which includes the writing of prescriptions. For this and other reasons discussed at length by the Court, the IR was held to exceed the authority of the attorney general under the CSA. The legalization of physician aid in dying has gained a great deal of momentum in the past decade. Following the lead of Oregon, the state of Washington passed a similar law through the referendum process. The Vermont and California legislatures have more recently enacted aid-in799

dying legislation. In Montana, the state Supreme Court ruled that current law did not preclude physicians from providing such assistance to terminally ill patients with decisional capacity who requested it.49 The issue is also currently before the New Mexico Supreme Court. In 2015, the Canadian Supreme Court ruled that sections of the criminal code violated the national Charter of Rights to the extent that they prohibited physician-assisted death for a competent adult who (1) clearly consents to the termination of life and (2) has a grievous and irremediable medical condition (including an illness, disease, or disability) that causes enduring suffering that is intolerable to the individual in the circumstances of his or her condition.50 The decision was stayed in order to provide the government with time to enact legislation consistent with the ruling. In June of 2016, the Canadian House of Commons and Senate passed an aid in dying law.51 However, because it limited the access to patients whose natural deaths were reasonably foreseeable, it is currently being challenged in court.52 The issue of the legitimate medical use of marijuana reached the Supreme Court in the case of Gonzales v Raich. The plaintiffs in this case, Angel Raich and Diane Monson, were California residents suffering from a variety of serious medical conditions. Raich carries at least 10 diagnoses, including an inoperable brain tumor, seizure disorder, and several chronic pain syndromes. Monson suffered from severe chronic back pain and muscle spasms related to a degenerative disease of the spine. California was one of a growing number of states that enacted legislation insulating seriously ill patients or their physicians from prosecution under state law for cultivating or possessing cannabis for use by the patient pursuant to the physician’s written recommendation or approval. The plaintiffs in this case argued that they were being treated by board-certified family practitioners who had determined after prescribing a wide variety of standard medications that marijuana is the only drug available that provides effective relief of their symptoms. As a Schedule I drug, the CSA recognizes no legitimate basis for patients such as Raich and Monson to possess or use marijuana, even though their physicians authorized it pursuant to the California statute. The plaintiffs filed suit against Attorney General Ashcroft and the administrator of the DEA in 800

federal district court seeking declaratory and injunctive relief preventing the federal government from prosecuting them under the CSA. The crux of their argument was that enforcement of the CSA against them required that interstate commerce be implicated in their acquisition and use of medical marijuana. The district court ruled against the plaintiffs, finding that the Commerce Clause of the Constitution applied to them despite the fact that the marijuana they used was grown in California. The Ninth Circuit Court of Appeals reversed the district court, holding that the plaintiffs’ intrastate, noncommercial cultivation, possession, and use of marijuana for personal medical purposes on the advice of a physician does not constitute drug trafficking. Much of the court’s discussion involved arcane legal principles and Supreme Court precedents. Ultimately, it was these very principles and precedents that provided the basis for the Supreme Court’s reversal of the Ninth Circuit. Simply stated, the Court held that “Congress’ power to regulate interstate markets for medicinal substances encompasses the portions of those markets that are supplied with drugs produced and consumed locally. . . . The CSA is a valid exercise of federal power, even as applied to the troubling facts of this case.”53 Thus, the Court’s ruling in Gonzales v Raich cannot be understood as a pronouncement on the clinical question of whether the known risks and purported benefits of medical marijuana use ever justify a physician recommending it to patients when standard therapies are found to be inadequate. Since this decision, not only have additional states permitted the use of “medical marijuana” but also some have legalized recreational marijuana and other states have this change on the ballot in November of 2016. Nevertheless, the DEA in August of 2016 reaffirmed its position that marijuana has no legitimate medical purpose and will remain a Schedule I drug that is illegal for any purpose.54

Lessons from the Litigation Generalizations that meet minimal criteria of accuracy and practicality concerning the lessons one should learn from the varieties of litigation surveyed in this chapter are both difficult and dangerous. They are difficult 801

because of the wide variation in cases; for example, state and federal courts, some patients who were dying, others facing chronic noncancer pain, still others who were addicted to prescription drugs or simply “planted” as a part of ongoing investigations by law enforcement. They are dangerous when they constitute gross oversimplifications of complex phenomena that have only superficial similarities. Nevertheless, some attempt at synthesis is both necessary and appropriate. • Lesson 1: A new medical ethos has clearly emerged, grounded on the recognition that timely and effective assessment and management of all types of pain is essential to sound patient care. Nationally recognized clinical practice guidelines and organizational policies (such as The Joint Commission) affirm this basic proposition. • Lesson 2. Evidence- or consensus-based guidelines and policies reinforce the proposition that there are recognized standards of care for the management of acute, chronic noncancer, and pain associated with terminal illness. These standards apply to all clinicians who care for patients with pain and not merely pain medicine or palliative care specialists. • Lesson 3. Material departures from these standards render clinicians vulnerable to a variety of adverse legal consequences. Egregiously conservative approaches to opioid analgesia may result in civil liability for undertreatment of pain or professional licensing board sanctions. Excessively liberal approaches to the prescribing of opioids, particularly when a reasonable clinician would have recognized red flags or other warning signs, may result in criminal prosecution at the state or federal level. • Lesson 4. Prudent practitioners should ensure that their knowledge, skills, and attitudes (at least insofar as they affect professional practice) are informed by the current authoritative clinical practice guidelines and policy statements. When that is the case, their approach to pain management will reflect a reasonable balance between effective pain management for their patients and due diligence to ensure that their prescribing practices are neither harming their patients nor contributing to the phenomena of prescription drug abuse and diversion. 802

• Lesson 5. As with any other aspect of patient care, timely, accurate, and thorough documentation in the medical record that reflects not only what was done but also what informed the decision on what to do and what alternatives were considered is absolutely essential. In every legal setting, incomplete, inaccurate, or untimely documentation of professional conduct is problematic, sometimes devastatingly so. • Lesson 6. Clinicians who heed Lessons 1 to 5 earlier are not at any serious risk of adverse legal action arising out of their responsible efforts to relieve the pain of their patients. References 1. Prosser WL, Keeton WP, Dobbs DB, et al. Prosser and Keeton on Torts. 5th ed. St. Paul, MN: West; 1984. 2. Brookoff D. Commentary on state medical boards and pain management. J Pain Symptom Manage 1998;15:381–382. 3. Gilson AM, Joranson DE. Controlled substances and pain management: changes in knowledge and attitudes of state medical regulators. J Pain Symptom Manage 2001;21:227–237. 4. Matter of DiLeo, 661 So2d 162 (1995). 5. Hoover v Agency for Health Care Administration, 676 So2d 1380 (1996). 6. Martino AM. In search of a new ethic for treating patients with chronic pain: what can medical boards do? J Law Med Ethics 1998;26:263, 332–349. 7. Federation of State Medical Boards. Model Guidelines for the Use of Controlled Substances for the Treatment of Pain. Euless, TX: Federation of State Medical Boards; 1998. 8. Hill CS. The negative influence of licensing and disciplinary boards and drug enforcement agencies on pain treatment with opioid analgesics. J Pharm Care Pain Symptom Control 1993;1:43–62. 9. Oregon Board of Medical Examiners. Stipulated Order in the Matter of Paul A. Bilder, M.D. Portland, OR: Oregon Board of Medical Examiners; 1999. 10. Oregon Board of Medical Examiners. Oregon medical board: board action report. Available at: http://www.oregon.gov/omb/BoardActions/October%2016,%202008%20%20November%2015,%202008.pdf. Accessed October 10, 2016. 11. Medical Board of California. In the Matter of the Accusation against Eugene B. Whitney, M.D. Sacramento, CA: Medical Board of California; 2003. 12. Medical Board of California. In the Matter of the Accusation against Eugene B. Whitney, M.D. Decision. Sacramento, CA: Medical Board of California; 2003. 13. Federation of State Medical Boards. Model Policy for the Use of Controlled Substances for the Treatment of Pain. Euless, TX: Federation of State Medical Boards; 2013. 14. Federation of State Medical Boards. Pain management policies, board-by-board overview. Available at: http://www.fsmb.org/globalassets/advocacy/key-issues/pain-management-bystate.pdf. Accessed Apirl 24, 2018. 15. Cushing M. Pain management on trial. Am J Nurs 1992;92:21–23. 16. Estate of Henry James v Hillhaven Corporation, 89 CVS 64 (NC Super Ct 1991) 17. Shapiro RS. Liability issues in the management of pain. J Pain Symptom Manage 1994;9(3):146–52. 18. North Carolina General Assembly General Statute §§10–15(b), 1D-25 (2003).

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19. Rich BA. Moral conundrums in the courtroom: reflections on a decade in the culture of pain. Camb Q Healthc Ethics 2002;11:180–190. 20. California Welfare and Institutions Code, §15610 (2006). 21. Bergman v Chin, No. H205732-1 (Cal Super Ct, Alameda County 1999). 22. Agency for Health Care Policy and Research. Management of Cancer Pain. Washington, DC: U.S. Department of Health and Human Services; 1994. Clinical practice guideline no. 9. 23. Cassell EJ. The nature of suffering and the goals of medicine. N Engl J Med 1982;306:639– 645. 24. Tomlinson v Bayberry Care Center, C 02-00120 (Cal Super Ct, Contra Costa County 2002). 25. Medical Board of California. In the Matter of the Accusation against Eugene B. Whitney, M.D. No. 12 2002 133376. Stipulation for Public Reprimand. Filed January 14, 2004. Sacramento, CA: Medical Board of California; 2004. 26. AHC Media. Pain cases settled: nursing home fined. Available at: https://www.ahcmedia.com/articles/26746-pain-cases-settled-nursing-home-fined. Accessed September 20, 2016. 27. Tugg Valley Pharmacy LLC, et al. v All Plaintiffs Below in Mingo County, 14-0144, WL 3401425 (West Va 2015). 28. Annas GW. Medicine, death and the criminal law. N Engl J Med 1995;333:527–530. 29. State v Naramore, 965 P2d 211 (Kan Ct App 1998), cert denied. 30. Alpers A. Criminal act or palliative care? Prosecutions involving the care of the dying. J Law Med Ethics 1998;26:308–331. 31. Federal Bureau of Investigation, Louisville Division. Cincinnati doctor sentenced for illegal distribution of prescription pills. Available at: https://archives.fbi.gov/archives/louisville/press-releases/2010/lo051410.htm. Accessed September 26, 2016. 32. Gerber M, Girion L, Queally J. California doctor convicted of murder in overdose deaths of patients. Los Angeles Times. October 30, 2015. Available at: http://www.latimes.com/local/lanow/la-me-ln-doctor-prescription-drugs-murder-overdoseverdict-20151030-story.html. Accessed October 3, 2016. 33. Gerber M. Doctor convicted of murder for patients’ drug overdoses gets 30 years to life in prison. Los Angeles Times. February 5, 2016. Available at: http://www.latimes.com/local/lanow/la-me-ln-doctor-murder-overdose-drugs-sentencing20160205-story.html. Accessed October 3, 2016. 34. Freeman M. Jury acquits former pain clinic doctor of murder, convicts him of minor drug charge. SunSentinel. September 16, 2015. Available at: http://www.sunsentinel.com/local/palm-beach/fl-doctor-murder-trial-verdict-watch-20150915-story.html. Accessed October 3, 2016. 35. Associated Press. Kentucky settles lawsuit with OxyContin maker for $24 million. CBS News. December 23, 2015. Available at: http://www.cbsnews.com/news/kentucky-settleslawsuit-with-oxycontin-maker-for-24-million/. Accessed October 3, 2016. 36. Bernstein L. Pfizer agrees to truth in opioid marketing. The Washington Post. July 5, 2016. Available at: https://www.washingtonpost.com/national/health-science/pfizer-agrees-to-truthin-opioid-marketing/2016/07/05/784223cc-42c6-11e6-88d0-6adee48be8bc_story.html. Accessed October 3, 2016. 37. United States v Rosen, 582 F2d 1032, 1033 (1978). 38. United States Attorney’s Office, Eastern District of Virginia. News Release. April 14, 2005. Newport News, VA: United States Attorney’s Office, Eastern District of Virginia; 2005. 39. U.S. Drug Enforcement Administration. DEA administrator Karen Tandy’s remarks on Hurwitz sentencing. Available at: http://www.dea.gov/pubs/pressrel/pr041405b.html.

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40. 41. 42. 43. 44.

45. 46. 47. 48. 49. 50. 51.

52.

53. 54.

Accessed April 14, 2005. United States v Hurwitz, 459 F3d 463 (4th Cir 2006). United States v McIver, 470 F3d 550 (4th Cir 2006). McIver, DO v United States of America, Petition for a Writ of Certiorari to the Supreme Court of the United States (2007). United States v Debra Roggow. 2:11-CR-114-FTM-29SPC (MD Fla, Fort Myers 2012). Bolen J. Board-certified doctor cleared of criminal charges for high-dose opioid prescribing. Available at: http://www.practicalpainmanagement.com/resources/ethics/board-certifieddoctor-cleared-criminal-charges-high-dose-opioid-prescribing. Accessed September 26, 2016. Washington v Glucksberg, 521 US 702 (1997). Vacco v Quill, 521 US 793 (1997). Burt Robert A. The Supreme Court speaks—not assisted suicide but a constitutional right to palliative care. N Engl J Med 1997;337:1234–1236. Gonzales v Oregon, 546 US 243 (2006). Baxter v Montana, 224 P3d 1211 (2009). Carter v Canada, 1 SCR 331 (2015). House of Commons of Canada. Bill C-14. Available at: http://www.parl.gc.ca/HousePublications/Publication.aspx? Language=E&Mode=1&DocId=8309978. Accessed October 8, 2016. Julia Lamb and British Columbia Civil Liberties Association v Attorney General of Canada, Supreme Court of British Columbia. June 27, 2016. Available at: https://bccla.org/wpcontent/uploads/2016/06/2016-06-27-Notice-of-Civil-Claim-1.pdf. Accessed October 8, 2016. Gonzales v Raich, 545 US 1 (2005). Downs D. The science behind the DEA’s long war against marijuana. Scientific American. April 19, 2016. Available at: http://www.scientificamerican.com/article/the-science-behindthe-dea-s-long-war-on-marijuana/. Accessed October 3, 2016.

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CHAPTER 16 International Access to Therapeutic Opioids JAMES F. CLEARY, MARTHA A. MAURER, and S. ASRA HUSAIN Over three decades ago, the World Health Organization (WHO) concluded that most pain due to cancer could be relieved if health professionals followed a simple medical treatment method called the three-step analgesic ladder, which recommends using various types of analgesics (including opioid analgesics), in combination with adjuvant drugs when needed, depending on the severity of the patient’s pain.1 This approach also has been recognized by the WHO as appropriate with HIV/AIDS patients experiencing pain throughout the disease.2 United Nations (UN) health and regulatory agencies have repeatedly appealed to governments and health professionals to cooperate in order to implement the WHO analgesic method and remove barriers that block patient access to opioid pain medications.3–12 Although drug regulations and opioid availability have improved in some countries, the vast majority of cancer and HIV/AIDS patients in low- and middle-income countries (LMICs), and many in high-income countries (HICs), still lack access to these essential medications.13,14 The inadequate access to opioids is further illustrated by the disparity in reported medical consumption of opioid medicines between HICs comprising a small proportion of the global population and the large and growing population of LMICs.15 With the shifting burden of cancer to LMICs,16 the public health problem of inadequate availability of pain medications and unrelieved pain is projected to become far worse. The purpose of this chapter is to outline the body of knowledge and experience that is relevant to understanding and improving national opioid availability and patient access to controlled pain medicines. It is critically 806

important for health care professionals and government drug regulators, as well as advocates involved in the area of palliative care and pain relief, to understand the policies that govern the use of opioid medicines and how they can impact medication availability and patient access to opioid medicines. This chapter begins with background about the importance of pain relief in cancer and HIV/AIDS control. Focusing on opioids indicated for the relief of moderate to severe pain (e.g., hydromorphone, fentanyl, morphine, oxycodone), this chapter discusses the designation of these opioid medicines as both essential and controlled by international authorities. The disparities in opioid consumption globally and regionally are detailed, followed by an overview of common barriers preventing the adequate availability and accessibility of opioid medicines. Lastly, the UN’s recommendations to address the barriers to opioid availability are described followed by a summary of recent initiatives to improve the availability and access to opioid medications.

Pain Relief Is Part of Cancer and HIV/AIDS Control The global incidence and prevalence of cancer and HIV/AIDS is a public health problem of great concern. The WHO estimates that in 2012, approximately 14.1 million individuals were newly diagnosed with cancer and more than 8 million died from this noncommunicable disease.17 Experts predict that the cancer burden will increase by 70% in the next two decades, with major impacts on LMICs, where it is estimated that the majority of new cases and deaths from cancer, including children, will occur.17 The global occurrence of HIV/AIDS is also a public health problem of great concern. The Joint United Nations Programme on HIV/AIDS (UNAIDS) indicated that in 2015, 36.7 million people were living with HIV, and 1.1 million people died from HIV/AIDS.18 People with HIV/AIDS19,20 and/or cancer21–25 experience pain and a variety of other symptoms during the course of their disease that have a negative impact on their quality of life. Patients who are approaching the end of life are likely to experience even more severe symptoms,7,8,26,27 which include pain, anxiety, constipation, cough, depression, dyspnea, and nausea.1,7,8 Although it is necessary to address all symptoms, this chapter 807

focuses on the need for adequate pain relief and access to opioid pain medications. In LMICs, most cancers are diagnosed in late stages of the disease,16,28,29 when people often experience severe pain.7,8,26,27

PAIN AND PALLIATIVE CARE Palliative care, including the critically important component of pain management, is a model of care aimed at relieving symptoms of disease and its treatment and improving the patient and family’s quality of life throughout the course of the disease. The WHO has long recognized that relieving pain and other symptoms in cancer1 and HIV/AIDS2,30 is a necessary part of palliative care, including for children.31,32 In 2014, the Worldwide Hospice and Palliative Care Alliance and the WHO collaborated to produce the Global Atlas of Palliative Care at the End of Life, which examines the state of palliative care and hospice programs globally, quantifying the need for and availability of palliative care worldwide.26 They found that over 20 million people require palliative care at the end of life every year, with the highest proportion of adults in need of palliative care (78%) living in LMICs.26 Despite this great need, palliative care is underdeveloped in most of the world, and access to quality palliative care is very rare in LMICs.26 Palliative care and pain relief medicines should be available and accessible to all individuals who have pain and other symptoms.8,26 There is a strong international imperative that palliative care, including pain management, should be included in national cancer and HIV/AIDS control efforts. The WHO has repeatedly reaffirmed the necessity of including palliative care as a critical component of cancer or HIV/AIDS control efforts in a country.33,34 At the country level, national policies should provide a policy framework for developing and expanding health care services to reach patients who need disease treatment as well as relief of pain and other symptoms. Notably, in 2014, the World Health Assembly (WHA), for the first time in its history, adopted a palliative care resolution that urges member states to integrate palliative care into their health care systems, to improve training for health care workers, and to ensure that relevant medicines, including strong pain medicines, are available to patients.11 808

Opioids Are Essential Medicines and Controlled Substances Guidance from the WHO dating back to 1986 acknowledges the need for a varied approach to managing pain, including nonpharmacologic therapies, and that not all types of pain will respond equally, if at all, to opioids.1 Indeed, there are many useful pharmacologic and nonpharmacologic therapies for treating cancer pain.7,27 And yet, opioid medicines, and in particular orally administered morphine, are regarded by international health experts as the first choice for relieving moderate to severe pain due to cancer.35–37 Since 1977, the WHO Expert Committee on the Selection and Use of Essential Medicines has designated morphine as an essential medicine for the treatment of cancer pain.38 According to WHO, essential medicines are those medicines that “ . . . satisfy the priority health care needs of the population . . . are selected with due regard to public health relevance, evidence on efficacy and safety, and comparative costeffectiveness.”39 By giving them this designation, the WHO is asserting that these medicines “ . . . are intended to be available within the context of functioning health systems at all times in adequate amounts, in the appropriate dosage forms, with assured quality and adequate information, and at a price the individual and the community can afford.”39 In 2012, at the request of the WHO, the International Association for Hospice and Palliative Care (IAHPC) led an expert group to develop a summary of the evidence available for essential medicines for palliative care. As a result of these recommendations, the WHO’s 18th Model List of Essential Medicines published in April 2013 contained a new section specific to palliative care, which included both immediate- and sustainedrelease morphine for the treatment of pain and listed hydromorphone and oxycodone as alternatives to morphine.40 The WHO’s 20th Model List of Essential Medicines published in March 2017 expanded the opioid medicines indicated to treat cancer pain to include transdermal fentanyl and methadone.41 In addition to being medicines that are essential for relieving pain, opioids have a potential for being misused or abused, which can result in harms. Therefore, they are designated as controlled substances by an 809

international treaty, the Single Convention on Narcotic Drugs, 1961, as amended by the 1972 Protocol Amending the Single Convention on Narcotic Drugs, 1961 (Single Convention) (Fig. 16.1).42 The term narcotic drugs refers to a subset of controlled substances and is a legal term that will be used where the context requires. Nearly every government in the world has formally acceded to the Single Convention, thereby agreeing to adopt laws, regulations, and administrative procedures to carry out the dual aims of the Single Convention, which are to prevent the abuse and diversion of opioid medicines while making them available for medical purposes.

FIGURE 16.1 The United Nations Single Convention on Narcotic Drugs, 1961, as amended by the 1972 Protocol Amending the Single Convention on Narcotic Drugs, 1961.

The Single Convention establishes an international framework of prohibitions and requirements for governments concerning the legitimate production, manufacture, and distribution of narcotic drugs that is intended to prevent illicit trafficking, nonmedical use of narcotic drugs, and 810

diversion (the illegal movement of controlled medications from the licit distribution system into the illicit market). The principal international requirement is that the legitimate trade in narcotic drugs is regulated, including the cultivation of opium and manufacture of medicinal opioids such as codeine and morphine. To prevent diversion, an import–export system is established to limit trade to the amounts necessary for medical use; trade is regulated by the International Narcotics Control Board (INCB), an independent and quasi-judicial monitoring body to implement UN international drug control conventions.43 The Single Convention establishes several national obligations, among them that governments must regulate all entities that handle controlled substances. The goal is to create a closed distribution system, including security and record keeping. Only clinical professionals authorized under national law, using “medical prescriptions,” may prescribe and dispense controlled substances to individuals and only for medical purposes. Distribution outside of the regulated system is prohibited in order to prevent diversion of controlled drugs from medical to nonmedical uses. Efforts to prevent diversion should be balanced so as not to interfere in medical practice and patient care.4,10 Examples of efforts to lessen the risks of abuse and diversion include clinical training of health care professionals and students regarding appropriate pain management as a means to reduce inappropriate use.6,44–46 Some countries have provided informational sessions for health officials and drug regulators when policies were updated to facilitate their knowledge of the new legal requirements.45,46 Some areas of India47 and countries such as Sierra Leone48 and Uganda49 have successfully increased the availability of morphine without experiencing diversion and abuse of these medicines; such activities require sound security, record keeping, and prescriptive practices.

GOVERNMENTS MUST ENSURE ADEQUATE OPIOID AVAILABILITY In addition to controlling drugs to prevent their diversion and nonmedical use, the Single Convention stipulates a second obligation to ensure adequate availability of narcotic drugs for medical and scientific purposes. 811

The Single Convention clearly recognizes the importance of narcotic drugs as analgesic medications and asserts that medical access to opioids for relief of pain is to be assured by governments because they are obligated to conform their laws to the Single Convention, “ . . . the medical use of narcotic drugs continues to be indispensable for the relief of pain and suffering and that adequate provision must be made to ensure the availability of narcotic drugs for such purposes.”42 The availability obligation is no less important than the obligation to prevent diversion, but it is poorly understood and implemented by health professionals and governments. There is no indication that the medical value of controlled substances is lessened as a result of scheduling under the Single Convention. Scholars of international narcotic drug policy have concluded that the Single Convention, as amended, recognizes that the basic purpose of international drug control is to reduce the availability of drugs for nonmedical purposes but “that this should not affect or limit their therapeutic use.”50 The Single Convention establishes a critically important policy framework, the principle of balance, which asserts that governments’ obligation to control controlled medicines is not only to prevent drug abuse but also to ensure their availability for medical purposes.10 Controls aimed at preventing drug abuse and diversion must not prevent the adequate availability of opioid medicines for patients’ pain relief. Drug abuse controls that hinder opioid availability and patient access to effective pain treatment would be considered unbalanced and should be identified and corrected (Table 16.1). TABLE 16.1 The Central Principle of “Balance” The central principle of “balance” represents a dual obligation of governments to establish a system of control that ensures the adequate availability of controlled substances for medical and scientific purposes, while simultaneously preventing abuse, diversion and trafficking. Many controlled medicines are essential medicines and are absolutely necessary for the relief of pain, treatment of illness and the prevention of premature death. To ensure the rational use of these medicines, governments should both enable and empower healthcare professionals to prescribe, dispense and administer them according to the individual medical needs of patients, ensuring that a sufficient supply is available to meet those needs. While misuse of controlled substances poses a risk to society, the system of control is not intended to be a barrier to their availability for medical and scientific purposes, nor interfere in their legitimate medical use for patient care.10(p11)

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Reprinted with permission from World Health Organization. Ensuring Balance in National Policies on Controlled Substances: Guidance for Availability and Accessibility of Controlled Medicines. 2nd ed, rev ed. Geneva, Switzerland: World Health Organization; 2011.

To accomplish these dual objectives, the Single Convention requires that governments adopt laws, regulations, and administrative procedures to implement two specific mechanisms that are intended to ensure adequate availability of opioid medicines in countries while preventing nonmedical use. First, governments must annually establish an estimate of the amounts of opioids that will be required for all medical and scientific needs for the coming year.51 Licit trade in narcotic drugs can be lawfully conducted only within this amount. If imports exceed a country’s estimated requirements, exporters are obligated to refrain from further trade with the country, unless the INCB approves a supplementary estimate from the importing country that increases the estimated amount of the narcotic. Governments are encouraged to develop valid estimation methods, to establish estimates that take increasing demand into consideration, to cooperate with health professionals to obtain information about unmet needs, and to increase the estimate whenever necessary to always satisfy medical needs.51 Second, governments must report the amounts of each narcotic drug consumed (i.e., distributed to the retail level) to allow identification of consumption that either exceeds or falls short of the estimate.52 Each Party to the Single Convention is expected to establish a drug control program not only to prevent illicit trafficking and diversion but also to ensure the adequate availability of narcotic drugs for medical and scientific purposes4 and to designate an agency called the Competent National Authority (CNA) to implement the functions required by the Single Convention.43 This office is usually located in the pharmaceutical department of the Ministry of Health, the national drug control, or public security agency, or the functions may be divided between agencies. The CNA is the principal national administrative authority for carrying out the estimation and statistical reporting procedures that are necessary for ensuring that opioid medicines are adequately available for medical and scientific purposes. Guidelines for estimating the amounts of opioids required for medical and scientific use and for reporting consumption 813

statistics are useful for those who want to understand the administrative procedures to be followed by CNAs.51–53 The INCB provides guidelines for CNAs to comply with the Single Convention, including the administration of effective mechanisms to ensure opioid availability.54

Disparities in Opioid Consumption The Single Convention requirement that national governments report annual consumption statistics provides a unique source of data to describe global and national opioid consumption trends and to study disparities. Consumption means the amounts of opioid medicines distributed for medical purposes to the “retail” level in a country (i.e., to those institutions and programs that are licensed to dispense to patients, such as hospitals, nursing homes, pharmacies, hospices, and palliative care programs). The INCB uses consumption statistics to (1) monitor compliance of governments with the provisions of the Single Convention, (2) identify trade discrepancies between importing and exporting countries, (3) detect imbalances between quantities of medications available and disposed within a country, (4) identify trends in the worldwide availability of opioids and other drugs for medical needs, and (5) monitor and maintain a global balance of supply and demand of opioids for medical and scientific needs.52 Opioid consumption statistics have several useful applications for those who study and improve opioid availability to (1) identify whether a country has available opioids that can relieve moderate to severe pain, (2) learn whether the amounts indicate any substantial current consumption or progress over time,27 and (3) evaluate the outcome of efforts to improve opioid availability. Consumption statistics provided in INCB reports have several limitations that should be considered when using them as an indicator of opioid availability: 1. In any given year, the data may be incomplete or invalid as a result of some governments reporting late, not reporting for a particular year or period, or submitting inaccurate data. These deficiencies may be corrected in subsequent years. Each year, the INCB publishes 814

updated statistics for the previous 4 years of data which reflect corrections to previous reports and data submitted after the deadline. 2. The INCB’s published reports do not include the exact amounts of consumption for quantities less than 1 kg. Instead, the symbol “80% pain relief and McAuley et al.125 found that 92% and 100% had >50% pain relief immediately and at long-term follow-up (median of 11 years), respectively. These studies propose that SCS for PLP may be an effective intervention for select patients who have not obtained adequate relief with other interventions. Direct stimulation of the DRG is a relatively novel therapeutic treatment option that offers more targeted paresthesia stimulation. A pilot study of eight patients with PLP looked at percentage of pain relief and change in analgesic medication intake immediately after placement and at 5- to 24month follow-up. The average immediate pain relief was 50%. Of the seven patients available for follow-up, three continued to have >50% pain relief.126 The use of radiofrequency stimulation prior to DRG implantation has been proposed as a method to improve accurate coverage of the phantom limb by targeting the DRG.127 Peripheral nerve stimulation allows even more focused targeting of electrical stimulation. A few devices have been marketed specifically for PLP based on limited pilot data and case reports.128–131 Larger studies are needed to evaluate long-term efficacy of these devices. Bittar and colleagues132 concluded that deep brain stimulation has been 1261

utilized successfully for the treatment of PLP resulting in decreased pain scores, decreased opiate intake, and improved quality of life. Bittar et al.133 published a meta-analysis supporting this pain improvement as well, especially in the burning component—perhaps via a reorganization in the central nervous system. Sol et al.134 used chronic motor cortex stimulation in three patients with intractable PLP after upper limb amputation. fMRI correlated to anatomical MRI permitted frameless image guidance for electrode placement. Pain control was obtained for all the patients initially, and the relief was stable in two of the three patients at 2-year follow-up. fMRI data may be useful in assisting the neurosurgeon in electrode placement for this indication.134

SURGICAL INTERVENTIONS PLP has generally been difficult to treat with surgical interventions. Part of the difficulty in addressing PLP and stump pain surgically lies in the postsurgical restriction or growth retardation of stump neuromas. Residual limb neuromas develop at the site of the severed end of peripheral nerves. Surgical management may involve implanting the end of severed nerves into a nearby/adjacent large muscle belly, which may alleviate stump pain somewhat, although it does not permanently cure patients.93 Sakai et al.135 theorized that preventing neuroma formation might also significantly decrease the incidence of postamputation stump pain. Techniques to prevent neuroma formation include nerve transposition or ligation, embedding of the nerve end in bone or muscle, and capping of the nerve stump with a nerve graft, epineurium, or atelocollagen.135,136 Sehirlioglu et al.137 retrospectively studied 75 patients who were treated for painful neuroma after lower limb amputation following landmine explosions between the years 2000 and 2006.137 The average time period from use of prosthesis to start of symptoms suggesting neuroma was 9.6 months. The average time period from start of pain symptoms to neuroma surgery was 7.8 months. All clinically proven neuromas were surgically resected.137 In the mean follow-up of 2.8 years, all patients were satisfied with the end results, and all were free of any pain symptoms.137 In a painful residual limb with clinical diagnostic findings of neuroma, if 1262

conservative measures fail, surgery may be considered as a therapeutic option.137 Aggressive surgical techniques, such as anterolateral cordotomy and dorsal root entry zone lesions, have been attempted in PLP but do not have large multicenter studies supporting their use at all and have significant morbidity and some mortality.

BEHAVIORAL MEDICINE INTERVENTIONS Many psychological modalities have been investigated for managing symptoms of PLP, including biofeedback, relaxation techniques, mirror therapy, virtual reality training, and eye movement desensitization and reprocessing.138 Biofeedback treatments resulting in vasodilatation or decreased muscle tension in the residual limb may help to reduce PLP and seem promising in patients in whom peripheral factors contribute to the pain.139 Harden et al.140 conducted a pilot study that examined the effectiveness of biofeedback in the treatment of nine individuals with PLP who received up to seven thermal/autogenic biofeedback sessions over the course of 4 to 6 weeks. Pain was assessed daily using the VAS, the sum of the sensory descriptors, and the sum of the affective descriptors of the McGill short form. Interrupted time series analytical models were created for each of the participants, allowing biofeedback sessions to be modeled as discrete interventions.140 Analyses of the VAS revealed that a 20% pain reduction was seen in five of the nine patients in the weeks after session 4 and that at least 30% pain reduction (range: 25% to 66%) was seen in six of the seven patients in the weeks following session 6.140 Relaxation training has also been shown to provide significant benefit in many patients. One report noted that 12 of 14 patients with chronic PLP improved with muscular relaxation training.138 Hypnotic imagery has been used alone and with relaxation training; however, further studies need to be done before any conclusions regarding this therapy can be made.141 Ramachandran and Rogers-Ramachandran16 described another behaviorally oriented approach: A mirror was placed in a box, and the patient inserted his or her intact arm and the residual limb. The patient was then asked to look at the mirror image of the intact arm, which is perceived 1263

as an intact hand where the phantom used to be, and to make symmetrical movements with both hands, thus suggesting real movement from the lost arm to the brain. This procedure may reestablish control over the phantom limb and alleviate pain in some patients, although controlled data are lacking. Graded motor imagery is a promising, nonpharmacologic means of treating PLP. A randomized controlled trial using graded motor imagery to treat complex regional pain syndrome type 1 and PLP showed number needed to treat of 3 at 6 months for a composite endpoint of 50% pain reduction and improvement in function.142 Patients in the placebo arm of this study received standard physical therapy and usual medical care. Graded motor imagery involves training patients to improve right/left discrimination and imagine pain-free movements of affected and normal limbs followed by practicing pain-free movements with the aid of a mirror box.142 Murray et al.143 reported three patients who experienced PLP (two with an upper limb amputation and one with a lower limb amputation) that took part in between two and five immersive virtual reality (IVR) sessions over a 3-week period. The movements of patients’ anatomical limbs were transposed into the movements of a virtual limb.143 All patients reported the transferal of sensations into the muscles and joints of the phantom limb, and all patients reported a decrease in phantom pain during at least one of the sessions.143 The authors suggested the need for further research studying IVR for PLP using controlled trials. Schneider et al.144 evaluated eye movement desensitization and reprocessing (EMDR) treatment with extensive follow-up. Five patients with PLP ranging from 1 to 16 years who were on extensive medication regimens underwent 3 to 15 sessions of EMDR, which was used to treat the pain and the psychological ramifications.144 EMDR resulted in a significant decrease or elimination of phantom pain, reduction in depression and PTSD symptoms to subclinical levels, and significant reduction or elimination of medications related to the phantom pain and nociceptive pain at long-term follow-up.144 Further research is needed to explore the theoretical and treatment implications of this informationprocessing approach.144 1264

MISCELLANEOUS TREATMENTS FOR RESIDUAL LIMB PAIN Chronic RLP may occur as a result of skin pathology, vascular insufficiency, infection, bone spurs, or neuromas.12,39,40,136 Fitting of a prosthetic socket is a critical stage in the process of rehabilitation of a transtibial amputation (TTA) patient because a misfit may cause pressure ulcers or a deep tissue injury (DTI; necrosis of the muscle flap under intact skin) in the residual limb.145 To date, prosthetic fitting topically depends on the subjective skills of the prosthetist and is not supported by biomedical instrumentation that allows evaluation of the quality of fitting.145 Portnoy et al.145 concluded that real-time patientspecific finite element analysis of internal stresses in deep soft tissues of the residual limb in TTA patients is feasible. This method may be improving the fitting of prostheses in the clinical setting and protecting the residual limb from pressure ulcers and DTI.145 The use of a myoelectric prosthesis might be one way to influence PLP. Intensive use of a myoelectric prosthesis was positively associated with both less PLP and less cortical reorganization.146 One study found that use of a forearm prosthesis with somatosensory feedback is effective in reducing PLP.147 Topical clonidine patches (and other topical therapies) have been utilized on the residuum but have not been studied. For relatively superficial neuromas, lidocaine via iontophoresis (e.g., LidoSite patch [developed and manufactured by Vyteris, Inc, Fair Lawn, NJ]) theoretically may be useful. Gruber et al.148 prospectively evaluated “neurosclerosis” of residual limb neuromas, present after amputation, on 82 patients by means of highresolution sonographically guided injection with up to 0.8 mL of 80% phenol solution. During treatment, all patients had marked improvement in terms of reduction of pain measured with a VAS.148 Twelve (15%) of the subjects were pain-free after one to three treatments, with 9 of the 12 achieving relief with the initial instillation.148 After 6 months, patients had an overall decrease in median VAS score from 10.0 ± 1.5 (standard deviation) (range, 2 to 10) to 3.0 ± 2.6 (range, 1 to 10) after one (25 patients), two (12 patients), and three treatment sessions (15 patients). At 1265

the 6-month follow-up evaluation, 20 (38%) of the 52 patients reported almost unnoticeable pain, and 33 (64%) reported pain equal to the minimum pain they had reached during phenol injection therapy. In 18 (35%) of the 52 patients, the incidence of painful periods had markedly decreased.148 The “neurosclerosis” procedure had a low complication rate (5% rate of minor complications, 1.3% rate of major complications).148 Pulsed radiofrequency treatment of the DRG at the L4 and L5 nerve root level was utilized as a therapeutic option for two patients with peripherally mediated intractable stump pain. A decrease in pain intensity and improved toleration of the limb prosthesis was appreciated in both patients.136 Anecdotes of other analgesic strategies such as acupuncture149 and electroconvulsive therapy117 for postamputation pain exist.

Summary Phantom pain remains an incompletely understood, difficult to treat pain condition. It is present, at least in the early stages after amputation, in a majority of postamputation patients. It is a painful condition in which an obvious loss of sensory information coupled with a disruption of the nervous system leads to pain. Phantom pain also appears to be a painful condition in which the involvement of supraspinal mechanisms may be more intuitive than in the case of other painful conditions. Optimal treatment approaches involve the coordination of an interdisciplinary pain medicine team familiar with the therapy of postamputation pain syndromes. A combination of pharmacologic, physical medicine and rehabilitation, behavioral medicine, neuromodulation, and interventional treatments may be needed to achieve optimal outcomes. Further basic and clinical research is needed to better understand the pathophysiologic mechanisms, prevention strategies, and optimal treatment approaches for different patients and their varying phantom conditions. References 1. Weinstein SM. Phantom limb pain and related disorders. Neurol Clin 1998;16(4):919–935. doi:10.1016/S0733-8619(05)70105-5. 2. Mitchell SW. Injuries of Nerves and Their Consequences. London: Smith Elder; 1872. 3. Parkes CM. Factors determining the persistence of phantom pain in the amputee. J Psychosom

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131. Rauck RL, Cohen SP, Gilmore CA, et al. Treatment of post-amputation pain with peripheral nerve stimulation. Neuromodulation 2014;17:188–197. doi:10.1111/ner.12102. 132. Bittar RG, Otereo S, Carter H, et al. Deep brain stimulation for phantom limb pain. J Clin Neuerosci 2005;12:399–404. 133. Bittar RG, Kar-Purkayastha I, Owen SL, et al. Deep brain stimulation for pain relief: a metaanalysis. J Clin Neurosci 2005;12:515–519. 134. Sol JC, Casaux J, Roux FE, et al. Chronic motor cortex stimulation for phantom limb pain: correlation between pain relief and functional imaging studies. Stereotact Funct Neurosurg 2001;77:172–176. 135. Sakai Y, Ochi M, Uchio Y, et al. Prevention and treatment of amputation neuroma by an atelocollagen tube in rat sciatic nerves. J Biomed Mater Res B Appl Biomater 2005;73:355– 360. 136. Ramanavarapu V, Simopoulos TT. Pulsed radiofrequency of lumbar dorsal root ganglia for chronic post-amputation stump pain. Pain Physician 2008;11:561–566. 137. Sehirlioglu A, Ozturk C, Yazicioglu K, et al. Painful neuroma requiring surgical excision after lower limb amputation caused by landmine explosions. Int Orthop 2009;33:533–536. 138. Sherman RA, Gall N, Gormley J. Treatment of phantom limb pain with muscular relaxation training to disrupt the pain-anxiety-tension cycle. Pain 1979;6:47–55. 139. Sherman RA. Stump and phantom limb pain. Neurol Clin 1989;7:249–264. 140. Harden RN, Houle TT, Green S, et al. Biofeedback in the treatment of phantom limb pain: a time-series analysis. Applied Psycho Biofeed 2005:30:83–93. 141. Oakley DA, Whitman LG, Halligan PW. Hypnotic imagery as a treatment for phantom limb pain: two case reports and a review. Clin Rehabil 2002;16:368–377. 142. Moseley GL. Graded motor imagery for pathologic pain: a randomized controlled trial. Neurology 2006;67:2129–2134. 143. Murray CD, Pettifer S, Howard T, et al. The treatment of phantom limb pain using immersive virtual reality: three case studies. Disabil Rehabil 2007;29:1465–1469. 144. Schneider J, Hoffman A, Rost C, et al. EMDR in the treatment of chronic phantom limb pain. Pain Med 2008;9:76–82. 145. Portnoy S, Yarnitzky G, Yizhar Z, et al. Real-time patient-specific finite element analysis of internal stresses in the soft tissues of a residual limb: a new tool for prosthetic fitting. Ann Biomed Eng 2007;35:120–135. 146. Lotze M, Flor H, Grodd W, et al. Phantom movements and pain: an fMRI study in upper limb amputees. Brain 2001;124:2268–2277. 147. Dietrich C, Walter-Walsh K, Preissler S, et al. Sensory feedback prosthesis reduces phantom limb pain: proof of a principle. Neurosci Lett. 2012;507(2):97–100. doi:10.1016/j.neulet.2011.10.068. 148. Gruber H, Glodny B, Bodner G, et al. Practical experience with sonographically guided phenol instillation of stump neuroma: predictors of effects, success, and outcome. AJR Am J Roentgenol 2008;190:1263–1269. 149. Bradbrook D. Acupuncture treatment of phantom limb pain and phantom limb sensation in amputees. Acupunct Med 2004;22:93–97.

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CHAPTER 27 Herpes Zoster and Postherpetic Neuralgia SIDDARTH THAKUR, ROBERT H. DWORKIN, and RAJBALA THAKUR The objective of this chapter is to provide an overview of the clinical presentation and management of herpes zoster and its most common complication in immunocompetent patients, postherpetic neuralgia (PHN). Herpes zoster is a viral infection caused by the reactivation of the varicella-zoster virus (VZV). The primary varicella infection occurs when the patient contracts chicken pox. Following the resolution of chicken pox, the virus then remains dormant in dorsal sensory ganglia and cranial nerve ganglia for years to decades. Individuals are asymptomatic while the virus is dormant, and reactivation of VZV results in a characteristic and usually painful vesicular dermatomal rash. Some patients with herpes zoster develop PHN, and this persisting neuropathic pain can last for years. Herpes zoster afflicts millions of older adults worldwide each year and causes significant suffering and disability because of both the acute pain that occurs in association with the rash and the chronic pain that is present in those patients who develop PHN. VZV-induced neuronal destruction and inflammation causes pain that interferes with activities of daily living and reduces quality of life. Contemporary advances have improved our ability to both diminish the incidence of these conditions as well was manage the remaining cases more effectively. These include the development of herpes zoster vaccines, consensus that antiviral therapy and aggressive pain management can reduce the burden of this disease, the identification of efficacious treatments for PHN, and the recognition of PHN as a study model for neuropathic pain research. An interesting ongoing development is recognition of phenotype-based identification of subsets of patients that may help clinicians make individualized 1274

therapeutic decisions.1–4

Clinical Picture and Natural History of Herpes Zoster Herpes zoster is a neurodermatomal illness that does not cross the midline. Typically, a single dermatome is affected in immunocompetent patients, although in some cases, involvement of adjacent dermatomes can be seen due to normal variation of cutaneous innervation. In immunocompromised patients, there can be cutaneous dissemination and, rarely, visceral dissemination. The sequence of events described in the following sections is typically observed.

PRODROME Herpes zoster may begin with fatigue, headache, or flu-like symptoms, including fever, neck stiffness, malaise, and nausea. This may be accompanied by unilateral dermatomal pain and abnormal sensations, including pruritus. The prodromal symptoms usually precede the appearance of a rash by 3 to 7 days, although longer periods have been reported. The prodrome probably occurs in association with the initiation of viral replication and the accompanying inflammatory response. This process results in ganglionitis as well as the destruction of neurons and supporting cells in the dorsal root ganglion (DRG) and accompanying dermatome.5,6 In cases where patients experience a prolonged course of prodromal symptoms, diagnostic investigations are frequently undertaken to identify other medical conditions that may cause pain in the affected anatomic distribution. Common examples include pursuing the diagnosis of glaucoma in cases of herpes zoster ophthalmicus; sciatica in cases of sacral dermatomal involvement; and angina, renal colic, or cholecystitis in cases of truncal involvement. Diffuse or regional adenopathy is seen in a minority of cases and has not been correlated with any residual or longterm complications.

RASH The reactivated virus replicates in the sensory ganglion and travels antidromically via the cutaneous nerves to the nerve endings at the

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dermoepidermal junction. Further replication in the skin results in tissue inflammation and necrosis which ultimately leads to the appearance of a rash in the same distribution as the prodrome. The rash is initially maculopapular and evolves into the classic appearance of grouped vesicle formations on an erythematous base. Regional lymphadenopathy may appear at this stage. Over the next 7 to 10 days, the lesions progress to a pustular rash. Open lesions will develop superficial crusting. Scabs are cleared within 2 to 3 weeks. Skin in the affected region may be left completely normal or may develop a patchwork of either hypo- or hyperpigmented scarring (Fig. 27.1).

FIGURE 27.1 Herpes zoster rash progression. (Reprinted from Weinberg JM. Herpes zoster: epidemiology, natural history, and common complications. J Am Acad Dermatol 2007;57(6 Suppl):S130–S135. Copyright © 2007 American Academy of Dermatology, Inc. With permission.)

PAIN Pain often precedes or accompanies the herpes zoster rash.7,8 Pain may be accompanied by other sensations such as itching, paraesthesias (i.e., nonpainful abnormal sensations that are not unpleasant), and dysesthesias (i.e., nonpainful abnormal sensations that are unpleasant). The timing of the pain may be constant or intermittent, and the quality of the pain is variously described as burning, throbbing, stabbing, electric shock-like, or various combinations of these. It is frequently associated with increased 1276

tactile sensitivity and allodynia (i.e., pain in response to a normally nonpainful stimulus). The pain may interfere with the patient’s sleep and other aspects of physical and emotional functioning. The acute pain associated with herpes zoster gradually resolves in most patients around the time that the rash resolves. Pain that persists beyond the acute phase of the rash is considered subacute herpetic neuralgia or PHN, depending on its duration. A distinction between these three phases of pain associated with herpes zoster has been identified and is useful in both clinical and research settings.9 Acute herpetic neuralgia has been defined as pain that occurs within 30 days of rash onset, subacute herpetic neuralgia as pain that persists beyond 30 days from rash onset but that resolves before the diagnosis of PHN can be made, and PHN as pain that persists for 120 days or more after rash onset (Fig. 27.2).

FIGURE 27.2 Natural history of herpes zoster and postherpetic neuralgia.

DISTRIBUTION OF HERPES ZOSTER Thoracic dermatomes are the most commonly affected sites. These are followed, in order of incidence, by the ophthalmic division of the trigeminal nerve, other cranial nerves, and cervical, lumbar, and sacral dermatomes10 (Table 27.1). The reason for this pattern is not understood, but it has been speculated that this may reflect the characteristic distribution of the chicken pox rash. The pattern of rash seen in herpes zoster follows the same centripetal distribution observed with the primary varicella infection. Patients can develop lesions in the adjoining dermatomes, and much less commonly, a diffuse cutaneous or even visceral dissemination can occur, most often in immunocompromised individuals. 1277

TABLE 27.1 Dermatomal Distribution of Herpes Zoster in Immunocompetent Patients Thoracic: up to 50% of all cases Cranial: 10%–20% Cervical: 10%–20% Lumbar: 10%–20% Sacral: 2%–8% Generalized: 75 y of age, 300 mg daily in divided doses

Nausea/vomiting, constipation, sedation, dizziness, seizures, postural hypotension

3,600 mg daily (1,200 mg 3 times daily;

Sedation, dizziness, peripheral edema

daily

every 2 days as tolerated

Pregabalin

75 mg at bedtime or 75 mg twice daily

Increase by 75 twice daily every 3 days as tolerated

Tricyclic antidepressants, especially nortriptyline

25 mg at bedtime

Increase by 25 mg daily every 2–3 days as tolerated

Oral corticosteroid (dosages given for prednisone)

60 mg daily for 7 days

After 60 mg daily for 7 days, decrease to 30 mg daily for 7 days, then decrease to 15 mg daily for 7 days, and then discontinue.

reduce if renal function is impaired) 600 mg daily (300 mg twice daily; reduce if renal function is impaired) 150 mg daily

60 mg daily

Sedation, dizziness, peripheral edema

Sedation, dry mouth, blurred vision, weight gain, urinary retention Gastrointestinal distress, nausea, changes in mood, edema

NOTE: Dose of opioids, pregabalin, and tricyclic antidepressants can be reduced in frail elderly individuals. Consider a screening electrocardiogram for patients with preexisting cardiac disease. CV, cardiovascular; NSAID, nonsteroidal anti-inflammatory drugs. Adapted from Dworkin RH, Johnson RW, Breuer J, et al. Recommendations for the management of herpes zoster. Clin Infect Dis 2007;44(1):S1–S26. Reproduced by permission of Infectious Diseases Society of America.

CORTICOSTEROIDS The use of corticosteroids in the treatment of herpes zoster has been controversial.80,81 One placebo-controlled trial demonstrated a benefit in terms of significantly accelerated return of uninterrupted sleep, cessation of analgesic therapy, and return to normal activity in patients treated with the combination of a corticosteroid and acyclovir as compared to those treated with acyclovir alone.81 The patients in this trial were 60 years of age on average and possessed no contraindications to corticosteroid treatment. Based on these results, the addition of oral corticosteroids can be considered in healthy older adults with moderate-to-severe pain unrelieved by antiviral therapy and analgesics, provided there are no contraindications to steroid use. Oral steroids are empirically used in VZV-induced facial nerve palsy or 1294

other cases of cranial neuritis, although there is limited evidence supporting the effectiveness of such treatment. It must be emphasized that corticosteroids should not be used alone in herpes zoster and must be initiated in combination with antiviral therapy.

Lidocaine Patch A 5% lidocaine patch is traditionally used for PHN pain and approved by the FDA for the same indication. A randomized placebo-controlled study showed that lidocaine patches reduced pain associated with herpes zoster82; based on this information and the excellent side effect profile of lidocaine patches, their use can be considered. The patch should only be applied to intact skin after the initial rash has completely healed.

NEURAL BLOCKADE Although no conclusive and strong recommendations can be made for the use of any invasive interventions due to lack of consistent data, if pain is not controlled with medical management, referral to a pain specialist should be considered for possible interventions. These may include neuraxial injections of local anesthetics and steroids, neuraxial local anesthetic infusion, paravertebral blocks, or sympathetic blocks. All these interventions have been used for years in clinical practice, but few controlled studies have been conducted to systematically examine their effects on herpes zoster acute pain or the development of PHN. As per NeuPSIG recommendations, moderate quality of available evidence provided the basis for a weak recommendation for the use of epidural or paravertebral blocks with local anesthetic and steroids injections for herpes zoster pain.83 These guidelines were based on three RCTs.84–86 One of the RCTs84 found significant reduction in acute pain following a single epidural injection of steroid and local anesthetic within the first month after rash onset as compared to standard therapy alone. The incidence of developing PHN, however, was not reduced in this study. A more recent systematic review and meta-analysis also showed a favorable outcome with the use of interventional procedures for the management of acute herpes zoster related pain; in addition, these authors also addressed the role of interventions in reducing the incidence of PHN.87,88 The findings 1295

suggest that nerve blocks do shorten the duration of acute pain in herpes zoster and repeat or continuous epidural blocks and paravertebral blocks reduce the likelihood of PHN. Single stellate ganglion blocks fail to decrease the incidence, but multiple blocks may have a beneficial effect in this regard.87,88 The exact mechanism by which sympathetic or somatic blocks could prevent PHN or lessen its severity is poorly understood. The sympathetic nervous system is important in mediating pain in some neuropathic pain conditions. It has been hypothesized that in the acute phase of herpes zoster, inflammation induces intense stimulation of the sympathetic nervous system leading to reduced intraneural blood flow with resultant neuronal hypoxia and endoneural edema. Other putative mechanisms of sympathetic nervous system involvement include the formation of ephaptic connections between the sensory system and the sympathetic system as well as the upregulation of adrenoreceptors. These phenomena could result in inappropriate activation of primary nociceptive fibers in response to sympathetic nervous system activation. Blockade of sympathetic nerves with local anesthetics may reverse these effects. It is also hypothesized that these interventions may favorably affect the progression of herpes zoster acute pain to PHN because the effective treatment of acute pain may prevent the development of PHN or at least decrease the severity of subsequent PHN. In conclusion, we do not make a strong recommendation for routine use of interventions for acute herpes zoster pain. Interventions can be considered if the pain is not well controlled, or if pharmacotherapy results in intolerable side effects. The use of local interventions should be carefully considered, and the type of intervention should be guided by the patient’s condition and the provider’s expertise.

COMPLEMENTARY AND ALTERNATIVE MEDICINE Complementary and alternative medicine modalities are becoming increasingly popular in patients with acute as well as chronic pain conditions and herpes zoster, and related pain syndromes are no exception. Integrative (complementary) therapies include meditation, hypnosis, relaxation therapy, imagery, music therapy, magnet therapy, dietary and herbal supplements, and acupuncture. There are no reliable data available 1296

that will help make strong and specific recommendations in the treatment of zoster-related pain with these approaches. Acupuncture has been examined in small studies for the treatment of herpes zoster pain. One of the mechanisms of action is thought to be associated with endorphin release at both the spinal and supraspinal levels. In a small randomized study, subjects were randomized to receive weekly acupuncture treatment versus standard therapy including pregabalin, local anesthetic injections for all patients and opioids for patients who had intractable pain.89 Patients in the acupuncture arm were only allowed acetaminophen as a rescue analgesic. No significant differences were observed between the groups in terms of mean pain reduction, incidence of PHN or total pain burden, concluding that acupuncture could have similar efficacy as conventional analgesic therapies. Although this study alone does not provide high-quality evidence to support the routine use of acupuncture, it does provide some evidence as to the potential role of acupuncture in the treatment of acute herpes pain.

SPINAL CORD STIMULATION Spinal cord stimulation (SCS) has been tried in a case series of four patients with active herpes zoster and reported to be effective.90 It is difficult to extrapolate these results to routine clinical practice as the majority of patients with herpes zoster have resolution of their symptoms as part of the natural history of the disease; hence, authors do not recommend this modality of treatment for acute zoster.

Prevention of Herpes Zoster CHILDHOOD VACCINATION The propensity to develop herpes zoster and PHN can ultimately be traced back to an individual’s primary varicella infection. Thus, one obvious prevention strategy would include the prevention of the primary VZV infection through the use of varicella vaccination in childhood. Two types of vaccines are approved by the FDA for vaccination in children from 12 months to 12 years of age; both are based on the Oka virus. The first agent is a single-antigen vaccine, and the more recent vaccine is a combination 1297

product and protects against multiple childhood infections (i.e., measles, mumps, rubella, and varicella). The current recommendations for routine immunization of immunocompetent children are two doses of varicella vaccine (either single antigen or combined product) with the first dose at 12 to 15 months, followed by a second dose at 4 to 6 years of age.91 The live attenuated Oka vaccine virus establishes latency in sensory ganglia, like wild-type VZV, but it appears to cause herpes zoster much less frequently. Hence, childhood varicella vaccination should eventually result in an overall decrease in the incidence of herpes zoster and PHN.

VARICELLA-ZOSTER IMMUNOGLOBULIN Temporary passive immunization may be required in specific circumstances. The CDC currently recommends administration of purified varicella-zoster immune globulin preparation, VariZIG (Cangene Corp, Winnipeg, Canada), to prevent or modify clinical illness in immunocompromised or pregnant seronegative persons and a select group of infants with recent exposure to patients with chicken pox or zoster. VariZIG should be administered as soon as possible, ideally within 96 hours of exposure to provide maximum benefit, but it may be used within 10 days.92 Treatment with VariZIG should be followed by vaccination in eligible patients 5 months after administration.

HERPES ZOSTER VACCINATION FOR ADULTS Herpes zoster is caused by reactivation of VZV from a single sensory ganglion. The precise mechanism of reactivation is not known but thought to be due to waning VZV specific cell-mediated immunity. Therefore, adult vaccination can confer the immunologic boost to prevent herpes zoster and the associated pain, suffering, and decreased quality of life. In 2006, a live attenuated Oka virus–based varicella vaccine was approved by the FDA for adults 60 years of age or older. The approval was based on the results of the Shingles Prevention Study—a large, multicenter, randomized, placebo-controlled trial—that established efficacy and safety of a single-dose herpes zoster vaccination.33 The results of the trial indicated that the herpes zoster vaccine reduces the likelihood of developing herpes zoster in immunocompetent individuals 60 1298

years of age or older. Important results of this study included a decrease in the incidence of herpes zoster by 51.3%, a reduction in the overall burden of illness (BOI) by 61.1%, and a decrease in the incidence of PHN by 66.5%.93 Subsequently, in order to investigate the durability of benefit from vaccination, the Short-Term Persistence Substudy (STPS) was performed by the same group of investigators.94 The study was designed to evaluate efficacy up to 7 years postvaccination. The major findings included a drop in efficacy in herpes zoster BOI by 11%, 6.4% for PHN incidence, and 11.7% for herpes zoster incidence. The results regarding incidence for BOI and incidence of herpes zoster were significant through 5 years postvaccination leading the authors to conclude the persistence of efficacy at 5 years but the benefit beyond that time point was unclear. To address this question, the same group performed the Long-Term Persistence Substudy (LTPS) evaluating patients 7 to 11 years postvaccination.95 All participants in the prior two studies had been vaccinated, leaving no controls to use for comparison. Therefore, the authors used regression models to estimate incidences of herpes zoster and PHN, finding that efficacy of the vaccine continued to decline. Only for herpes zoster BOI was efficacy retained at 10 years, efficacy for incidence of herpes zoster persisted through year 8. The findings from the LTPS have been supported by an analysis of over 175,000 vaccinated individuals from an integrated health care organization, which found the effectiveness of the vaccine drops from 68.7% in the first year to 4.2% in the 8-year postvaccination.96 In order to address the issue of waning efficacy the logical next step would be evaluation of a “booster” dose of vaccine. In fact, that work has been initiated and demonstrated enhanced VZVspecific cell-mediated immunity in individuals >70 years of age who received a second dose of varicella zoster vaccine.97 The findings are promising and support further investigation of the use of booster doses to prevent herpes zoster. Recently, a novel glycoprotein-based herpes zoster subunit vaccine has been developed, potentially for adults older than 50 years and immunocompromised hosts. It has been evaluated in two phase 3, large, international, multicenter, randomized, placebo-control trials. The first demonstrated an overall vaccine efficacy against herpes zoster of 97.9 % 1299

for those 70 years or older and 97.2% for all individuals greater than 50 years of age.98 The second looked specifically at those 70 years of age or older and found an overall vaccine efficacy of 89.9%.99 A pooled analysis from the two trials demonstrated an 88.8% vaccine efficacy against PHN for individuals greater than 70 years of age and 91.2% for those greater than 50 years of age. The results from these studies are very encouraging and the vaccine is currently under review by the FDA.

Clinical Picture of Postherpetic Neuralgia PHN is the most common complication of herpes zoster in the immunocompetent patient. This condition can result in significant patient suffering and causes a large economic burden to society. Our ability to diagnose and treat PHN has benefited from consensus among researchers as to its definitions and guidelines for treatment of chronic neuropathic pain conditions. Currently, the term PHN is used to describe dermatomal pain that persists for more than 90 to 120 days after the onset of the herpes zoster rash.9,33 Pain persisting for more than 180 days after the rash onset is less likely to resolve and hence can be considered “well-established PHN” to reflect its recalcitrant nature.100 Following the same pattern as herpes zoster, PHN is most commonly found in the thoracic, cervical, and trigeminal dermatomes. A variety of signs and symptoms are characteristic of patients with PHN, although none are pathognomonic. These include various types of stimulus-independent pain, for example, intermittent sharp, shooting, or electric shock-like pain and continuous burning or throbbing pain. Stimulus-evoked pain is also very common in patients with PHN and includes tactile allodynia, one of the most debilitating symptoms associated with this condition. Tactile allodynia can be so severe that patients with truncal PHN may not be able to tolerate the sensation of clothing against their skin and those with craniofacial PHN may not be able to wear hats, glasses, or tolerate even breezes or air conditioning on the affected site. Estimates of allodynia in PHN patients have ranged from 48.6% to over 90%, with differences likely due to varied quantitative sensory testing (QST) protocols and patient heterogeneity.101–103 1300

Hyperalgesia, which is an abnormally increased perception of pain in response to a painful stimulus, can occur with application of painful thermal or mechanical stimuli. These types of stimulus-independent and stimulus-evoked pain are caused by nerve damage (i.e., neuropathic pain), but musculoskeletal pain can also occur in patients with PHN as a result of excessive guarding of the affected area. Myofascial trigger points, atrophy, and reduced joint range of motion may be seen in severe cases where pain has resulted in excessive guarding. Additional sensory abnormalities are also common in PHN. Involved areas may be hypoesthetic, which can occur even in regions that exhibit tactile allodynia. The areas of altered tactile sensitivity may become larger than the sites originally affected by the zoster rash. Alterations in temperature sensation have also been demonstrated. Furthermore, various paresthesias and dysesthesias (abnormal or unpleasant but not painful sensations) can occur. Chronic pruritus can persist or develop following herpes zoster and is particularly problematic for some individuals; it may be present with or without comorbid pain. Areas of hyperpigmentation, hypopigmentation, or scarring may be present in the affected dermatomes following rash healing, and affected areas may also exhibit a persistent reddish or brownish hue. These cosmetic changes do not occur in all patients, and the skin in the affected dermatome is normal in appearance in many patients with PHN. Although less well-studied and generally less disabling than pain, altered motor function occurs in herpes zoster and can persist after rash healing. Facial paralysis may be evident in the form of ptosis or loss of the nasolabial fold in cases of facial nerve involvement. In cases of thoracic involvement, a truncal bulge resulting from intercostal muscle weakness may be present (see Fig. 27.6).

DIAGNOSIS AND ASSESSMENT OF POSTHERPETIC NEURALGIA PHN is diagnosed primarily based on clinical findings. A history of herpes zoster rash, followed by persistent pain in the same distribution, usually establishes the diagnosis. The presence of known risk factors (see the following text) on history and sensory abnormalities on physical exam 1301

such as allodynia or hyperalgesia also support the diagnosis. Occasionally, patients report having a quiescent period between the resolution of the initial herpes zoster–associated pain and the onset of the pain associated with PHN. In a study of 156 patients with PHN, Watson et al.104 noted that 25% of patients with a poor outcome said that they could recall a time after the rash when they had little or no pain. This pain-free hiatus has been observed to last for a period of weeks to as much as 12 months. The recurrence of dermatomal pain is not associated with a recurrent episode of herpes zoster but may coincide with changes in the patient’s emotional or physical status. As mentioned in the earlier discussion, a clear history of rash may not be present in all patients (i.e., zoster sine herpete). In these cases, a definitive diagnosis of VZV-related pain would require serial serologic assessments that are unlikely to be obtained in most clinical settings. In addition to assessing the location, intensity, and characteristics of the pain, it is important to evaluate the overall impact that the pain has had on the patient. PHN can cause significant deleterious impacts on physical, emotional, and social functioning and therefore can have a widespread adverse effect on health-related quality of life.105–108 In addition, PHN can lead to excess health care costs, albeit not as costly as painful diabetic peripheral neuropathy.109,110 PHN can result in fatigue, insomnia, anxiety, depression, and suicidal ideation, and careful screening for the presence of any psychiatric comorbidities or any escalation of preexisting psychiatric symptoms should be performed.

Laboratory Diagnosis Diagnostic tests have limited application in the clinical management of PHN patients. A variety of studies may be used but are predominately limited to clinical research settings. These include QST, skin biopsy, and nerve conduction studies. QST has been used to identify different phenotypic subtypes of PHN patients with distinct constellations of signs and symptoms, which are thought to reflect different pathophysiologic mechanisms. This is an especially interesting area of future research, and the hope is that such phenotypic subtypes will ultimately be used to guide mechanism-based treatment.1,2 1302

Epidemiology and Natural History of Postherpetic Neuralgia High-quality systematic studies of the epidemiology of specific chronic pain conditions are limited, including PHN. The large variation in definitions utilized, study design, and study population makes accurate estimates of incidence and prevalence of PHN difficult to obtain. Estimates of the prevalence of PHN have ranged from 500,000 to 1 million in the United States111,112 but should decrease as herpes zoster vaccination becomes more widespread. One systematic review analyzed data from 49 studies and found the risk of developing PHN after herpes zoster varied from 5% to more than 30% worldwide.18 Subsequent data from population-based studies113–115 and large clinical trials95,99 had similar findings; however, the precise figures differ greatly depending on whether patients in the community or in clinical trials were studied. PHN is a chronic pain syndrome that can last for years. There is a relative paucity of data on its natural history due to the lack of populationbased studies of zoster-related pain. Multiple studies consistently indicate that the majority of patients experience resolution of pain over weeks to months following rash onset.62,104,105,107,116,117 The presence of persistent pain at 6 months after initial PHN diagnosis has been estimated to be 48% and 20% at 1 year.10,118–120 There are few prospective studies that have followed and characterized patients for more than 6 months following the diagnosis of PHN. Hence, the exact number of patients who enjoy a complete resolution of PHN is unknown.

RISK FACTORS FOR POSTHERPETIC NEURALGIA The most well-established risk factors for PHN in patients with herpes zoster include older age, presence of a painful prodrome, greater severity of acute pain, greater rash severity, and ophthalmic involvement.105,121,122 Increasing age is a particularly potent risk factor for the development of PHN. The risk for PHN increases by 1.22 to 3.11 for every 10 year increase in age.123 Approximately 20% of patients older than 50 years of age continue to have pain at 6 months after the onset of rash despite starting antiviral agents in a timely fashion.62,67,121,124 Using a shorter 1303

duration of pain, patients 50 years of age or older were shown to have a 14.7-fold higher prevalence (95% confidence interval [CI], 6.8 to 32.0) of pain 30 days after rash onset compared with patients younger than 50 years.125 Elderly patients also seem to be predisposed to developing particularly refractory cases of PHN that do not respond to currently available treatments.104 Other risk factors for PHN are listed in Table 27.6. TABLE 27.6 Risk Factors for Postherpetic Neuralgia10,22,118,123,126 Well Replicated Older age Severity of rash Severity of acute pain Prodromal pain Less Well Replicated Ophthalmic distribution Female gender Greater sensory abnormalities in the affected dermatomes Polyneuropathy Psychosocial variables Severe immunosuppression Diabetes mellitus

Pathophysiology of Postherpetic Neuralgia Viral replication is thought to result in a combination of neural and inflammatory damage, leading to sensitization of the peripheral and central sensory neural elements. There is evidence that various risk factors identified for the development of PHN make independent contributions to the likelihood of developing this chronic pain condition,105,126 and these risk factors may reflect distinct underlying pathophysiologic mechanisms. For instance, elderly patients who are at high risk for PHN are more likely to have a subclinical polyneuropathy, which may reduce the amount of viral damage needed to cause PHN.127,128 Other examples of the possible relationships between risk factors for PHN and underlying mechanisms include the presence of a prodrome, reflecting earlier and more extensive viral damage in the affected sensory ganglion129; greater rash severity, reflecting greater damage to and loss of epidermal nerve fibers130–132; and severe acute pain, reflecting the initiation of processes that ultimately

1304

result in central and peripheral sensitization.133,134 These relatively independent processes may combine to cause more severe cases of PHN. More severe zoster infections are accompanied by greater neural damage, and it has been proposed that this neural damage contributes prominently to the development of PHN.133,135 However, knowledge of the pathophysiologic mechanisms of PHN remains limited. It is mainly derived from autopsy and skin biopsy neuroanatomic studies and research on patterns of sensory dysfunction and pharmacologic response. A variety of pathophysiologic mechanisms have been described and are hypothesized to be causally related to the qualitatively different types of pain associated with PHN. Different mechanisms may coexist in an individual patient, and there may be pathophysiologically distinct subgroups of patients.136–138 Modern anatomic understanding is based on data limited by the small number of patients studied to date. Watson and colleagues129 compared autopsy tissue from patients with and without PHN following herpes zoster. They found that patients with PHN showed marked atrophy of the spinal cord dorsal horn on the ipsilateral versus contralateral side, a difference that was not present in the patients with a history of zoster but not PHN. Punch skin biopsy permits quantitative measurement of epidermal sensory nerve endings. Such studies have shown that PHN patients have reduced innervation density in the affected dermatome compared to the contralateral side (Fig. 27.7). In one murine study of PHN, the severity of dermal denervation correlated to the development of allodynia and hyperalgesia beyond the margins of the initial herpes zoster rash.139 Notably, in both the postmortem and skin biopsy studies, pathologic features were only identified in PHN patients and were not found in patients with a history of zoster who did not go on to develop PHN.

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FIGURE 27.7 Representative, immunolabeled, dermal sensory nerve endings from skin biopsies of previously shingles-affected skin, with and without postherpetic neuralgia (PHN). A: Biopsy from the previously affected shingles site on the back of a 75-year-old woman without PHN (1,672 epidermal neuritis/mm2). B: Biopsy from the previous affected shingles site of a 72-year-old woman with PHN (145 neurites/mm2). The epidermis is at the top of the image, and the dermis is at the bottom. Individual neurites and neurite bundles are visible in the superficial dermis. (Reprinted with permission from Oaklander AL. The density of remaining nerve endings in human skin with and without postherpetic neuralgia after shingles. Pain 2001;92[1]:139–145.)

Sensory testing can be used to investigate the function of small afferent fibers including nociceptors. This type of testing helps create a detailed sensory profile of the affected area. Rowbotham and Fields have conducted a landmark series of studies of sensory dysfunction and pharmacologic response in an attempt to address the pathophysiology of PHN.136,137 The results of this research, along with that of others, have emphasized the role of central processes in interpreting sensory dysfunction and its relationship to pain in patients with PHN140–142 and have suggested that at least two different pathophysiologic mechanisms contribute to the development of PHN and other peripheral neuropathic pain conditions—sensitization and deafferentation. Both peripheral and central sensitization appear to contribute to PHN. Peripheral sensitization occurs predominately in small unmyelinated Cfiber nociceptors. Clinically, there can be minimal sensory loss in areas of marked allodynia.132,136,141 However, thermal sensory thresholds can be decreased (heat hyperalgesia) by up to 2° to 4° C95,105 in allodynic regions. 1306

Heat hyperalgesia is a well-known consequence of peripheral nociceptor sensitization.130 These observations all suggest that sensitization of C nociceptors can be responsible for the spontaneous burning pain and heat hyperalgesia seen in some patients. In many PHN patients, the area of mechanical or tactile allodynia is much larger than the area originally affected during herpes zoster and the painful area may continue to change with time. Allodynia in a subset of PHN patients may be caused by ectopic discharges from damaged C nociceptors maintaining a state of central sensitization.136,143 The major excitatory neurotransmitter involved in spinal cord pain processing is glutamate, and binding at the N-methyl-Daspartic acid (NMDA) receptor has been thought to play a key role in central sensitization. The importance of persistent sensitization has been supported by the work of Petersen and Rowbotham,135 who found patients with PHN were more likely to have a positive response to capsaicin application with expansion of allodynic area when compared to those with no pain at 6 months after having herpes zoster. Dynamic and tactile allodynia may also result from sprouting of Aβ fibers into the superficial layers of the dorsal horn in response to partial loss of C-fiber input. This sprouting may lead to connections between these fibers, which normally do not transmit pain, and the ascending pain pathways that were formerly responsive to C-fiber input. This process would explain why nonpainful stimuli such as light touch or pressure can become painful in patient with PHN. Deafferentation may also be playing a significant role in the maintenance of PHN. In a subset of patients, there is a loss of both large and small diameter sensory afferent fibers. This loss of peripheral input can result in the development of spontaneous discharge in deafferented central neurons. This may produce constant pain in the area of sensory loss.136 Interestingly, these patients may still suffer from severe mechanical allodynia.144 Assuming that the DRG and central connections are lost in such patients, the pain may be due to intrinsic CNS changes. However, there have been some studies that question the role of deafferentation in PHN due to the findings of persistent sensory abnormalities in patients with PHN and those without pain after HZ.135,145 The mentioned data suggest that there may be subsets of patients within 1307

the PHN population who have different underlying mechanisms responsible for the generation and maintenance of their chronic pain. These different mechanisms may account for the varied presentations of pain in patients with PHN. Unfortunately, these observations have yet to provide the foundation for a mechanism-based approach for selecting specific pharmacologic treatment options in clinical practice. This, of course, would be an extremely desirable goal to improve the therapeutic effects of existing treatments.

Treatment of Postherpetic Neuralgia Tricyclic antidepressants, various anticonvulsants, opioid analgesics, and topical lidocaine are efficacious in the management of PHN (Table 27.7). There is a limited role of invasive interventions and alternative modalities, but these are utilized for patients who are refractory to conservative modalities. The choice of which therapy is used is often individualized based on the patient’s comorbidities, concomitant medication use, and associated symptoms. Recent studies have evaluated the relative efficacy of these treatments.146,147 Additionally, consensus recommendation and guidelines for the pharmacotherapeutic treatment of neuropathic pain, including PHN, have been published and serve as useful guides in selecting between the growing list of treatment options.148–151 Despite the publication of treatment recommendations, many patients in the community with PHN do not receive evidence-based pharmacotherapy.152 In clinical practice, certain anticonvulsants, topical lidocaine, and tramadol are often used as first-line medications, followed by serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, opioids, and high-dose capsaicin patch. Capsaicin patch as a second-line therapy is used in part because of better tolerance in elderly patients. Needless to say, all patients should have a thorough assessment, and treatment should be tailored to address their individual needs.

TABLE 27.7 Pharmacologic Options for the Treatment of Postherpetic Neuralgi Medication

Starting Dose

Dose-Escalation Scheme

Common Side Effects

Contraindications/ Caution

Comments

Gabapentin

100–300 mg

Start qhs and

Somnolence,

Decrease dose in

No clinically

1308

increase to tid dosing; increase by 100–300 mg every 3 d to total dose of 1,800–3,600 mg

dizziness, fatigue, ataxia, peripheral edema, and weight gain

patients with renal impairment; qod dosing in dialysis patients

Gastroretentive o

Pregabalin

50 mg tid or 75 mg bid

300–600 mg/d in 1 wk

Somnolence, fatigue, dizziness, peripheral edema and weight gain, blurred vision, and euphoria

Decrease dose in patients with renal impairment by 50% or more based on CL creatinine

Caution with

SNRIs Duloxetine Venlafaxine

30 mg qd 37.5 mg qd

Increase by 30 mg weekly to a max dose of 60–120 mg/d Increase by 37.5– 75 mg weekly to a max dose of 150–225 mg/d

Nausea Insomnia, somnolence, fatigue, dizziness Nervousness, sexual dysfunction Constipation Decreased appetite

Be careful in

Increase by 10– 25 mg weekly

Sedation, dry mouth, blurred

Concomitant use of tramadol, MAO inhibitors, SSRI, or TCAs duloxetine is contraindicated in patients with liver disease. Caution in patients with close angle glaucoma especially with duloxetine and hypertension especially with venlafaxine Cardiac arrhythmic disease,

TCAs Nortriptyline

10–25 mg qhs

1309

Venlafaxine has

The lower startin

with a target dose of 75–150 mg

Desipramine Amitriptyline

Topical lidocaine

High-dose % capsaicin patch

Tramadol

Strong opioids Morphine

5%, 1–2 patches

Can use up to 3 patches 12 h/d

vision, weight gain, urinary retention, constipation, sexual dysfunction

glaucoma, suicide risk, seizure disorder; concomitant use of tramadol, SSRI, or selective SNRIs

Local erythema, rash, blisters

Known hypersensitivity to amide local anesthetics

No significant

Amitriptyline ha

Caution in patien

Needs to be placed in a monitored setting 50 mg every 6 h prn

1–4 patches depending on the size of the affected area

Local irritation, erythema, and rash

Can lead to temporary increase in pain and discomfort

Need for systemi

Can titrate up to 100 mg every 6 h; max daily dose: 400 mg Extended release dosing once a day

Nausea/vomiting, constipation, drowsiness, and dizziness

Available as

5–10 mg every 4–6 h prn

Titrate at weekly intervals balancing analgesia and side effects if patient tolerating the medications can titrate faster.

Nausea/vomiting, constipation, drowsiness, and itching

Seizure disorder, concomitant use of SSRI, selective SNRI, TCA medications. Decrease dose in patients with hepatic or renal disease. Driving impairment and cognitive dysfunction during treatment initiation. Be careful in patients with sleep apnea. Additive effects of sedation with neuromodulators

1310

Gradual titration

Oxycodone

Methadone

2.5–5 mg every 6 h prn 2.5 mg tid

Fentanyl patch

12 µg/h

Botulinum toxin A

Needs specialist services

50–200 units injected subcutaneously over multiple sites of the affected area in small aliquots.

Allergic reaction, rash, itching, headache, localized pain, muscle stiffness, shortness of breath, nausea, diarrhea, flulike symptoms

Only should be prescribed by provider familiar with its titration and in opioidtolerant patient Only should be prescribed by provider familiar with its titration and in opioidtolerant patient Be cautious if patient on medications that can affect the neuromuscular junction function like aminoglycosides

NOTE: Must start a patient on short-acting opioid medications before changing over to a fentanyl patch. Differences in recommended dosages of medications between Tables 27.5 and 27.7 are in part because of the acuity of pain in herpetic neuralgia versus postherpetic neuralgia. ACE, angiotensin-converting enzyme; CL, clearance; CNS, central nervous system; GI, gastrointestinal; MAO, monoamine oxidase; MME, morphine milligram equivalents; prn, when necessary; qd, every day; qhs, every night or at every bedtime; qod, every other day; SNRI, serotonin norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant; tid, three times a day. Originally adapted from Wu CL, Raja SN. An update on the treatment of postherpetic neuralgia. J Pain 2008;9(1 Suppl):S19–S30. Copyright © 2008 American Pain Society. Modified based on our clinical practice and guidelines for neuropathic pain : Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol 2015;14(2):162–173. Copyright © 2015 Elsevier. With permission.

ANTICONVULSANTS: GABAPENTIN AND PREGABALIN Although a number of anticonvulsants have been used for many years for the treatment of PHN and other neuropathic pain conditions, the greatest evidence of efficacy exists for gabapentin and pregabalin. Both are welltolerated and much less toxic than the first-generation anticonvulsants 1311

Contraindicated

previously used to treat neuropathic pain. There is good evidence to support the use of gabapentin in PHN. In two large clinical trials,153,154 its use was associated with a statistically significant reduction in daily pain ratings as well as improvements in sleep, mood, fatigue, and depression as well as other quality of life indicators like improved function and work at daily dosages of 1,800 to 3,600 mg. A meta-analysis of these trials indicated the number needed to treat (NNT) for gabapentin in the treatment of PHN is approximately 4.4 (95% CI, 3.3 to 6.1).76 The precise mechanism of its analgesic action is not known, but evidence derived from rodent models suggests that gabapentin acts at the α2δ subunit of voltagedependent calcium channels to decrease calcium influx. This effect inhibits the release of the excitatory neurotransmitters, including glutamate.155,156 As noted in the earlier discussion, glutamate, via its effect at the NMDA receptor, is the primary neurotransmitter responsible for maintaining central sensitization. Gabapentin is rapidly absorbed after oral administration. However, its absorption is mediated by a transport mechanism present only in the proximal part of small intestine that becomes saturated at higher doses. This phenomenon reduces the bioavailability of gabapentin as the dose is increased. For example, the bioavailability of gabapentin at a dose of 300 mg is about 60%, but the bioavailability falls to 40% with a 600-mg dose. Additionally, its half-life is 5 to 7 hours, necessitating three or four doses in a day. Peak serum concentrations are achieved approximately 3 hours after oral administration. Gabapentin does not exhibit significant protein binding, is eliminated unchanged via the kidneys, and is not metabolized by the liver. The optimal dosing schedule for gabapentin has not been well characterized. One review suggested that dosing should be initiated at 300 mg on the first day, followed by 300 mg twice daily on the second day, and then increased to 300 mg three times daily on the third day.157 At that point, the titration should be slowed down with a goal of reaching 600 mg three times daily over the ensuing 2 weeks. Daily dosages of up to 3,600 mg have been studied and shown efficacious.153 The daily dosage should be divided into three or four doses per day as this drug has a relatively short half-life. In elderly patients, dosages should be reduced and titration 1312

should be executed more slowly. In frail patients, it is typical to start with 100 mg per day, increasing by 100 mg every 3 to 4 days. Once patients are tolerating a daily dose of 600 mg, the titration rate may be increased by 300 mg per day every 3 to 4 days to a target of 1,800 to 2,400 mg per day. The titration schedule may need to be modified if efficacy is achieved at lower dosages or unmanageable side effects are encountered. As gabapentin is excreted renally, dosages need to be adjusted in patients with renal insufficiency. Patients on dialysis should be started on a single dose of 100 mg given 1 hour after dialysis treatment on alternate days. This dose then can be titrated up slowly and cautiously. Of note, gabapentin is also available as an oral solution in 250 mg/5 mL preparation. Side effects associated with gabapentin include somnolence, dizziness, peripheral edema, and gait or balance problems. In general, the side effects are short lived, but they can require monitoring and occasionally dosage adjustment. Newer formulations of gabapentin have attempted to circumvent the issue of variable bioavailability of gabapentin. These include gastroretentive formulation of gabapentin (G-GR) and gabapentin enacarbil (GEn). The G-GR preparation is designed in a way that leads to a slow and steady release of gabapentin, resulting in a more efficient absorption, improved bioavailability, and possibly reduced side effects of somnolence and dizziness compared to regular gabapentin. Patients can titrate up an effective dose more quickly than regular gabapentin. An 11week randomized, double-blind, placebo-controlled phase 3 clinical trial showed significant reduction in pain intensity and sleep interference in patients with PHN.158 It is administered as a once-daily dosing of 1,200 to 1,800 mg with an evening meal. The dose should be adjusted in patients with renal impairment and is contraindicated in patients on hemodialysis. Once-daily dosing could be a tremendous help in terms of patient compliance. GEn is a prodrug of gabapentin that is actively transported and provides sustained, dose-proportional exposure to gabapentin. It is absorbed by a high-capacity transport system throughout the gut in comparison with the low-capacity transporter system in the upper intestine for regular gabapentin, hence, is said to provide a dose-proportional and extended 1313

exposure to gabapentin. It can be dosed in twice-daily dosing. Three different doses have been studied: 1,200, 1,800 and 3,600 mg total daily dose (divided into two dosages). All three daily dosages were efficacious in reducing pain intensity in patients with PHN, but the 1,200-mg dose demonstrated the most favorable balance between efficacy and adverse effects.159 G-GR or GEn are not as popular in clinical practice as the regular gabapentin despite significant advantages over the latter. The possible reasons could be provider familiarity and lower costs of standard generic gabapentin. Pregabalin appears to have a similar mechanism of action as gabapentin, and several large randomized clinical trials have demonstrated its efficacy in the treatment of PHN and other neuropathic pain conditions. Three double-blind trials comprising 776 patients with PHN showed that pregabalin resulted in superior pain relief and improved pain-related sleep interference compared to placebo. Dosages in these studies ranged between 150 and 600 mg per day,160 and both fixed as well as flexible dosing schedules have been efficacious in clinical trials.161,162 Pregabalin can be given in two divided doses each day. Frequently reported side effects are the same as with gabapentin: somnolence, dizziness, peripheral edema, and balance problems. Pregabalin has also been demonstrated to possess an anxiolytic effect in patients with generalized anxiety disorder.163,164 As patients with chronic pain often have comorbid anxiety disorders, it is possible that this anxiolytic effect may provide additional benefit in PHN patients. The analgesic efficacy and side effect profiles of gabapentin and pregabalin appear to be comparable. Pregabalin has greater convenience than gabapentin because of its twice-daily dosing and simpler titration, however, and an effective analgesic dosage can be reached more rapidly with pregabalin. Pregabalin CR is an extended release preparation in oncedaily dosing. In a recent study, it was found to be more effective in decreasing weekly mean pain scores when compared with placebo as early as week 1 and the effect was maintained until the final end point.165 Primary efficacy outcome was time to loss of therapeutic response (LTR) ( pla

SCI

Cardenas et al. 2002177,a

84

Amitriptyline 125 mg

Ami = pla

SCI

Rintala et al. 2007178

38

Amitriptyline 150 mg

Ami > pla

MS

Österberg and

23

Ami > pla

SCI/CPSP

Boivie 2005179 Vranken et al. 2011180

Amitriptyline 75 mg

48

Duloxetine 120 mg

Dul = pla

Pregabalin/gabapentin MS Kim et al. 2011253

220

Pre = pla

SCI

Siddall et al. 2006181

137

Pregabalin 600 mg Pregabalin 600 mg

SCI

Cardenas et al. 2013182

220

Pregabalin 600 mg

Pre > pla

SCI/CPSP

Vranken et al. 2008254

40

Pregabalin 600 mg

Pre > pla

SCI

Levendoglu et al. 2004255

20

Gabapentin 3,600 mg

Gab > pla

SCI

Rintala et al. 2007178

38

Gabapentin 3,600 mg

Gab = pla

Other Anticonvulsants CPSP Vestergaard et al. 2001183

30

Lamotrigine 200 mg

Lam > pla

SCI

Finnerup et al. 2002184

30

Lamotrigine 400 mg

Lam = pla

MS

Breuer et al. 2007256

17

Lamotrigine 400 mg

Lam = pla

CPSP

Leijon and Boivie 1989176

15

Carbamazepine 800 mg

Car = pla

MS

Österberg and

23

Carbamazepine 600 mg

Car = pla

20

Valproate 2,400 mg

Val = pla

Antidepressants CPSP

Boivie, 2005179 SCI

Drewes et al. 1994257

1359

Pre > pla

SCI

Finnerup et al. 2009258

36

Levetiracetam 3,000 mg

Lev = pla

CPSP

Jungehulsing et al. 2012259

42

Levetiracetam 3,000 mg

Lev = pla

CPSP

Falah et al. 2012260

30

Levetiracetam 3,000 mg

Lev = pla

Norrbrink and Lundeberg 2009261

36

Tramadol 400 mg

Tra > pla

Svendsen et al. 2004262

24

Dronabinol 10 mg

Can > pla

MS

Rog et al. 2005263,a

66

Sativex spray

Can > pla

MS

Langford et al. 2013264

339

Sativex spray

Can = pla

SCI

Clinicaltrials.gov (NCT01606202)

111

Sativex spray

Can = pla

Chiou-Tan et al. 1996265

11

Mexiletine 450 mg

Mex = pla

SCI

Han et al. 2016266

40

SCI

Andresen et al. 2016267

73

Botulinum toxin type A Palmitoylethanolamide 600 mg

BTX-A > pla PEA = pla

Opioids SCI

Cannabinoids MS

Other SCI

aStudy

includes nonneuropathic pain conditions. Ami, amitriptyline; BTX-A, botulinum toxin type A; Can, cannabinoid; Car, carbamazepine; CPSP, central poststroke pain; Dul, duloxetine; Gab, gabapentin; Lam, lamotrigine; Lev, levetiracetam; Mex, mexiletine; MS, multiple sclerosis; PEA, palmitoylethanolamide; pla, placebo; Pre, pregabalin; SCI, spinal cord injury; Tra, tramadol; Val, valproate.

First-line Pharmacologic Treatments First-line pharmacologic treatments in central pain include tricyclic antidepressants (TCAs), serotonin-noradrenaline reuptake inhibitors (SNRIs), pregabalin, and gabapentin (Fig. 28.3).175

1360

FIGURE 28.3 Treatment algorithm for the pharmacologic treatment of central pain.

TCAs and SNRIs inhibit the presynaptic reuptake of serotonin and noradrenaline, and in addition, TCAs act on voltage-gated sodium channels and opioid and N-methyl-D-aspartate (NMDA) receptors.186,187 The site of action is through descending aminergic pathways at spinal or supraspinal sites, but a peripheral site of action via sympathetic fiber sprouting in the dorsal root ganglia may also be involved.186,187 The analgesic action of noradrenaline is likely to be mediated through both α2A and β2 adrenoceptors.187 The combined NNT for TCAs in neuropathic pain was 3.6 (95% CI, 3.0 to 4.4) with a moderate quality of evidence, and the combined NNT for SNRIs was 6.4 (5.2 to 8.4) with a high quality of evidence.175 NNTs are not directly comparable due to differences in study design. The effect of antidepressants is independent of the antidepressant effect,176 although in a study in SCI patients, the effect on pain was more pronounced in those with considerable depressive symptomatology.178 Amitriptyline is the TCA most often studied in neuropathic pain, but there is no clinical evidence to suggest superior efficacy of one TCA, and imipramine and the TCAs with secondary amine structure (nortriptyline and desipramine) are often better tolerated.188 The first study in central pain compared the effect of amitriptyline 75 mg per day with that of carbamazepine 800 mg per day and placebo in 15 patients with CPSP (see Table 28.2).176 Amitriptyline, 1361

but not carbamazepine, significantly relieved central pain, and the effect size was highest if the total plasma concentrations of amitriptyline and its metabolite nortriptyline exceeded 300 nmol/L. Later studies also found an effect of amitriptyline in SCI- and MS-related pain,178,179 whereas one study failed to show an effect of amitriptyline in SCI pain, but this study did not exclusively include neuropathic pain.177 In one small study, duloxetine relieved CPSP and SCI pain, but the difference was not statistically significant.180 Side effects to TCAs include drowsiness, fatigue, weight gain, and effects related to anticholinergic actions such as dry mouth, constipation, urinary retention, and orthostatic hypotension. TCAs should not be used in patients with heart failure, and precautions should be taken in patients with cardiac conduction disturbances, seizures, and glaucoma. Tertiary amine TCAs (amitriptyline, imipramine, and clomipramine) and high TCA doses are not recommended in patients above 65 years of age due to the increased risk of falls or sudden cardiac death.189,190 TCAs should be used with caution in combinations with other serotonergic agents due to the risk of serotonin syndrome. TCAs should be titrated slowly, starting at 10 to 25 mg daily and titrated up to 75 to 100 mg per day. TCAs are metabolized by the hepatic cytochrome P450 system, and genetic polymorphisms at CYP2D6 cause variability in pharmacokinetics. Titration is normally guided by the clinical response, but serum drug concentration measurements may improve the outcome.186 SNRIs and selective serotonin reuptake inhibitors may cause nausea, abdominal pain, sedation, dizziness, sweating, and sexual dysfunction. They may also cause blood pressure elevation. Duloxetine is given at doses of 60 mg daily and should be avoided in patients with moderate liver disease and renal impairment with creatinine clearance below 30 mL per minute. Venlafaxine treatment should be titrated slowly up to 150 mg per day, with reduced dosage in patients with renal and liver impairment. For both drugs, drug–drug interactions concern serotonergic agents and drugs affecting coagulation. Gabapentin and pregabalin are ligands of the α2δ subunit of voltagegated calcium channels, and the analgesic effects is thought to be mediated through an attenuation of calcium channels influx into cells and a reduced release of neurotransmitters, although other actions such as an effect on 1362

glia cells and expression of proinflammatory cytokines may also be involved.187 The expression of the α2δ calcium channel subunit can be increased in some neuropathic pain conditions, but the effect of gabapentin and pregabalin does not require increased α2δ subunits.187 Gabapentin and pregabalin act at peripheral, spinal, and supraspinal levels.187,191–193 The combined NNT for gabapentin in neuropathic pain was 6.3 (95% CI, 5.0 to 8.3), and the NNT for pregabalin was 7.7 (95% CI, 6.5 to 9.4) with a high quality of evidence. Six studies have examined the effect of gabapentin or pregabalin in central pain, of which four were positive on the primary outcome (see Table 28.2). The two largest studies in SCI pain found an effect of pregabalin as add-on therapy on pain, pain-related sleep interference, and anxiety with a combined NNT of 7.0 (4.5 to 16.5).181,182 Pregabalin showed an effect on anxiety scores on the Hospital Anxiety and Depression Scale (HADS) in one study181 and on depression scores in another study,182 although patients did not have clinically relevant levels of anxiety and depression. Pregabalin tended to be more effective in those with a high HADS score.181,194 Side effects include somnolence, dizziness, peripheral edema, and weight gain. The frequency of somnolence may be higher in patients with central pain,181 possibly due to a high frequency of concomitant medication for pain and spasticity. Gabapentin is initiated at 100 to 300 mg per day and increased up to 1,800 to 3,600 mg daily in three divided doses, and pregabalin is increased from 75 mg twice daily to 300 to 600 mg per day. Doses should be decreased in patients with renal insufficiency.

Second- and Third-Line Pharmacologic Treatments Tramadol is a weak agonist of µ-opioid receptors and a SNRI. The combined NNT for tramadol in neuropathic pain was 4.7 (95% CI, 3.6 to 6.7) with a moderate quality of evidence, and tramadol is recommended as a second-line drug.175 Tramadol is particularly useful in the treatment of episodic exacerbations of pain.195 The combined NNT for strong opioids, including morphine and oxycodone, in neuropathic pain was 4.3 (95% CI, 3.4 to 5.8) with a moderate quality of evidence.175 Due to potential safety concerns with risk of abuse, cognitive impairment, and endocrine and 1363

immunologic changes,196–199 the final strength of recommendation was weak, and opioids were recommended as third-line drugs.175

Other Drugs, Combination Therapy, and Intrathecal Drug Administration The recommendations for other antiepileptics for neuropathic pain are inconclusive due to conflicting and overall negative results.175 However, some patients do seem to respond to sodium channel blockers,200 and there was an effect of lamotrigine in one study of CPSP,183 and post hoc analyses suggested effect of lamotrigine in SCI subjects with incomplete lesions and evoked pain.184 In addition, a recent study in peripheral neuropathic pain found that oxcarbazepine was effective in patients with preserved nociceptors and evoked pain but not in those without this pain phenotype.201 Therefore, sodium channel blockers may be indicated in some patients, although further studies are needed to confirm the specific predictors for effects.202 For neuropathic pain in general, there was an overall weak recommendation against the use of cannabinoids.175 Also in central pain, the results are conflicting (see Table 28.2), and more studies on the long-term efficacy and safety are needed to establish whether there is a role for the use of cannabinoids in central pain. When treatment with a single drug is only partly effective, combination with another drug of a complementary mechanism of action may be tried. Side effects should be carefully monitored, and normally sequential add-on therapy is recommended. In refractory cases, spinal drug administration may be considered. There is, however, little evidence from randomized controlled trials. One study examined clonidine, morphine, and their combination in SCI pain.203 Each drug alone did not provide significant pain relief, but the combination of clonidine and morphine provided effect on central pain. The effect size correlated with the concentration of morphine in the cervical cerebrospinal fluid, and it was suggested that if there is a pathology restricting the flow of cerebrospinal fluid, the drugs need to be administered above the level of injury.203 Ziconotide—a drug that is given intrathecally—is recommended for moderate to severe chronic pain and can be combined with intrathecal morphine or baclofen, but there is limited experience with central pain, 1364

and the treatment is often associated with severe side effects.204 Short-term side effects to spinal drug administration include nausea, sedation, hypotension, and respiratory depression. Lidocaine, ketamine, and opioids given intravenously have also been shown to relieve central pain, but these treatments have a limited role in chronic pain treatment.205–209

PSYCHOLOGICAL AND PHYSIOTHERAPY TREATMENT The treatment of central pain often requires a multidisciplinary approach. A large proportion of patients use nonpharmacologic treatments, and patients with SCI reported that massage and heat were the nonpharmacologic treatments to result in the best pain alleviation.210 Concomitant psychological distress, anxiety, and depression should be treated. Cognitive-behavioral therapy and other psychological interventions may be useful.211 A Cochrane review evaluated the effects of psychological treatments on pain, disability, mood, and health care used in patients with neuropathic pain and found that there was insufficient evidence of psychological interventions with only two eligible studies.212 Smaller studies have found some effect of hypnosis on the impact of MSrelated pain,213,214 personalized positive psychology exercises in different central pain conditions,215 and multidimensional pain management programs comprising educational, cognitive, and behavioral intervention in SCI pain.216,217 Another systematic review with less strict criteria concluded that virtual reality interventions and hypnosis are effective for pain related to MS and SCI.218 Physical therapy may be useful in alleviating musculoskeletal pain, spasticity, and other complications to a CNS disorder. Visual illusion, where patients see a movie of a lower body walking aligned with a mirror image of their own upper body, has been shown to decrease pain in SCI in small trials.219,220 Other studies have found increased pain following movement imagery in patients with complete SCI,168 and neurofeedback aimed at self-regulating abnormal brain activity during imaged movement has been suggested to be effective in central pain in SCI.221 More information is needed on the methodology, long-term efficacy, and predictors of response of various techniques related to visual illusion and 1365

neurofeedback.

NEUROSURGICAL MANAGEMENT The neurosurgical management of central pain can be utilized when noninvasive treatment options fail. A multitude of techniques have been employed with myriad anatomical targets in the peripheral nervous system and CNS with varying degrees of efficacy. Lack of consistent evidence secondary to the variability in techniques across centers as well as small sample sizes has led to difficulty in drawing definitive conclusions. Currently, evidence for the majority of neurosurgical treatment options lies within case reports or small case series that consistently find improvement in variable degree in a subset of patients. Central pain syndromes are notoriously recalcitrant to medical treatment, and consideration should be given to offering neurosurgical intervention depending on the type of pain, severity, and influence on quality of life in each individual case.

Targeted Drug Delivery Targeted drug delivery into the subarachnoid space for the treatment of refractory central pain has been attempted through various techniques including most commonly via a catheter inserted into the intrathecal space in the spinal column or less commonly directly into the brain via an intraventricular catheter. The catheters are subsequently connected to a subcutaneously implanted drug delivery pump allowing the controlled infusion of a variety of medications. Infused drugs of choice have included GABAergic agonists like baclofen or midazolam, sometimes in combination with an adrenergic agent such as clonidine.222,223 One randomized, double-blind study in 15 patients undergoing intrathecal drug delivery for the treatment of neuropathic pain after SCI found that the combination of morphine and clonidine produced significantly greater pain control than placebo or either medication given alone.203 Much of the literature about pain reduction via subarachnoid infusion of medication in central pain states comes from patients with SCI and MS undergoing intrathecal therapy for the treatment of spasticity and suggests that there is direct additional suppression of neuropathic pain distinct from the suppression of spasm-related pain,224 although no controlled studies have 1366

been published and there is general consensus that the effects are limited.

Neuroablation Since the introduction of stereotactic surgery in the late 1940s, targeted neuroablative techniques have been utilized to intervene in central pain pathways in the most refractory patients suffering from pain syndromes. Some of the more successfully targeted regions include the sensory thalamus in patients undergoing stereotactic or radiosurgical thalamotomy and the spinothalamic and quintothalamic pathways in stereotactic mesencephalotomy225 most commonly used for the treatment of CPSP. New techniques have largely replaced these ablative procedures with the capacity for reversible and titratable modulation of deep brain-stimulating electrodes. These are now most often used in the treatment of pain except in certain circumstances where ablative techniques are preferred, most notably in the palliative treatment of cancer-related pain. Technologic advancements in our ability to create lesions in the brain through incisionless techniques, including new technology such as MR-guided high-intensity focused ultrasound, as well as improvements in the use of focused radiation may forecast a resurgence in interest in the revival of these ablative techniques.

Neuromodulation Motor Cortex Stimulation Perhaps the most robust evidence in the neurosurgical treatment of central pain lies in epidural cortical stimulation (ECS), most commonly of the motor cortex. This treatment modality was first reported in 1991 by Tsukobawa et al.,226 after investigating the cortical patterns associated with burst hyperactivity of thalamic neurons in an animal model of STT deafferentation. They found that stimulation of the motor cortex provided complete, long-term inhibition of this burst hyperreactivity and applied this model to a case series of patients with thalamic pain syndrome by inserting epidural electrode over the motor cortex, ultimately achieving “excellent or good” pain control in all cases. Indications for motor cortex stimulation (MCS) have expanded over the last decade to include refractory SCI pain, phantom limb pain, and neuropathic facial pain among 1367

many others.227 This procedure is performed via a small craniotomy or burr hole contralateral to the region of pain. The sensory and motor cortices are typically mapped intraoperatively using electrophysiology to identify the central sulcus. Typically, one or two 4-contact strip electrodes are then placed in the targeted region in either a longitudinal orientation over the motor cortex or perpendicular to the central sulcus in the epidural space. The electrodes are then sutured down, and extension wires are typically externalized for a 3- to 7-day trial during which pulse width, frequency, and amplitude are optimized. There is a considerable amount of variation in stimulation parameters, and typically, the stimulus intensity is increased to test the motor threshold and decreased subsequently as a percentage of this amplitude. Patients typically do not experience paresthesias or other stimulation-induced sensory phenomena. If patients are felt to achieve sufficient (typically 40% or more) pain relief, stage 2 of the trial involves removing the trial extension wires and tunneling the lead to an infraclavicular implantable pulse generator (IPG), most often placed in the infraclavicular space.228 MCS has risks that are typical of most cranial procedures, including infection and the possibility of hemorrhage, as well as seizures and hardware problems; however, these complications are rare, and the procedure is considered overall to be safe.229,230 Although the mechanisms that underlie the effects of MCS have not been clearly identified, studies suggest that activity in the first- and second-order somatosensory pathways is affected,231 and various patterns of cerebral blood flow changes have been noted in thalamus and other regions of the brain in successful cases.232 In a critical review of the literature, greater than 40% improvement in pain scores were reported in 54% of 117 patients with central pain.230 Good results have also been reported in isolated cases of patients with pain secondary to MS233 and pain after posttraumatic brain injury234; however, CPSP has been the most comprehensively studied central pain indication. In a review of its efficacy, Nguyen et al.235 reported that MCS showed a greater than 40% pain reduction on the VAS in 60% of patients with CPSP. Although these and other trials have demonstrated the efficacy of MCS in the treatment of various types of neuropathic pain, they include a limited number of 1368

patients and often patients with various etiologies of pain are analyzed concurrently. These findings thus need to be confirmed by larger, randomized controlled multicenter trials and include more methodical selection of patient cohorts.235,236 Deep Brain Stimulation Deep brain stimulation has been used for the treatment of pain since the 1950s and became widely employed by the 1970s for the treatment of neuropathic pain of various origins.236 Enthusiasm for using this treatment modality for chronic, refractory pain was dampened when two industry supported open-label studies failed to reach their clinical endpoints for success.237 Critics of these trials contend that they were neither randomized nor case-controlled, had variability in patient selection, inconsistencies in neurosurgical technique, and lack of rigorous evaluation of individual pain etiologies which have been shown to have dramatically variable responses to invasive treatment.236,238,239 Utilizing improvements in hardware, imaging modalities, and with attention to patient selection, specialized centers across the country continue to use deep brain stimulation effectively for the treatment of various types of pain syndromes on an “off label” basis. Currently, there is no consensus for best anatomical target in the treatment of pain, and many regions of the brain have been trialed over past several decades. The most commonly utilized targets the sensorydiscriminative sphere of pain circuitry and includes the PAG area/periventricular gray area (PVG)240 and the Vc (ventral posterior lateral) nucleus of the sensory thalamus.227,241 More recently, efficacy has been found in regions targeting the affective components of pain including ACC242 and the anterior limb of the internal capsule (ALIC).243 The surgical approach is similar in nature and risk to the technique widely used for implanting deep brain-stimulating leads for the treatment of movement disorders including Parkinson’s disease and essential tremor. Risks are rare but potentially serious and include most commonly infection, hemorrhage, and hardware complications. A variety of case reports and case series have demonstrated efficacy in the treatment of various central pain pathologies including MS,244 pain 1369

from malignancy,245 and pain after SCI246,247 as well as CPSP.239,243,245 One large series comprising a variety of pain etiologies found overall that 60% of patients gained benefit and that the degree of efficacy varied by pathophysiology.239 In this cohort, 15 patients were treated with deep brain stimulation for CPSP with stimulators placed in the PVG, Vc, or both. VAS scores revealed a mean improvement of 48.8% with a wide variability between patients and was found to be an effective treatment overall in 70% of patients.239,245 In 2016, the European Academy of Neurology (EAN) published guidelines on the role of neurostimulation in the treatment of neuropathic pain and concluded that studies for deep brain stimulation were heterogeneous and imprecise and despite some clear demonstration of efficacy were inconsistent in their findings. This lead the committee to an “inconclusive” recommendation as to the efficacy of this treatment modality.248 Although deep brain stimulation has proven to be a potentially effective tool for those patients with severe, refractory central pain who have failed all other less invasive treatment modalities, prospective, randomized controlled trials are needed to further delineate effective targets, reliable stimulation parameters, and to refine patient selection criteria. Spinal Cord Stimulation Spinal cord stimulation (SCS) therapy is used most often to treat peripheral neuropathic pain, pain from failed back surgery syndrome, or complex regional pain syndrome and is not commonly employed in the treatment of central pain,249 with some claiming that it plays no role in the treatment of brain central pain.223 Few case reports support its use in CPSP,250,251 citing modest long-term improvement. Reports of SCS in the use of pain from SCI similarly vary in their efficacy and are generally lacking. In one seminal series from 1972 of 30 patients undergoing SCS, 5 were implanted for pain from traumatic SCI including spinal fractures, gunshot wounds to the spine, and cord contusions, none of whom had an “excellent” response to treatment.252 Since then, further reports have corroborated a generally poor response in these patients when compared to traditional indications like failed back surgery syndrome and pain from 1370

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pain: a randomized, double-blind, placebo-controlled trial of a flexible-dose regimen. Pain 2008;136:150–157. Levendoglu F, Ogün CO, Ozerbil O, et al. Gabapentin is a first line drug for the treatment of neuropathic pain in spinal cord injury. Spine (Phila Pa 1976) 2004;29:743–751. Breuer B, Pappagallo M, Knotkova H, et al. A randomized, double-blind, placebo-controlled, two-period, crossover, pilot trial of lamotrigine in patients with central pain due to multiple sclerosis. Clin Ther 2007;29:2022–2030. Drewes AM, Andreasen A, Poulsen LH. Valproate for treatment of chronic central pain after spinal cord injury. A double-blind cross-over study. Paraplegia 1994;32:565–569. Finnerup NB, Grydehøj J, Bing J, et al. Levetiracetam in spinal cord injury pain: a randomized controlled trial. Spinal Cord 2009;47:861–867. Jungehulsing GJ, Israel H, Safar N, et al. Levetiracetam in patients with central neuropathic post-stroke pain—a randomized, double-blind, placebo-controlled trial. Eur J Neurol 2013;20:331–337. Falah M, Madsen C, Holbech JV, et al. A randomized, placebo-controlled trial of levetiracetam in central pain in multiple sclerosis. Eur J Pain 2012;16:860–869. Norrbrink C, Lundeberg T. Tramadol in neuropathic pain after spinal cord injury: a randomized, double-blind, placebo-controlled trial. Clin J Pain 2009;25:177–184. Svendsen KB, Jensen TS, Bach FW. Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomised double blind placebo controlled crossover trial. BMJ 2004;329:253. Rog DJ, Nurmikko TJ, Friede T, et al. Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis. Neurology 2005;65:812–819. Langford RM, Mares J, Novotna A, et al. A double-blind, randomized, placebo-controlled, parallel-group study of THC/CBD oromucosal spray in combination with the existing treatment regimen, in the relief of central neuropathic pain in patients with multiple sclerosis. J Neurol 2013;260:984–997. Chiou-Tan FY, Tuel SM, Johnson JC, et al. Effect of mexiletine on spinal cord injury dysesthetic pain. Am J Phys Med Rehabil 1996;75:84–87. Han ZA, Song DH, Oh HM, et al. Botulinum toxin type A for neuropathic pain in patients with spinal cord injury. Ann Neurol 2016;79:569–578. Andresen SR, Bing J, Hansen RM, et al. Ultramicronized palmitoylethanolamide in spinal cord injury neuropathic pain: a randomized, double-blind, placebo-controlled trial. Pain 2016;157:2097–2103.

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PSYCHOLOGICAL CONTRIBUTIONS TO PAIN CHAPTER 29 The Psychophysiology of Pain C. RICHARD CHAPMAN and FADEL ZEIDAN Psychophysiology is a field of study that seeks to relate subjective awareness and behavior to physiologic events.1–3 As a field of scientific inquiry, it concerns itself with central mechanisms of perception, cognition, and behavior, including learning, the emotions, and the relationship of brain activity to consciousness. As a clinical area, psychophysiology has classically addressed somatoform disorders, stress (most recently posttraumatic stress disorders), and affective disorders in general. As a domain, psychophysiology is an important resource for the pain field for two primary reasons. On one hand, it offers a framework for understanding how stress contributes to pain, including the persistence of chronic pain. On the other hand, it uncovers links between cognitive processes (attention, expectancy, meaning, belief) and pain as well as pain relief through psychological intervention. Most physicians and pain researchers think of pain as an unpleasant sensation that originates in traumatized or inflamed tissues; however, pain is more than sensory information about the condition of the body. Affect is an intrinsic dimension of pain. Any reasonable and unbiased observer studying mammals, particularly humans, would have to conclude that pain’s affective features rather than its sensory properties govern behavioral responses to injury. People who experience pain do not quietly report the fact; they express negative emotions. Is the affective dimension of pain as important as its sensory aspect? The linguist, Elaine Scarry,4 described pain’s qualities as comprising extreme aversiveness, an ability to annihilate complex thoughts and other feelings, an ability to destroy language, and a strong resistance to objectification. Her perspective resonates with the lessons of everyday life: 1384

Although pain has sensory features and lends itself to sensory description, it is above all else a powerful negative feeling state. One cannot evaluate and address the suffering of a person in pain without an appreciation of its emotional nature. The International Association for the Study of Pain (IASP) acknowledged the central role of emotion in its keystone definition: “Pain [is] an unpleasant sensory and emotional [emphasis added] experience associated with actual or potential tissue damage, or described in terms of such damage.”5 This definition clearly emphasizes the role of affect as an intrinsic component of pain. Emotion is not a consequence of pain sensation that occurs after a noxious sensory message arrives at sensory cortices. Rather, it is an integral part of the pain experience. Psychophysiology has revealed that emotion and cognition are interdependent. Strong emotions can alter thought processes, perceptions, beliefs, attitudes, and expectancies. Conversely, thoughts can generate negative or positive emotional states, and the physiologic changes associated with such states can interact with tissue injury or inflammation and alter both the sensory and affective aspects of pain. Because pain states rarely exist in isolation, it is important to consider the psychophysiologic context of a pain problem. The cognitive, emotional, and physiologic state of the patient presenting with pain is potentially very important for both assessment and intervention. We propose here that the best framework for characterizing this state is stress theory. The purposes of this chapter are to describe the psychophysiologic mechanisms supporting the subjective experience of pain and to explore the importance of said mechanisms for the assessment and care of patients with pain. The psychophysiology of pain requires an incursion into mind– body issues, consideration of the nature of emotion and its interdependence with cognition, and the overarching influence of stress. In this chapter, we show that (1) pain (awareness of tissue trauma) has intrinsic affective properties, including negative emotional arousal; (2) the brain creates bodily states of arousal (negative emotions) in response to threat to biologic and psychological integrity; and (3) the affective dimension of pain is intrinsically linked to the related processes of defense and stress, and the physiologic mechanisms of these processes shapes the 1385

affective dimension of pain.

Historical Perspective: Mind–Body Issues Through most of the 20th century, our understanding of the relationship between mental processes and the body stemmed directly from Cartesian notions of mind–body dualism. For Descartes, a 17th century philosopher and mathematician, human beings are dualistic: The mind and body are separate entities. Descartes described the life processes of the body as though they were clockwork mechanisms. The actions of the mind were, in his thinking, the workings of the soul. Descartes believed that the awareness of pain, like awareness of other bodily sensations, must take place in a specific location where the mind observes the body. Dennett6 termed this hypothetical seat of the mind the Cartesian theater. In this theater, the mind observes and interprets the array of multimodality signals that the body produces. The body is a passive environment; the mind is the nonphysical activity of the soul. Today, most people will agree that such a theater of the mind cannot exist. Scientifically, the activity of the brain and the mind are inseparable; yet, Cartesian dualism is endemic in Western thought and culture. Classical approaches to psychophysiology stemmed from Cartesian thinking, as did psychophysics. Early work on psychosomatic disorders focused on mind–body relationships. Today, much of the popular movement favoring integrative medicine emphasizes the “mind–body connection,” keeping one’s self healthy through health-promoting cognitive approaches to better regulate immune responses. It is hard to avoid Cartesian thinking when the very fabric of our language carries it along as we reason and speak. Cartesian assumptions are a subtle but powerful barrier for someone seeking to understand the affective dimension of pain. Relegating emotions to the realm of the mind and their physiologic consequences for the body is classical Descartes. It prevents us from appreciating the intricate interdependence of subjective feelings and physiology, and it detracts from our ability to comprehend how the efferent properties of autonomic nervous function can contribute causally to the realization of an

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emotional state. This chapter emphasizes the interdependence of mental processes and physiology. What we call the mind is consciousness, and consciousness is an emergent property of the activity of the brain. In a feedback-dependent manner, the brain regulates the physiologic arousal of the body, and emotion is a part of this process.

Emotions: Definition and Mechanisms WHAT ARE EMOTIONS? The first step in understanding the nociceptive experience as an affective response is by appreciating the origins and purposes of emotion. Many physicians regard emotions as epiphenomenal feeling states associated with mental activity, subjective in character, and largely irrelevant to the state of a patient’s physical health. In fact, emotions are primarily physiologic and only secondarily subjective. Because they can strongly affect cardiovascular function, visceral motility, genitourinary function, and immune competence, patient emotions can have an important role in health overall and especially in pain management. Simple negative emotional arousal can exacerbate certain pain states such as sympathetically maintained pain, angina, headache, neuropathic pain, and fibromyalgia. It contributes significantly to musculoskeletal pain, pelvic pain, and other pain problems in some patients. Emotions are complex states of physiologic arousal and awareness that impute positive or negative hedonic qualities to a stimulus (event) in the internal or external environment. The objective aspect of emotion is autonomically and hormonally mediated physiologic arousal. The subjective aspects of emotion, feelings, are phenomena of consciousness. Emotion represents in consciousness the biologic importance or meaning of an event to the perceiver. Emotion as a whole has two defining features: valence and arousal. Valence refers to the hedonic quality associated with an emotion—the positive or negative feeling attached to perception. Arousal refers to the degree of heightened activity in the central nervous system and autonomic nervous system (ANS) associated with perception. Although emotions as a whole can be either positive or negative in 1387

valence, pain research addresses only negative emotion. Viewed as an emotion, pain represents a threat to the biologic, psychological, or social integrity of the person. In this respect, the emotional aspect of pain is a protective response that normally contributes to adaptation and survival. If uncontrolled or poorly managed in patients with severe or prolonged pain, it produces suffering.

EMOTION IN A SOCIOBIOLOGIC PERSPECTIVE Psychologists have many frameworks for studying emotion. Nature has equipped us with the capability of negative emotion for a purpose; bad feelings are not simply accidents of human consciousness. They are protective mechanisms that normally serve us well, but like uncontrolled pain, sustained and uncontrolled negative emotions can become pathologic states that can produce both maladaptive behavior and physiologic pathology. By exploring the emotional dimension of pain from the sociobiologic perspective, the reader may gain some insight about how to prevent or control the negative affective aspect of pain, which fosters suffering. Unfortunately, implementing this perspective requires that we change conventional language habits that involve describing pain as a transient sensory event. Pain is a compelling and emotionally negative state of the individual that has as its primary defining feature awareness of, and adaptive adjustment to, tissue trauma or disease.

ADAPTIVE FUNCTIONS OF EMOTION Emotions, including the emotional dimension of pain, characterize mammals exclusively, and they foster mammalian adaptation by making possible complex behaviors and adaptations. Importantly, they play a strong role in consciousness, producing and summarizing information that is important for selection among alternative behaviors. According to MacLean,7 emotions “impart subjective information that is instrumental in guiding behavior required for self-preservation and preservation of the species. The subjective awareness that is an affect consists of a sense of bodily pervasiveness or by feelings localized to certain parts of the body [emphasis added].” Because negative emotions, such as fear, evolved to 1388

facilitate adaptation and survival, emotion plays an important defensive role. The ability to experience threat when encountering injurious events protects against life-threatening injury. The strength of emotional arousal associated with an injury indicates and expresses the magnitude of perceived threat to the biologic integrity of the person. Within the contents of consciousness, threat is a strong negative feeling state and not a pure informational appraisal. In humans, threatening events, such as injury that are not immediately present, can exist as emotionally colored somatosensory images. Phenomenal awareness consists largely of the production of images. Visual images are familiar to everyone: We can readily imagine seeing things. We can also produce auditory images by imaging a familiar tune, a bird song, or the sound of a friend’s voice. Similarly, we can generate somatosensory images. We can, for example, imagine the feeling of a full bladder, the sensation of a particular shoe on a foot, or a familiar muscle tension or ache. Cognition operates largely on images and plays a strong role in the experience of symptoms. Patients can react emotionally to the mental image of a painful event before it happens (e.g., venipuncture), or for that matter, they can respond emotionally to the sight of another person’s injury. The emotional intensity of such a feeling marks the adaptive significance of the event that produced the experience for the perceiver. In general, the threat of a minor injury normally provokes less feeling than one that incurs a risk of death. The emotional magnitude of a pain is the internal representation of the threat associated with the event that produced the pain.

EMOTIONS AND BEHAVIOR Negative emotions compel action, such as fight or flight, along with expression through vocalization, posture, variations in facial musculature patterns, and alterations of activity. This represents communication and often elicits social support, thus contributing to survival. Darwin,8 observing animals, noted that emotions enable communication through vocalization, startle, posture, facial expression, and specific behaviors. He held that emotions must be inborn rather than learned tendencies. Darwin8 pursued this issue by comparing the facial and other emotional expressions 1389

of children born blind with those of other children, reasoning that blind children would express emotion differently if emotion is primarily a learned behavior. As others have since confirmed,9 Darwin8 learned that the basic blueprints for human emotional expression are innate. Contemporary investigators who study emotions and human or animal social behavior emphasize that communication is a fundamental adaptive function of emotional expression.10,11 Social mammals, including humans, depend on one another or their social group as resources for adaptation and survival. The emotional expression of pain in the presence of supportive persons is socially powerful; it draws on a fundamental sociobiologic imperative: communicating threat and summoning assistance.

THE CENTRAL NEUROANATOMY OF EMOTION: LIMBIC STRUCTURES The limbic brain represents an anatomical common denominator across mammalian species,7 and emotion is a common feature of mammals. Consequently, investigators can learn much about human emotion by studying mammalian laboratory animals. Humans and animals differ in that the limbic brain is more developed in humans, the frontal lobes are unique to our species, and the interdependence of cognition and emotion is greatest in humans. Early investigators focused on the role of olfaction in limbic function, and this led them to link the limbic brain to emotion. Emotion may have evolutionary roots in olfactory perception. MacLean12 introduced the somewhat controversial term “limbic system” and characterized its functions. He identified three main subdivisions of the limbic brain: amygdala, septum, and thalamocingulate7 that represent sources of afferents to parts of the limbic cortex. He also postulated that the limbic brain responds to two basic types of input: interoceptive and exteroceptive. These refer to sensory information from internal and external environments, respectively. Figure 29.1 summarizes and extends this concept. Noxious signaling can arise from an injurious event in the external environment or from a pathologic condition in the internal environment.

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FIGURE 29.1 Three subdivisions of the limbic brain and their relationship to limbic cortices. MacLean7 proposed a three-part grouping of limbic structures and functions: amygdalar, septal, and thalamocingulate subdivisions. These divisions receive information, including noxious signaling, from the external environment (exteroceptors) and the internal environment (interoceptors). Cortical areas related to limbic function include the prefrontal and frontal cortices (related to executive function and sense of self), the cingulate cortices (the anterior cingulate cortex is related to attentional states), the parahippocampal and entorhinal cortices, which are important in memory, and the insular cortex (emotional–motivational integration).

Over the last decade, numerous studies have employed functional brain imaging to investigate how the human brain responds to painful laboratory stimulation as well as how it behaves in chronic pain conditions. These studies reveal unequivocally that limbic structures involved in emotion and cognition are active during pain. In addition, related studies show that cognitive processes such as threat appraisal and perceived control are related to pain modulation. Early brain imaging studies have shown that the following brain structures are consistently active during states of pain: thalamus, primary and secondary somatosensory cortices, insular cortex, anterior cingulate, and the prefrontal cortices (PFC) as well as deactivation of the posterior cingulate cortex and medial prefrontal cortex,13–15 which compose of the default mode network involved in self-referential processing.16 Thalamus and the somatosensory cortices played a prominent role in early neurophysiologic models of pain and processing of ascending nociceptive information. Insular cortex may play a role in the somatosensory representation of the body, and it appears to integrate multimodal sensory information.17 PFC control the executive functions of the brain and the sense of self. They are involved in threat appraisal, meaning, and the integration of information from the internal and external environment.

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PERIPHERAL NEUROANATOMY OF EMOTION: THE AUTONOMIC NERVOUS SYSTEM The ANS plays a major role in regulating the constancy of the internal environment, and it does so in a feedback regulated fashion under the direction of the hypothalamus, the solitary nucleus (nucleus tractus solitarius) and ventral lateral medulla, the amygdala, and other brain structures.18,19 In general, it regulates activities that are not normally under voluntary control. The hypothalamus is the principal integrator of autonomic activity. Stimulation of the hypothalamus elicits highly integrated patterns of response that involve the limbic system and other structures.20 Many researchers hold that the ANS has three divisions: the sympathetic, the parasympathetic, and the enteric.21,22 Others subsume the enteric under the other two divisions. Broadly, the sympathetic nervous system makes possible the arousal needed for fight and flight reactions, whereas the parasympathetic system governs basal heart rate, metabolism, and respiration. The enteric nervous system innervates the viscera via a complex network of interconnected plexuses. The sympathetic and parasympathetic systems are largely mutual physiologic antagonists—if one system inhibits a function, the other typically augments it. There are, however, important exceptions to this rule that demonstrate complementary or integratory relationships. The mechanism most heavily involved in the affective response to tissue trauma is the sympathetic nervous system. During emergency or injury to the body, the hypothalamus uses the sympathetic nervous system to increase cardiac output, respiration rate, and blood glucose. It also regulates body temperature, causes piloerection, alters muscle tone, provides compensatory responses to hemorrhage, and dilates pupils. These responses are part of a coordinated, well-orchestrated response pattern called the defense response.23–25 It resembles the better known orienting response in some respects, but it can only occur following a strong stimulus that is noxious or frankly painful. It sets the stage for escape or confrontation, thus serving to protect the organism from danger. In an awake cat, both electrical stimulation of the hypothalamus and infusion of norepinephrine into the hypothalamus elicit a rage reaction 1392

with hissing, snarling, and attack posture with claw exposure, and a pattern of sympathetic nervous system arousal accompanies this.26–28 Circulating epinephrine and norepinephrine produced by the adrenal medulla during activation of the sympathoadrenomedullary (SAM) axis accentuate the defense response, fear responses, and aversive emotional arousal in general.

Autonomic Arousal and Subjective Experience Because the defense response and related changes are involuntary in nature, we generally perceive them as something that the environment does to us. We typically describe such physiologic changes not as the bodily responses that they are but rather as feelings. We might describe a threatening and physiologically arousing event by saying that “It scared me” or that “It made me really mad.” Phenomenologically, feelings seem to happen to us; we do not “do” them in the sense that we think thoughts or choose actions. Emotions are who we are in a given circumstance rather than choices we make, and we commonly interpret events and circumstances in terms of the emotions that they elicit. ANS arousal, therefore, plays a major role in the complex psychological experience of injury and is a part of that experience. Early views of the ANS followed the lead of Cannon23 and held that emergency responses and all forms of intense aversive arousal are undifferentiated, diffuse patterns of sympathetic activation. Although this is broadly true, research has shown that definable patterns characterize emotional arousal and that these are related to the emotion involved, the motor activity required, and perhaps the context.18,19 An investigator attempting to understand how humans experience emotions must remember that the brain not only recognizes patterns of arousal but also creates them.

The Role of Feedback One of the primary mechanisms in the creation and management of emotion is feedback. Feedback means that information about the output of a system passes back to the input and thereby dynamically controls the level of the output. System self-regulation and self-organization depend on 1393

feedback, as does self-direction. Feedback loops can be negative or positive. Negative feedback permits stability, whereas positive feedback allows the organism to mount emergency responses. The regulatory processes of homeostasis and allostasis are negative feedback dependent. Negative feedback ensures system stability and maintains homeostasis. Feedback is positive when a variable changes and the system responds by changing that variable even more in the same direction, generating escalation and rapid acceleration.29 This process abandons stability for instability. From an adaptation point of view, positive feedback loop capability is essential for meeting acute threat with defensive arousal. Each mode of operation has adaptive value as a short-range response in certain types of injurious events. In general, defensive reactions involve a pattern of rapid arousal created through positive feedback that prepares the body and brain for emergency response, followed by a negative feedback-controlled transition to recovery and return to normalcy. Because smaller physiologic systems are nested within larger physiologic systems, higher order systems typically limit positive feedback processes in smaller systems. In some cases, top– down regulation of positive feedback fails, for example, in a panic attack. In other cases, the event that triggered the emotion terminates, and the positive feedback process then stops. Sustained periods of positive feedback have the potential for destructive consequences. Feedback is the basis of neuroendocrine regulation, as we describe it in the following discussion. Neuroendocrine feedback depends on bloodborne messengers that are typically hormones or peptides. The ANS uses feedback for afferent and efferent functions. The afferent mechanisms signal changes in the viscera and other organs, whereas efferent activity conveys commands to those organs. Consequently, the ANS can maintain feedback loops related to viscera, muscle, blood flow, and other responses. The visceral feedback system exemplifies this process. The feedback concept is central to the field of psychophysiology: Awareness of physiologic changes elicited by a stimulus is a primary mechanism of emotion. The patient presenting with panic attack, phobia, or anxiety in a mental health setting is reporting a subjective state based on patterns of physiologic signals and not an existential crisis that exists 1394

somewhere in the domain of the mind, somehow apart from the body. Similarly, the patient in a medical context expressing emotional distress during a painful procedure, or during uncontrolled postoperative pain, is experiencing the sensory features of that pain against the background of a cacophony of sympathetic arousal and neuroendocrine stress response.

Relationship of Central and Peripheral Mechanisms Figure 29.2 illustrates that noxious signaling undergoes parallel processing at the cognitive, affective, and sensory levels. An event representing a threat to biologic integrity elicits strong patterns of sympathetic and neuroendocrine response. These, in turn, contribute to the awareness of the perceiver. Sensory processing provides information about the environment, but this information exists in awareness against a background of emotional arousal, either positive or negative, and that arousal may vary from mild to extreme.

FIGURE 29.2 Parallel sensory, affective, and cognitive processing of noxious signaling arising from nociceptive or neuropathic sources. Parallel activation of sensory transmission and noradrenergic/limbic pathways leads to processing in somatosensory, limbic, and prefrontal/frontal cortical areas. In addition, noxious signaling triggers activity in the sympathoadrenomedullary (SAM) and the hypothalamo–pituitary–adrenocortical (HPA) axes. DNB, dorsal noradrenergic bundle; LC, locus coeruleus; PAG, periaqueductal gray.

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The transition from acute to chronic pain may involve complex changes in these pathways. The hypothalamo–pituitary–adrenocortical (HPA) and SAM axes are vulnerable to dysregulation with prolonged exposure to a stressor or series of stressors. This can include prolonged noxious signaling, as might occur with degenerative disease, or unrelenting noxious neuropathic signaling. Dysregulation in these systems may cause sensitization or impair normal inhibitory modulation. Moreover, neural networks associated with threat, dysphoria, or other negative emotions such as the frontal-amygdalar system may strengthen and become selfsustaining so that they can persist even in the absence of noxious signaling. Duric and McCarson30 demonstrated that prolonged noxious signaling can produce stress-like damaging effects on the hippocampus, which is involved in the pathogenesis of depressive symptoms.

NOXIOUS SIGNALING AND CENTRAL LIMBIC PROCESSING Central sensory and affective pain processes share common sensory mechanisms in the periphery. As other chapters in this book describe, Aδ and C fibers serve as tissue trauma transducers (nociceptors) for both, the chemical products of inflammation sensitize these nociceptors, and peripheral neuropathic mechanisms such as ectopic firing excite both processes. In some cases, neuropathic mechanisms may substitute for transduction as we classically define it, producing afferent signal volleys that appear, to the central nervous system, like signals originating in nociceptors. Differentiation of sensory and affective processing begins at the dorsal horn of the spinal cord. Sensory transmission follows spinothalamic pathways and transmission destined for affective processing takes place in spinoreticular pathways. Noxious centripetal transmission engages multiple pathways: spinoreticular, spinomesencephalic, spinolimbic, spinocervical, and spinothalamic tracts,31,32 as Figure 29.3 indicates. The spinoreticular tract contains somatosensory and viscerosensory afferent pathways that arrive at different levels of the brain stem. Spinoreticular axons possess receptive fields that resemble those of spinothalamic tract neurons projecting to medial thalamus, and, like their spinothalamic counterparts, they transmit 1396

tissue injury information.33,34 Most spinoreticular neurons carry noxious signals, and many of them respond preferentially to noxious activity.35,36 The spinomesencephalic tract comprises several projections that terminate in multiple midbrain nuclei, including the periaqueductal gray (PAG), the red nucleus, nucleus cuneiformis, and the Edinger-Westphal nucleus.32 Spinolimbic tracts include the spinohypothalamic tract, which reaches both lateral and medial hypothalamus37,38 and the spinoamygdalar tract that extends to the central nucleus of the amygdala.39 The spinocervical tract, like the spinothalamic tract, conveys signals to the thalamus. All of these tracts transmit tissue trauma signals rostrally.

FIGURE 29.3 Multiple pathways of corticopetal noxious signal transmission. A, spinoreticular; B, spinohypothalamic; C, spinomesencephalic; D, spinothalamic.

Central Neurotransmitter Systems Central processing of noxious signals to produce affect undoubtedly involves multiple neurotransmitter systems. Four extrathalamic afferent pathways project to neocortex: the dorsal noradrenergic bundle (DNB) originating in the locus coeruleus (LC), the serotonergic fibers that arise in the dorsal and median raphe nuclei, the dopaminergic pathways of the ventral tegmental tract that arise from substantia nigra, and the acetylcholinergic (ACh) neurons that arise principally from the nucleus basalis of the substantia innominata.40 Of these, the noradrenergic and serotonergic pathways link most closely to negative emotional states.41–43 1397

The set of structures receiving projections from this complex and extensive network corresponds to classic definition of the limbic brain.7,43–45 Although other processes governed predominantly by other neurotransmitters almost certainly play important roles in the complex experience of emotion during pain, we emphasize the role of central noradrenergic processing here. This limited perspective offers the advantage of simplicity, and the literature on the role of central noradrenergic pathways in anxiety, panic, stress, and posttraumatic stress disorder provides a strong basis.41,46 This processing involves two central noradrenergic pathways: the dorsal and ventral noradrenergic bundles (VNBs) (Fig. 29.4).

FIGURE 29.4 Central noradrenergic transmission. This parasagittal view identifies cell bodies of neurons that produce norepinephrine as black circles. The major projections of these cell bodies are the dorsal noradrenergic bundle (DNB) and the ventral noradrenergic bundle (VNB). The solid blue lines are DNB projections, whereas the broken blue lines are VNB. The projection from the locus coeruleus (LC) to the cerebellum appears as a dotted line. Hypothalamus is orange. Noxious signaling from spinoreticular pathways excites the primarily noradrenergic LC, activating the DNB, which extends throughout the limbic brain and to neocortex. CBL, cerebellum; HB, habenula; INF, infundibulum; LRN, lateral reticular nucleus; ME, median eminence; NSC, nucleus subcoeruleus; NTS, nucleus tractus solitaries; PAG, periaqueductal gray; PVN, paraventricular nucleus of the hypothalamus.

LOCUS COERULEUS AND THE DORSAL NORADRENERGIC BUNDLE Substantial evidence supports the hypothesis that noradrenergic brain 1398

pathways are major mechanisms of anxiety and stress.41 The majority of noradrenergic neurons originate in the LC. This pontine nucleus resides bilaterally near the wall of the fourth ventricle. The locus has three major projections: ascending, descending, and cerebellar. The ascending projection, the DNB, is the most extensive and important pathway for our purposes.47 Projecting from the LC throughout limbic brain and to all of neocortex, the DNB accounts for about 70% of all brain norepinephrine.48 The LC gives rise to most central noradrenergic fibers in spinal cord, hypothalamus, thalamus, and hippocampus,49 and in addition, it projects to limbic cortex and neocortex. Consequently, the LC exerts a powerful influence on higher level brain activity. The noradrenergic stress response hypothesis holds that any stimulus that threatens the biologic, psychological, or psychosocial integrity of the individual increases the firing rate of the LC, and this in turn results in increased release and turnover of norepinephrine in the brain areas involved in noradrenergic innervation. Studies show that the LC reacts to signaling from sensory stimuli that potentially threaten the biologic integrity of the individual or signal damage to that integrity.48 Spinal cord lamina I cells terminate in the LC.33 The major sources of LC afferent input are the paragigantocellularis and prepositus hypoglossi nuclei in the medulla, but destruction of these nuclei does not block LC response to somatosensory stimuli.50,51 Other sources of afferent input to the locus include the lateral hypothalamus, the amygdala, and the solitary nucleus. Whether noxious signaling stimulates the LC directly or indirectly is still uncertain. It is quite clear that noxious signaling inevitably and reliably increases activity in neurons of the LC, and LC excitation appears to be a consistent response to noxious signaling.48,52–54 Notably, this does not require cognitively mediated attentional control because it occurs in anesthetized animals. Foote et al.55 reported that slow, tonic spontaneous activity at the locus in rats changed under anesthesia in response to noxious stimulation. Experimentally induced phasic LC activation produces alarm and apparent fear in primates,56,57 and lesions of the LC eliminate normal heart rate increases to threatening stimuli.58 In a resting animal, LC neurons discharge in a slow, phasic manner.59 1399

The LC reacts consistently, but not exclusively, to noxious signaling. LC firing rates increase following nonnoxious but threatening events, such as strong cardiovascular stimulation,53,60 and certain visceral events, such as distention of the bladder, stomach, colon, or rectum.48,61 Highly novel and sudden stimuli that could represent potential threat, such as loud clicks or light flashes, can also excite the LC in experimental animals.59 Thus, the LC responds to biologically threatening or potentially threatening events, of which tissue injury is a significant subset. Amaral and Sinnamon62 described the LC as a central analog of the sympathetic ganglia. Viewed in this way, it is an extension of the autonomic protective mechanism described earlier. Invasive studies confirm the linkage between LC activity and threat. Direct activation of the DNB and associated limbic structures in laboratory animals produces sympathetic nervous system response and elicits emotional behaviors such as defensive threat, fright, enhanced startle, freezing, and vocalization.63 This indicates that enhanced activity in these pathways corresponds to negative emotional arousal and behaviors appropriate to perceived threat. LC firing rates increase two- to threefold during the defense response elicited in a cat that has perceived a dog.26 Moreover, infusion of norepinephrine into the hypothalamus of an awake cat elicits a defensive rage reaction that includes activation of the LC noradrenergic system. In general, the mammalian defense response involves increased regional turnover and release of norepinephrine in the brain regions that the LC innervates. The LC response to threat, therefore, may be a component of the partly “prewired” patterns associated with the defense response. Increased alertness is a key element in early stages of the defense response. Normally, activity in the LC increases alertness. Tonically enhanced LC and DNB discharge corresponds to hypervigilance and emotionality.41,55,64 The DNB is the mechanism for vigilance and defensive orientation to affectively relevant and novel stimuli. It also regulates attentional processes and facilitates motor responses.40,43,48,65 In this sense, the LC influences the stream of consciousness on an ongoing basis and readies the individual to respond quickly and effectively to threat when it occurs. 1400

LC and DNB support biologic survival by making possible global vigilance for threatening and harmful stimuli. Siegel and Rogawski66 hypothesized a link between the LC noradrenergic system and vigilance, focusing on rapid eye movement (REM) sleep. They noted that LC noradrenergic neurons maintain continuous activity in both normal waking state and non-REM sleep, but during REM sleep, these neurons virtually cease discharge activity. Moreover, an increase in REM sleep ensues after either lesion of the DNB or following administration of clonidine, an α2 adrenoceptor agonist. Because LC inactivation during REM sleep permits rebuilding of noradrenergic stores, REM sleep may be necessary preparation for sustained periods of high alertness during subsequent waking. Siegel and Rogawski66(p226) contended that “a principal function of NE in the CNS is to facilitate the excitability of target neurons to specific high priority signals.” Conversely, reduced LC activity periods (REM sleep) allow time for a suppression of sympathetic tone. Both adaptation and sensitization can alter the LC response to threat. Abercrombie and Jacobs67,68 demonstrated a noradrenergically mediated increase in heart rate in cats exposed to white noise. Elevated heart rate decreased with repeated exposure as did LC activation and circulating levels of norepinephrine. Libet and Gleason69 found that stimulation via permanently implanted LC electrodes did not elicit indefinite anxiety. This indicates that the brain either adapts to locus excitation or engages a compensatory response to excessive LC activation under some circumstances. In addition, central noradrenergic responsiveness changes as a function of learning. In the cat, pairing a stimulus with a noxious air puff results in increased LC firing with subsequent presentations of the stimulus, but previous pairing of that stimulus with a food reward produces no alteration in LC firing rates with repeated presentation.59 These studies show that, despite its apparently “prewired” behavioral subroutines, the noradrenergic brain shows substantial neuroplasticity. The emotional response of animals and people to a painful stimulus can adapt, and it can change as a function of experience. From a different perspective, Bremner et al.41 postulated that chronic stress can affect regional norepinephrine turnover and thus contribute to the response sensitization evident in panic disorder and posttraumatic 1401

stress disorder. Chronic exposure to a stressor (including perseverating noxious signaling) could create a situation in which noradrenergic synthesis cannot keep up with demand, thus depleting brain norepinephrine levels. Animals exposed to inescapable shock demonstrate greater LC responsiveness to an excitatory stimulus than animals who have experienced escapable shock.70 In addition, such animals display “learned helplessness” behaviors—they cease trying to adapt to, or cope with, the source of shock.71 From an evolutionary perspective, this is a failure of the defense response as adaptation; it represents surrender to suffering. Extrapolating this and related observations to patients, Bremner and colleagues41 suggested that persons who have once encountered overwhelming stress and suffered exhaustion of central noradrenergic resources may respond excessively to similar stressors that they encounter at a later time.

THE VENTRAL NORADRENERGIC BUNDLE AND THE HYPOTHALAMO-PITUITARY-ADRENOCORTICAL AXIS The VNB originates in the LC and enters the medial forebrain bundle. Neurons in the medullary reticular formation project to the hypothalamus via the VNB.72 Sawchenko and Swanson73 identified two VNB-linked noradrenergic and adrenergic pathways to paraventricular hypothalamus in the rat: the A1 region of the ventral medulla (lateral reticular nucleus [LRN]) and the A2 region of the dorsal vagal complex (the nucleus tractus solitarius, or solitary nucleus) which receives visceral afferents. These medullary neuronal complexes supply 90% of catecholaminergic innervation to the paraventricular hypothalamus via the VNB.74 Regions A5 and A7 contribute in a comparatively minor way to the VNB. The noradrenergic axons in the VNB respond to noxious stimulation48 as does the hypothalamus itself.75 Moreover, noxious-signaling neurons at all segmental levels of the spinal cord project to medial and lateral hypothalamus and several telencephalic regions.32,37,38 These projections link tissue injury and the hypothalamic response, as do hormonal messengers in some circumstances. The hypothalamic paraventricular nucleus (PVN) coordinates the HPA 1402

axis. Neurons of the PVN receive afferent information from several reticular areas including ventrolateral medulla, dorsal raphe nucleus, nucleus raphe magnus, LC, dorsomedial nucleus, and the nucleus tractus solitarius.73,76,77 Still other afferents project to the PVN from the hippocampus, septum amygdala.78 Nearly all hypothalamic and preoptic nuclei send projections to the PVN. This suggests that limbic connections mediate endocrine responses during stress. Feldman et al.78 note that limbic stimulation always increases adrenocortical activity in rats. In responding to potentially or frankly injurious stimuli, the PVN initiates a complex series of events regulated by negative feedback mechanisms, as Figure 29.5 indicates. These processes ready the organism for extraordinary behaviors that will maximize its chances to cope with the threat at hand,79 but they must limit overshooting and return to recover when the stressor has passed. Although laboratory studies often involve highly controlled and specific noxious stimulation, real-life tissue trauma usually involves a spectrum of afferent activity, and the pattern of activity may be a greater determinant of the stress response than the specific receptor system involved.80 Traumatic injury, for example, might involve complex signaling from the site of injury, including inflammatory mediators, baroreceptor signals from blood volume changes, and hypercapnia. Tissue trauma normally initiates much more than noxious signaling.

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FIGURE 29.5 Response of the hypothalamo–pituitary–adrenocortical (HPA) axis to noxious signaling. The feedback modulated response involves six steps. In step 1, noxious signaling excites the ventral noradrenergic bundle (VNB), including several medullary and pontine nuclei (designated A1, A2, A5, and A7). When such signals reach hypothalamus, they stimulate the paraventricular nucleus (PVN); this is step 2. The PVN produces corticotropin-releasing hormone (CRH). CRH-producing neurons extend from the PVN to the median eminence (ME) where they release CRH into the portal circulation (step 3). At this point, the response becomes neurohumoral rather than neuronal. The anterior pituitary responds to CRH by releasing adrenocorticotropin (ACTH) into the systemic circulation (step 4). ACTH causes the adrenocortex to release corticosteroids into systemic circulation (step 5). In addition to their extensive metabolic effects, the corticosteroids bind to receptors at the PVN (step 6), thus closing the negative feedback loop. PAG, periaqueductal gray.

Diminished noxious signal transmission during stress or injury helps people and animals to cope with threat without the distraction of pain. The medullary mechanisms involved in this are complex and include the response of the solitary nucleus to baroreceptor stimulation.81 Laboratory studies with rodents indicate that animals placed in restraint or subjected to cold water develop analgesia.82–84 Lesioning the PVN attenuates such stress-induced analgesia.85 Some investigators86,87 emphasize that neuroendocrine arousal mechanisms are not limited to emergency situations, even though most research emphasizes that such situations elicit them. In complex social contexts, submission, dominance, and other transactions can elicit neuroendocrine and autonomic responses, modified perhaps by learning 1404

and memory. This suggests that neuroendocrine processes accompany all sorts of emotion-eliciting situations. The hypothalamic PVN supports stress-related autonomic arousal through neural as well as hormonal pathways. It sends direct projections to the sympathetic intermediolateral cell column in the thoracolumbar spinal cord and the parasympathetic vagal complex, both sources of preganglionic autonomic outflow.88 In addition, it signals release of epinephrine and norepinephrine from the adrenal medulla. Adrenocorticotrophic hormone (ACTH) release, although not instantaneous, is quite rapid: It occurs within about 15 seconds.89 These considerations implicate the HPA axis in the neuroendocrinologic and autonomic manifestations of emotion associated with tissue trauma. In addition to controlling neuroendocrine and ANS reactivity, the HPA axis coordinates emotional arousal with behavior.90 As noted earlier, stimulation of the hypothalamus in animals can elicit well-organized action patterns, including defensive threat behaviors and autonomic arousal.91 The existence of demonstrable behavioral subroutines in animals suggests that the hypothalamus plays a key role in matching behavioral reactions and bodily adjustments to challenging circumstances or biologically relevant stimuli. Moreover, stress hormones at high levels may affect central emotional arousal, lowering startle thresholds and influencing cognition.89 Saphier92 observed that cortisol altered the firing rate of neurons in limbic forebrain. Clearly, stress regulation is a complex, feedback dependent, and coordinated process. The hypothalamus appears to coordinate behavioral readiness with physiologic capability, awareness, and cognitive function.

PRIMARY AND SECONDARY FEATURES OF THE AFFECTIVE DIMENSION OF PAIN The physiology of emotion suggests that the affective dimension of pain involves a two-stage mechanism. The primary mechanism generates an immediate experience akin to hypervigilance or fear. In nature, this rapid response to injury serves to disrupt ongoing attentional and behavioral patterns. At the same time, efferent messages from the hypothalamus, amygdala, and other limbic structures excite the ANS, and this in turn 1405

alters bodily states. Cardiac function, muscle tension, altered visceral function, respiration rate, and trembling all occur, and awareness of these reactions creates a strong negative subjective experience. This body state awareness is the second mechanism of the affective dimension of pain. Damasio93 contended that visceral and other event-related, autonomically mediated body state changes constitute “somatic markers.” That is, they serve as messengers, delivering affective evaluations of perceptual experiences that either confirm or deny the potential threat inherent in an event. A somatic marker is essentially a somatic image. Perceptually, the brain operates on images that are symbolic representations of external and internal objects or events. Just as it is more efficient for a listener to work with words in language as opposed to phonemes, cognition is more efficient when it uses images rather than simple sensations. The somatic marker images associated with tissue trauma are often complex patterns of physiologic arousal. They serve as symbolic representations of threat to the biologic (and sometimes the psychological or social) integrity of the person. Like other images, they can enter into complex patterns of association. Because the secondary stage of the affective response involves images and symbols, it represents cognition as well as emotion.

SUMMARY OF THE CONSTRUCTION AND MODULATION OF PAIN Pain is a complex and subjective conscious experience constructed and modulated by a constellation of sensory, cognitive, and affective factors including mood, psychological disposition, meaning-related cognitions (e.g., suffering), learning, desires, and pre-pain cognitive states (e.g., expectations, anxiety) to provide a continually changing experience. Feedback connections between low-level afferent and higher order neural processes foster the cultivation of a distributed, multidimensional network associated with the subjective experience of pain. Nociceptive sensory events are first registered by peripheral primary afferents (first pain = Aδ; second pain = C fibers) at the site of injury/tissue damage that then relay said nociceptive information to the dorsal horn of the spinal cord. From the spinal cord, nociceptive information ascends contralateral to the site of 1406

pain to the brain largely through the spinothalamic pathway. Nociceptive input is subsequently processed through feedback connections between lower level sensory regions including the parabrachial nucleus, PAG matter, thalamus, and primary and secondary somatosensory cortices.13–15,94–97 Ascending nociceptive information is then transmitted to the posterior and anterior insular cortices where it is “fine-tuned” to foster the subsequent evaluation of pain.98,99 The contextual meaning of pain is then facilitated through activation of higher order brain regions including the dorsal anterior cingulate cortex (dACC) and anterior cingulate cortex (ACC) and PFC.99–101 Yet, the subjective experience of pain is highly influenced by the context in which it occurs. That is, previous experiences, expectations, mood, conditioning, desires, sensitization/habituation, and other cognitive factors can dramatically amplify and/or attenuate pain.97,102–106 Nonpharmacologic-based pain manipulations attenuate the subjective experience of pain through a common final pathway including overlapping endogenously driven and neural systems. Although the cognitive modulation of pain is mediated through a host of endogenous modulatory systems including cannabinoid, serotonergic, dopaminergic, cholecystokinin, adrenergic, and other neurochemical systems (i.e., vasopressin), the endogenous opioidergic system is the most understood (and studied) pain modulatory system.107 Endogenous opioidergic mechanisms have been repeatedly demonstrated to mediate analgesia produced by placebo,108–112 conditioned pain modulation,113 acupuncture,114 hypnosis,115 and attentional control.116 Pain relief produced by said cognitive techniques is associated with significant reductions in pain-related brain activation (i.e., primary and secondary somatosensory cortices, posterior insula, parietal operculum) and activation in higher order brain regions such as the ACC, PFC, and insula.105,108,117–129 Importantly, the PFC, insula, and ACC contain high concentrations of opioid receptors and are associated with producing analgesia through descending inhibitory systems.124,130–134 The ACC and PFC project to the PAG matter,135 a structure that can be directly activated by opioids. The PAG projects to the rostral ventral medulla136–138 that in turn projects to the spinal dorsal horn and can inhibit nociceptive 1407

processing through multiple neurotransmitter systems.139

Emotion and Cognition Negative emotions and somatic markers are much more than reactions to undesirable events; in nature, they help an organism determine which things benefit and which things threaten survival, and they compel behavior consistent with such evaluations. Moreover, emotional expression communicates this judgment to others and thus sets up group approach or avoidance behaviors. MacLean7 described emotion as a process that imparts subjective information. In these respects, our feelings approximate crude intelligence. How we feel about something is often as important, or more important, than what we know about it. If emotion is a proto-intelligence, then evolutionarily newer structures, namely, the later stages of cortical development, should have demonstrable links with limbic structures and functions. Such interconnections exist. Parts of the frontal lobe (the dorsal trend) appear to have developed from rudimentary hippocampal formation, whereas other parts (the paleocortical trend) originated in olfactory cortex. Although these two areas interconnect anatomically, the former analyzes sensory information, whereas the latter contributes emotional tone to that sensory information.68,69,140 Pribram,141 noting that limbic function involves frontal and temporal cortex, offered a bottom–up concept for how cognition relates to feelings; that is, emotion determines cognition. However, the multimodal neocortical association areas project corticofugally to limbic structures,142 which suggests that cognitions may drive emotions. The debate on whether emotion or cognition is primary may never resolve. For immediate purposes, it seems best to conclude that knowing and feeling are closely interrelated. Still, these processes are not identical. We can know something about our feelings, and we can have emotional responses to what we know. The brain is a complex, dynamic organ, constantly constructing its internal model of reality from sensory input and memory storage. Feeling and thinking are major processes in this construction. 1408

The Sense of Self COGNITIVE PERSPECTIVE Pain informs the brain of injury to bodily integrity, and its emotional aspect reflects the importance of that injury to the individual. An injury does not just cause objective harm, it harms “me.” That is, it harms what I consider myself. Similarly, a social affront harms what I consider myself, and I might metaphorically describe the incident as something that “hurt” me. What constitutes the self? What would happen if an injured person had an altered or poorly developed sense of self? Clinical observations of schizophrenic patients and other psychiatric patients indicate that they sometimes mutilate themselves horribly and apparently with little or no pain.143 This suggests that the sense of self may be an intrinsic part of the complex experience of pain because it is the focal point around which perceptions form and from which cognitions arise.

MULTIPLE PERSPECTIVES ON THE SELF The self is a hierarchical construct that has different meanings at different levels of the neuraxis. Multiple levels of the self exist, and each level becomes a precondition for the existence of higher levels. At least two biologic definitions merit inclusion in the construct. At the level of the human genome, the self is the unique genetic code that makes each of us an individual. It sets the basic rules of life by defining sex, size and features, and basic abilities. At a higher biologic level, the self is what the immune system recognizes as “me” versus “not me.” The immunologic self is an enigma because “me” and my genetic code are not identical. Our bodies host elaborate microbial ecosystems, and disturbing or damaging these systems (e.g., via antibiotic use) compromises health. Various microorganisms in our digestive tracts, oropharyngeal passages, and on our skin qualify as self to our immune systems; we live comfortably with them in a symbiotic relationship. Our microbial floras are clearly us, even though they do not carry our genetic code. For the immune system, there is neither single chemical marker that defines individuality nor is the self-limited to certain biologic structures. Thus, even at this basic level, the boundaries of the self 1409

are fuzzy. At a neurologic level, the self exists as a central representation of the body. Melzack termed this the body neuromatrix.144–146 The brain maintains a detailed map of the body at several levels of the neuraxis. Study of phantom limb patients and patients born without limbs reveals that the brain has an elaborate internal representation of the body. If a person loses a leg, the brain maintains its representation of the leg, and the person experiences a phantom limb. Even patients born without limbs have an internal sense or representation of the absent body parts. Thus, humans and almost certainly higher order animals carry within them a phenomenal representation of a body self. These biologic selves exist below the level of consciousness. They are very much a part of every person, but they normally play little or no part in what we think of as “me.” Humans and animals do not differ with regard to self at this level. Multiple psychological dimensions of the self also exist. At the most fundamental level, there is the self-as-agent, which engages in biologic adaptation and survival. From an evolutionary perspective, it is the agent that struggles to survive. The self-as-agent sets goals, chooses among alternatives, and engages in behaviors. Animals and humans share self-asagent, and this self is, in part, social. That is, it exists not alone but in relation to others of its kind. Animals, including humans, engage in social dominance and submission. In this respect, each organism defines its relationship to others, often via struggle or conflict. The defined relationship often determines the extent of one’s opportunity to reproduce or one’s access to the resources necessary for survival. The self-as-agent is primitive and does not require cognition. It is something that the individual does, not something that the individual experiences as a phenomenal reality. In other words, this is a self of behavior. It does not entail subjective awareness. At a higher, and perhaps uniquely human, level, the psychological self is also a point of view (self-as-perspective). It is the center of experiential gravity about which the brain organizes present circumstances, past history, future goals, and expectations. This is an inevitable outcome of the higher order self-organizing processes of the brain. This aspect of the self 1410

stems from recognition of one’s physical being as an entity in the environment, and it becomes a frame of reference for all that happens to the person. On still another level, the self represents the individual’s complex sense of identity, to which we have referred earlier as “me,” vide supra. This self-as-identity resembles the self-as-agent in some respects, but it is an age-dependent, autobiographically based narrative and interpretation, modified by the immediate circumstances and surroundings. Unlike the self-as-agent, the self-as-identity is the product of a developmental process, and it changes over time. Finally, every human has a sociologic self. That is, we have an identity defined by our relationships to social groups and to society and culture as a whole. Gender roles, social class, education level, age roles, and our culture constrain who we are. To some degree, we are the roles that we play in our families, vocational settings, recreational pursuits, and elsewhere.

Stress, Sickness, and Pain BASIC DEFINITIONS: STRESS, HOMEOSTASIS, AND ALLOSTASIS Human life entails repeated adverse physical and psychosocial events, and these challenges require an adaptive response. The brain mounts a coordinated, adaptive reaction characterized by physiologic arousal. This response is often associated psychologically with the experience of threat or other negative affect. The term for this arousal reaction is the stress response, and any event that triggers such a response is a stressor. Some stressors are singular events, such as traffic accidents or surgery. Other stressors are constellations of vexing problems that never end. Examples include dysfunctional family relationships and vocational problems. Stress and negative emotion feed one another, and the processes involved affect pain. We have discussed the defense response earlier. It resembles the stress response and shares common mechanisms. The defense response and stress have historically different origins in science but seem to be different 1411

perspectives on a common adaptive mechanism. In order to integrate relevant information in these two fields, we consider the stress response to be a subset of the more general defense response. This position has the shortcoming of potentially obscuring an important distinction. Classically, the defense response pertained to threats appearing in the external environment and not the internal environment. However, the concept applies equally well to threatening internal events. The pain of a kidney stone, angina, or a migraine headache is threatening and can function as a stressor and elicit the physiologic changes common to the defense response and the stress response. In everyday life, stress is the resource-intensive process of mounting adaptive coping responses to challenges that occur in the external or internal environment. A stressor may be a physical or social event, an invading microorganism, or, in the case of a chronic pain, patient pain itself. Selye79 first described this response as a syndrome produced by “diverse nocuous agents.” He eventually characterized the stress response as having three stages: alarm reaction, resistance, and, if the stressor does not relent, exhaustion. The normal stress responses of daily living consist of the alarm reaction, resistance, and recovery. Stressors have as their primary features intensity, duration, and frequency. The impact of a stressor is the magnitude of the response it elicits. This impact involves cognitive mediation (thought processes) because it is a function of both the predictability and the controllability of the stressor. A stressor can threaten homeostasis,147 which strictly means a limited set of systems concerned with maintaining the essentials of the internal milieu. Homeostasis represents the control of internal processes truly necessary for life, such as thermoregulation, blood gases, acid–base balance, fluid levels, metabolite levels, and blood pressure. Generic threats to homeostasis include environmental extremes, extreme exercise, depletion of essential resources, abnormal feedback processes, aging, and disease. Of course, various defensive processes must exist to protect homeostasis. The term for the general adaptive process that protects against threats to homeostasis is allostasis. Allostatic processes dynamically adapt multiple internal systems to changes in the environment and coordinate their 1412

responses.147,148 Allostasis exists when changes in the external or internal environment trigger physiologic coping mechanisms such as autonomic arousal. These mechanisms ensure that the processes sustaining homeostasis stay within normal range. Allostasis is the essence of the stress response because it mobilizes internal resources to meet the challenge that a stressor represents. When a stressor, such as neuropathic signaling, persists for a long period of time, or when repeated stressors occur in rapid succession, allostasis may burn resources faster than the body can replenish them. The cost to the body of allostatic adjustment, whether in response to extreme acute challenges or to lesser challenges over an extended period of time, is called allostatic load.

PHYSIOLOGIC MECHANISMS OF STRESS The major mechanisms of the stress response are the HPA axis based in the hypothalamic PVN149 and the SAM axis,150 which includes the LC noradrenergic system (see Fig. 29.1). The peripheral effectors of these mechanisms are the ANS, the SAM circulating hormones, principally the catecholamines epinephrine and norepinephrine together with the sympathetic cotransmitter neuropeptide Y (NPY),151 all of which originate in the chromaffin cells of the adrenal medulla. Circulating catecholamines increase blood pressure and heart rate, dilate pupils, and increase skin conductance, thereby initiating arousal for the fight or flight response. The stress response involves hypothalamically induced release of peptides derived from pro-opiomelanocortin (POMC) at the anterior pituitary. The POMC-related family of anterior pituitary hormones includes ACTH, βlipotropin, β-melanocyte–stimulating hormone, and β-endorphin. The hypothalamic PVN initiates the HPA stress response and controls it through negative feedback mechanisms. Corticotropin-releasing hormone (CRH) produced at the PVN initiates the stress response. CRH initializes and coordinates the stress response at many levels,152 including the LC.153 It is the key excitatory central neurotransmitter and regulator in the endocrine response to injury. The PVN triggers another aspect of the stress response in the SAM axis by recruiting catecholaminergic cells in the rostral ventrolateral medulla. This structure is a cardiovascular regulatory area involved, along with the 1413

solitary nucleus, in the control of blood pressure. The rostral ventrolateral medulla activates the solitary nucleus and, together with it, provides tonic excitatory drive to sympathetic vasoconstrictor nerves that maintain resting blood pressure levels. A normal stress response involves a complex pattern of autonomic arousal that includes increased blood pressure followed by a period of recovery when blood pressure and other aspects of arousal return to normal.

Neural Substrates Viewing stress as a mechanism of defense brings additional neural substrates into focus. Chief among them are the medial hypothalamus, amygdala, and dorsal PAG. These structures respond reliably but not exclusively to noxious signaling; interact with one another; and actively integrate cognitive, sensory, and emotional processes. Some pain researchers have begun to address the issue of integration. Tracey et al.117 for example, employed functional brain imaging to study subjects attending to or distracting themselves from painful stimuli cued with colored lights. Distraction and pain reduction occurred in conjunction with activation of the PAG, linking cortical control and the PAG and the role of endogenous opioids to attenuate pain. Frontal-amygdalar circuits are a well-studied aspect of the defense response.154–156 Cognitive variables such as interpretation, attention, and anticipation can influence amygdalar response through the frontalamygdalar circuit. The amygdala, in turn, can influence the HPA axis.157–159 Frontal influences also affect patterns of activity at the LC, which is a part of the SAM axis. An important implication of viewing stress within the defense response framework is that endogenous cognitive activity (thoughts) generated during anticipation or memory reconstruction can activate complex neural circuits that mobilize the stress response in the absence of tissue trauma. In other words, mental activity may have direct and deleterious physiologic consequences. Patients with chronic pain can stress themselves through negative thought processes, termed catastrophizing, and in so doing exacerbate and perpetuate their pain.160 The central nucleus of the amygdala projects to the PAG, which 1414

coordinates defensive behaviors.161 In general, the amygdala is proving to be a key mechanism of conditioned fear.162,163 It communicates with the hypothalamus via neural circuitry164,165 as well as the frontal cortices. A second, and underestimated, aspect of the defense response depends predominantly on the immune system. The brain controls the immune system via the actions of the sympathetic nervous system and the hypothalamic secretion of releasing factors into the bloodstream. These messenger substances activate the anterior pituitary via the HPA axis.166 The pituitary body releases peptides related to POMC, such as ACTH and β-endorphin, and these in turn trigger the release of glucocorticoids. Because the cells and organs of the immune system express receptors for these hormones, they can respond to humoral messenger molecules of central origin. In this way, the brain enlists the immune system in the defense response.

Immune Mechanisms Just as the nervous system is the primary agent for detecting and defending against threat arising in the external environment, the immune system is the primary agent of defense for the internal environment. Kohl167 described the immune system as “a network of complex danger sensors and transmitters.” This interactive network of lymphoid organs, cells, humoral factors, and cytokines works interdependently with the nervous and endocrine systems to protect homeostasis. Physical trauma produces specific tissue breakdown, triggering release of nitric oxide (NO), bradykinin, histamine, and peptides, some of which are immunostimulatory. The neuropeptides substance P (SP) and neurokinin A (NKA) activate T cells and cause them to increase production of the proinflammatory cytokine interferon (IFN)-γ.168 In addition, another proinflammatory cytokine, interleukin (IL)1-β, stimulates the release of SP from primary afferent neurons.169 Thus, the neurogenic inflammatory response contributes to the immune defense response and at the same time is in part a product of that response.170 The immune system detects an injury event in at least three ways: (1) through bloodborne immune messengers originating at the site of injury, (2) through nociceptor-induced sympathetic activation and subsequent 1415

stimulation of immune tissues, and (3) through SAM endocrine signaling. Immune messaging begins with the acute phase reaction in the injured tissues.171 Local macrophages, neutrophils, and granulocytes produce and release into intracellular space and circulation the proinflammatory cytokines IL-1, IL-6, IL-8, and tumor necrosis factor (TNF)-α. This alerts and activates other immune tissues and cells that have a complex systemic impact. The acute phase reaction to tissue trauma is the immune counterpart to noxious signaling in the nervous system in that it encompasses transduction, transmission, and effector responses. This is a feedbackdependent process. Sympathetic outflow following tissue injury can directly modulate many aspects of immune activity and provide feedback. This can occur because all lymphoid organs have sympathetic nervous system innervation172 and because many immune cells express adrenoceptors.173–175 In addition to the familiar acute phase reaction, the immune system manifests several complex response patterns to tissue injury. In a primitive world, microbial invasion normally accompanies any breach of the skin, and when the microorganisms reach the bloodstream, sepsis occurs. Resultant inflammation therefore assists the immune system in defense. Redness, pain, heat, and swelling are its cardinal signs. The inflammatory process creates a barrier against the invading microorganisms and activates a variety of cells, including macrophages and lymphocytes that find and destroy invaders. It also sensitizes the injured tissue and thereby minimizes the risk of further injury. Inflammation reduces function and increases pain by sensitizing nociceptors. Tracey176 described the “inflammatory reflex” as an ACh-mediated process by which the nervous system recognizes the presence of, and exerts influence on, peripheral inflammation. Through vagal and glossopharyngeal bidirectional processes, the nervous system modulates circulating cytokine levels.177 Put another way, the nervous system can sense the activities of the immune system.

The Sickness Response The immune system can mount a system-wide defense response characterized by fatigue, fever, and sickness with associated pain.178–183 1416

This is the “sickness response,” and although it is cytokine mediated, it depends on the central nervous system. Macrophages and other cells release proinflammatory cytokines including IL1-β, IL-6, IL-8, IL-12, IFN-γ, and TNF-α in response to tissue trauma. These substances act on the vagus nerve, the glossopharyngeal nerve, the hypothalamus, and elsewhere to trigger a cascade of unpleasant, activity-limiting symptoms.180,184 Subjectively, the sickness response is a vivid and dysphoric experience characterized by fever, malaise, fatigue, difficulty concentrating, excessive sleep, decreased appetite and libido, stimulation of the HPA axis, and hyperalgesia. The sickness-related hyperalgesia may reflect the contributions of spinal cord microglia and astrocytes.182 Functionally, this state is adaptive; it minimizes risk by limiting normal behavior and social interactions and forces recuperation. Curiously, this response does not always resolve with physical healing.

The Sickness Response and Depression Mounting evidence supports the hypothesis that the sickness response and depression are related immune response patterns. This hypothesis derives from evidence that proinflammatory cytokines are agents of depression. The specific mechanisms are still at issue,185 but proinflammatory cytokines instigate the behavioral, neuroendocrine, and neurochemical features of depressive disorders.186–189 The therapeutic use of proinflammatory cytokines INF-α and IL-2 for cancer treatment produces depression,190,191 and their administration generates hyperactivity and dysregulation in the HPA axis. These are common features of severe depression. The sickness response and depression overlap in that many of the behavioral manifestations of sickness are also manifestations of a depressive disorder. Whether sickness and depression constitute separate states of the system is still uncertain. It is becoming clear, however, that the immune defense responses associated with tissue damage contribute to bodily awareness and the complex, multidimensional experience of pain.

SUMMARY OF THE PHYSIOLOGIC MECHANISMS OF STRESS 1417

This review of mechanisms reveals that the emotional aspects of pain are the product of the defensive and stress responses that tissue trauma, a related stressor, or a constellation of stressors evokes. These responses comprise two forms of allostasis. At the neuroendocrine level, the defense response is an adaptive reaction characterized by sympathetic arousal, hypervigilance, and a sense of threat. However, a coordinated immune system adaptive defense response also occurs at the immune level. Mediated by proinflammatory cytokines, it produces a sense of sickness and curtails normal activity. The sickness response produces fatigue, general malaise, fever, and hyperalgesia typically experienced as musculoskeletal pain. Depression is apparently related to the sickness response in that both are the product of proinflammatory cytokines. Thus, the defensive responses generate negative emotions in the general domains of anxiety/threat, depression, and fatigue and sickness.

STRESS AND CHRONIC PAIN Stress and related defensive responses can promote chronic pain and related disability in at least three ways. • First, noxious somatic or neuropathic signaling or a central mechanism generating the perception of pain can function as stressors, thereby triggering a defense response and stress. As the mechanism discussion indicates, this can lead to negative emotional states, depressed mood, general sickness, and fatigue. If this is prolonged, patients typically undergo physical deconditioning that makes the pain worse. • Second, psychosocial stressors such as dysfunctional family relationships or poor vocational adjustment can trigger the stress response and lead to all of the consequences noted earlier. • Third, comorbid disorders and associated interventions are stressors and can contribute to pain by producing negative affective states, the sickness response, and, ultimately, physical deconditioning. Immunologic diseases, cancer, diabetes, neurologic disorders, and other disease states can increase patient vulnerability to chronic pain through these mechanisms. The three mechanisms are not mutually exclusive; they can exist in any 1418

combination. The normal course of a stress response or defense response is immediate arousal with subsequent slow recovery to normalcy. When stressors confront a patient as a chain of events, the recovery process to the first mechanism may not finish before the second sets off another arousal pattern. A chain of stressors can dysregulate one or another feedback dependent aspect of the stress response system, such as the HPA axis. Hypercortisolemia, for example, characterizes almost half of severely depressed patients. Stress-induced chronobiologic dysregulation is perhaps more common. Patients with chronic pain often complain of disturbed sleep patterns.

Future Directions Psychophysiology is a rapidly expanding domain of inquiry. We have been able to cover only a small fraction of the field in this review. Other relevant areas include sleep and sleep disorders, chronobiology, physiologic mechanisms of learning and memory, somatic representation, and psychoneuroimmunology. Painful conditions influence these various domains and in turn change in response to changes within these domains. Furthermore, functional brain imaging has opened new opportunities for pursing the relationship of brain activity to physical and psychological manipulations and also subjective experience. Building an interdisciplinary scientific evidence base in the domain of psychophysiology should be a priority in pain research because this field bridges psychological states and physiologic health. Multisymptom syndromes such as fibromyalgia syndrome, irritable bowel syndrome, and temporomandibular disorder pose major challenges in pain medicine and other medical areas. It is clear that these problems are related to stress, but the causal mechanisms of such disorders and their resistance to treatment remain ill defined. These disorders are mind–body problems that refuse to yield to either purely physiologic or purely psychological intervention. Psychophysiology is the only approach formally organized to pursue such mechanisms from an integrated body– mind perspective. Future research on the nature of multisymptom disorders and the development of management strategies or curative interventions

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allostasis and costs of allostatic load and the trade-offs in health and disease. Neurosci Biobehav Rev 2005;29(1):3–38. Tsigos C, Chrousos GP. Hypothalamic–pituitary–adrenal axis, neuroendocrine factors and stress. J Psychosom Res 2002;53(4):865–871. Padgett DA, Glaser R. How stress influences the immune response. Trends Immunol 2003;24(8):444–448. Zukowska Z, Pons J, Lee EW, et al. Neuropeptide Y: a new mediator linking sympathetic nerves, blood vessels and immune system? Can J Physiol Pharmacol 2003;81(2):89–94. Elenkov IJ. Glucocorticoids and the Th1/Th2 balance. Ann N Y Acad Sci 2004;1024:138– 146. Rassnick S, Sved AF, Rabin BS. Locus coeruleus stimulation by corticotropin-releasing hormone suppresses in vitro cellular immune responses. J Neurosci 1994;14(10):6033–6040. Davidson RJ, Irwin W. The functional neuroanatomy of emotion and affective style. Trends Cogn Sci 1999;3(1):11–21. Hariri AR, Mattay VS, Tessitore A, et al. Neocortical modulation of the amygdala response to fearful stimuli. Biol Psychiatry 2003;53(6):494–501. Likhtik E, Pelletier JG, Paz R, et al. Prefrontal control of the amygdala. J Neurosci 2005;25(32):7429–7437. Merali Z, Michaud D, McIntosh J, et al. Differential involvement of amygdaloid CRH system(s) in the salience and valence of the stimuli. Prog Neuropsychopharmacol Biol Psychiatry 2003;27(8):1201–1212. Herman JP, Figueiredo H, Mueller NK, et al. Central mechanisms of stress integration: hierarchical circuitry controlling hypothalamo-pituitary–adrenocortical responsiveness. Front Neuroendocrinol 2003;24(3):151–180. Pessoa L, Padmala S, Morland T. Fate of unattended fearful faces in the amygdala is determined by both attentional resources and cognitive modulation. Neuroimage 2005;28(1):249–255. Keefe FJ, Rumble ME, Scipio CD, et al. Psychological aspects of persistent pain: current state of the science. J Pain 2004;5(4):195–211. Misslin R. The defense system of fear: behavior and neurocircuitry. Neurophysiol Clin 2003;33(2):55–66. Rosen JB. The neurobiology of conditioned and unconditioned fear: a neurobehavioral system analysis of the amygdala. Behav Cogn Neurosci Rev 2004;3(1):23–41. Pare D, Quirk GJ, Ledoux JE. New vistas on amygdala networks in conditioned fear. J Neurophysiol 2004;92(1):1–9. Forray MI, Gysling K. Role of noradrenergic projections to the bed nucleus of the stria terminalis in the regulation of the hypothalamic–pituitary–adrenal axis. Brain Res Rev 2004;47(1–3):145–160. Xu Y, Day TA, Buller KM. The central amygdala modulates hypothalamic–pituitary–adrenal axis responses to systemic interleukin-1beta administration. Neuroscience 1999;94(1):175– 183. Sternberg EM. Neuroendocrine factors in susceptibility to inflammatory disease: focus on the hypothalamic–pituitary–adrenal axis. Horm Res 1995;43(4):159–161. Kohl J. The role of complement in danger sensing and transmission. Immunol Res 2006;34(2):157–176. Lambrecht BN. Immunologists getting nervous: neuropeptides, dendritic cells and T cell activation. Respir Res 2001;2(3):133–138. Inoue A, Ikoma K, Morioka N, et al. Interleukin-1beta induces substance P release from primary afferent neurons through the cyclooxygenase-2 system. J Neurochem

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1999;73(5):2206–2213. Eskandari F, Webster JI, Sternberg EM. Neural immune pathways and their connection to inflammatory diseases. Arthritis Res Ther 2003;5(6):251–265. Gruys E, Toussaint M, Niewold T, et al. Acute phase reaction and acute phase proteins. J Zhejiang Univ SCI 2005;6(11):1045–1056. Elenkov IJ, Wilder RL, Chrousos GP, et al. The sympathetic nerve—an integrative interface between two supersystems: the brain and the immune system. Pharmacol Rev 2000;52(4):595–638. Vizi ES, Elenkov IJ. Nonsynaptic noradrenaline release in neuro-immune responses. Acta Biol Hung 2002;53(1–2):229–244. Kin NW, Sanders VM. It takes nerve to tell T and B cells what to do. J Leukoc Biol 2006;79(6):1093–1104. Oberbeck R. Catecholamines: physiological immunomodulators during health and illness. Curr Med Chem 2006;13(17):1979–1989. Tracey KJ. The inflammatory reflex. Nature 2002;420(6917):853–859. Maier SF, Goehler LE, Fleshner M, et al. The role of the vagus nerve in cytokine-to-brain communication. Ann N Y Acad Sci 1998;840:289–300. Dantzer R. Cytokine-induced sickness behavior: mechanisms and implications. Ann N Y Acad Sci 2001;933:222–234. Elenkov IJ, Iezzoni DG, Daly A, et al. Cytokine dysregulation, inflammation and well-being. Neuroimmunomodulation 2005;12(5):255–269. Watkins LR, Maier SF. Immune regulation of central nervous system functions: from sickness responses to pathological pain. J Intern Med 2005;257(2):139–155. Watkins LR, Maier SF. Implications of immune-to-brain communication for sickness and pain. Proc Natl Acad Sci U S A 1996;96(14):7710–7713. Wieseler–Frank J, Maier SF, Watkins LR. Immune-to-brain communication dynamically modulates pain: physiological and pathological consequences. Brain Behav Immun 2005;19(2):104–111. Steinman L. Elaborate interactions between the immune and nervous systems. Nat Immunol 2004;5(6):575–581. Romeo HE, Tio DL, Rahman SU, et al. The glossopharyngeal nerve as a novel pathway in immune-to-brain communication: relevance to neuroimmune surveillance of the oral cavity. J Neuroimmunol 2001;115(1–2):91–100. Reiche EM, Morimoto HK, Nunes SM. Stress and depression-induced immune dysfunction: implications for the development and progression of cancer. Int Rev Psychiatry 2005;17(6):515–527. Wichers M, Maes M. The psychoneuroimmuno-pathophysiology of cytokine-induced depression in humans. Int J Neuropsychopharmacol 2002;5(4):375–388. Anisman H, Merali Z. Cytokines, stress and depressive illness: brain-immune interactions. Ann Med 2003;35(1):2–11. Pucak ML, Kaplin AI. Unkind cytokines: current evidence for the potential role of cytokines in immune-mediated depression. Int Rev Psychiatry 2005;17(6):477–483. Schiepers OJ, Wichers MC, Maes M. Cytokines and major depression. Prog Neuropsychopharmacol Biol Psychiatry 2005;29(2):201–217. Wood LJ, Nail LM, Gilster A, et al. Cancer chemotherapy-related symptoms: evidence to suggest a role for proinflammatory cytokines. Oncol Nurs Forum 2006;33(3):535–542. Raison CL, Capuron L, Miller AH. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol 2006;27(1):24–31.

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CHAPTER 30 Pain and Learning ROBERT J. GATCHEL, BRIAN R. THEODORE, and NANCY D. KISHINO One of the major contributions of the behavioral sciences to the area of medicine has been the application of learning principles to the development of effective illness management techniques. This has been especially true in the area of pain management. Before discussing these learning-based management techniques, an overview of the three major principles of learning will be provided.

Overview of the Three Major Principles of Learning CLASSICAL CONDITIONING Classical conditioning is one of the most basic forms of learning in which a learned association or connection develops between two stimuli or objects. As noted by Baum et al.,1 the eminent Russian physiologist Ivan Pavlov (1849–1936) was the first to describe the process of classical conditioning with his work on the conditioned reflex. Reflexes are specific, automatic, unlearned reactions elicited by a specific stimulus. For example, if you have ever touched a surface that you did not know was hot (such as a hot stove), you showed a reflexive behavior—the immediate withdrawal of your hand from the stove. Similarly, if a piece of dust suddenly enters your eye, your eye will automatically blink and begin to secrete tears. These unconditioned reflexes are automatic and have a great deal of survival value for the organism. Pavlov demonstrated that such unconditioned reflexes could be conditioned, or learned. While studying dogs in order to understand more fully the digestive process, he began to notice that many of the dogs secreted saliva (an unconditioned reflex to the sight or smell of food) before food was delivered to them. He observed that this phenomenon occurred whenever the dogs either heard the 1429

approaching footsteps of the laboratory assistant who fed them or had a preliminary glimpse of the food. In order to investigate this phenomenon more systematically, Pavlov developed a procedure for producing a conditioned reflex. This procedure came to be called classical conditioning. It is one of the most basic forms of learning. Pavlov conducted a series of well-known studies on the process of classical conditioning using dogs as experimental subjects (Fig. 30.1). In these studies, Pavlov studied situations in which a neutral stimulus or event (such as a bell) was presented to a dog just prior to the presentation of food (an unconditioned stimulus that normally elicits an automatic unconditioned reflex of salivation). After a number of such presentations, the bell (now a conditioned stimulus) would elicit a conditioned or learned salivation response when presented by itself in the absence of food. The conditioned reflex of salivation occurred to the bell alone. This represents the process of classical conditioning, and it is based on the learned association or connection between two stimuli, such that the bell is associated with food, that have occurred together at approximately the same point in time. An association is learned between a weak stimulus (such as the bell) and a strong stimulus (such as the sight of food) so that the weak stimulus comes to elicit the response originally controlled only by the stronger one (i.e., salivation).

FIGURE 30.1 Pavlov’s procedure of classical conditioning. CR, conditioned reflex; CS, conditioned stimulus; UCR, unconditioned reflex; UCS, unconditioned stimulus.

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Pavlov also subsequently demonstrated what would happen if the neutral stimulus, such as a bell, was presented just prior to the presentation of an aversive stimulus such as an electric shock or a pinprick. Normally, such aversive stimuli presented alone will produce a variety of negative responses such as whining/whimpering and fear-type reactions such as urination. When the bell preceded such an aversive stimulus, eventually, the formerly neutral bell stimulus would automatically produce the negative emotional responses. In another variety of this design, Pavlov then evaluated what would happen if, instead of preceding food with the sound of the bell, it was preceded by the aversive stimulus such as electric shock. What Pavlov found in this situation was that, after this conditioning, the dogs subsequently failed to demonstrate any negative emotional responses to the aversive stimulus. Instead, these dogs began perceiving these painful stimuli as signals that food was on the way. The electric shock now actually elicited salivation and approach behaviors.

OPERANT CONDITIONING Operant conditioning (also referred to as instrumental conditioning) is a different form of learning that was originally formulated by Edward Thorndike (1874–1949) and then more comprehensively developed by B. F. Skinner (1904–1990). Unlike classical conditioning, operant conditioning develops new behaviors that bring about positive consequences or remove negative events. In classical conditioning, a new stimulus (such as a bell) is conditioned to elicit the same responses that had previously occurred to the unconditioned stimulus, whereas in operant conditioning, a new response is learned. For example, new behaviors that produce food, social approval, or other positive consequences, or that reduce damaging or aversive events, illustrate operant behavior. The behavior “operates” on the environment to bring about changes in it. Thus, animal training, such as that involved in the learned performance of circus animals, involves basic principles of operant conditioning. Although operant training has existed for centuries, the behaviorist revolution in psychology provided the first carefully delineated methods and procedures of operant conditioning so that such training could be accomplished most 1431

efficiently.1 The key stimulus is reinforcement. Reinforcement refers to any consequence that increases the likelihood that a particular behavior will be repeated or that strengthens that behavior. Extinction involves the gradual decrease in the strength or tendency to perform a response due to the elimination of reinforcement. Based on these principles, what came to be known as the “Skinner box” was devised as an enclosed plexiglas box in which there was a light above a lever. The lever could be pressed down by the animal with its paws (rats were used in these early studies). Below the lever was a food tray into which food pellets could be dispensed. The task of the animal was to learn that pressing the lever (a certain number of times or at a certain rate, predetermined by the experimenter) resulted in food pellets being dispensed in the food tray. Thus, the animal learned to operate on the environment (the lever in the box) in order to receive reinforcement (food pellets). Once the aforementioned response was learned, one could then introduce different reinforcement schedules in order to produce different patterns of responding. Reinforcement could now require variable numbers of bar presses or could be available every so often. Also, a discriminative stimulus could be introduced, so that the rat received reinforcement for pressing the bar only when the light was on in the box. The animal would soon learn not to respond when the light was off. In this manner, the rat’s bar-pressing behavior came under stimulus (e.g., light) control. This same shaping procedure is used in training circus and other animals to perform complicated acts. Dolphins can be shaped to leap out of the water, and lions can be taught to jump through flaming hoops in order to receive some reinforcement. These techniques are used in virtually every zoo and marine animal show.

OBSERVATIONAL LEARNING Finally, the third major form of learning is called observational learning. There has been a great deal of research indicating that learning can occur through simple observation without the presence of any form of tangible direct reinforcement. Such learning, besides being called observational learning, is sometimes called imitation learning, cognitive learning, vicarious learning, or modeling. Observational learning is defined simply 1432

as that learning which occurs without any apparent direct reinforcement.2 Many behaviors can be acquired if an individual sees the particular behavior performed or modeled by another person. In addition, behavior is often strongly guided by social norms, resulting in a given individual being motivated to adopt a set of behaviors that are consistent with these norms.3,4 Observational learning is one such mechanism that transmits knowledge of these norms to the individual. These norms can be either explicit or implicit, and they can operate at the level of specific groups an individual may identify with, in addition to norms dictated at the larger societal level. One of the earliest laboratory studies of observational learning5 involved nursery school children. One group of children observed an adult perform a series of aggressive acts, both verbal and physical, toward a large toy Bobo doll. Another group watched a nonaggressive adult, who simply sat quietly and paid no attention to the doll. A third group of children was not exposed to a model. Later, after being mildly frustrated, all children were placed in a room alone with the Bobo doll and their behavior was observed. It was found that the behavior of the two model groups tended to be similar to that of their adult model. That is, children who had viewed the aggressive adult performed more aggressive acts toward the doll in the free-play situation than the other groups and also made more responses that were exact imitations of the model’s aggressive behavior. Those children who had observed a nonaggressive adult model performed significantly fewer aggressive responses than the aggressive model group.

Operant Conditioning and Pain THE HALLMARK WORK OF WILBERT FORDYCE As discussed earlier, and as reviewed by Gatchel,6 operant conditioning refers to the strengthening of a response and behavior through reward or reinforcement. That is to say, the probability that a behavior will be performed again is increased if it is followed by some form of reinforcement. Behavior is controlled by its consequences. If a behavior is followed by a reward, it has a high probability of recurring; if it is ignored 1433

or punished, it has a low probability of recurring. Obviously, a great deal of our everyday behavior is learned and maintained through operant conditioning. For example, most of us work because of the rewards (both tangible, such as money, and intangible, such as a pleasant work environment) that it produces. In terms of pain, many times a person in pain will elicit a great deal of sympathy and attention (both of which are rewarding). In addition, suggestions are usually made by others to rest and stay inactive, painrelieving medications are usually administered, and often financial compensation is provided. The longer these reinforcing consequences continue, the longer the patient is likely to display the maladaptive pain behaviors such as inactivity and avoidance of work. Thus, this type of learning or conditioning can significantly contribute to the maintenance of pain behavior. As pointed out by Baum et al.,1 this operant conditioning conceptualization of pain was systematically employed in the operant pain treatment program originally developed at the University of Washington’s Department of Rehabilitation Medicine by Fordyce and colleagues.7 This program involved a 4- to 8-week inpatient period, designed to gradually increase the general activity level of the patient and to decrease medication usage. The program was based on the assumption that, although pain may initially result from some underlying organic pathologic condition, environmental reinforcement consequences (such as attention of the patient’s family and the rehabilitation staff) can modify and further maintain various aspects of “pain behavior,” such as complaining, grimacing, slow and cautious body movements, requesting pain medication, and so on. Viewing pain as an operantly conditioned behavior, Fordyce and colleagues7 assumed that the potentially reinforcing consequences, such as the concern and attention from others, rest, medication, and avoiding unpleasant responsibilities and duties, as well as other events, frequently follow and reinforce the maladaptive pain behavior and, as a consequence, hinder the patient’s progress in treatment. In their treatment program, Fordyce and colleagues7 systematically controlled environmental events (e.g., attention, rest, medication) and made them occur contingent on adaptive behaviors. A major goal of the 1434

program was to increase positive behaviors, such as participation in therapy and activity level, while simultaneously decreasing or eliminating negative pain behaviors. It should also be noted that members of the patient’s family were actively involved in the treatment program and worked closely with the rehabilitation staff. They were taught how to react to the patient’s behavior in a manner that would reduce pain and to maximize the patient’s compliance with, and performance in, the rehabilitation program. Using this operant approach, the patient was basically taught to reinterpret the sensation of pain and tolerate it while performing more adaptive behaviors that would gain the attention and approval of others. Such a program was initially conducted in the hospital and would later be continued on an outpatient basis. These programs proved to be very successful at decreasing pain behaviors while increasing the levels of activities of daily living. Of course, such examples do not imply that all pain is learned. The point being made is that our pain perceptions and responses often have a significant psychological learning component that directly and significantly contributes to these experiences of pain. Thus, psychological variables play a direct role in the pain experience. How one reacts to pain sensations is as important an issue as the specific physiologic mechanisms involved in transmitting and generating pain experiences. Pain is a complex behavior and not simply a sensory effect. With the aforementioned view in mind, it is clear that one must conceptualize pain like any other form of complex behavior, consisting of multiple behavioral components. As Fordyce and Steger8 have indicated, in order to describe pain, “there must be some form of pain behavior by which diagnostic inferences and treatment judgments can be made.” A patient will signal the type of pain he or she is experiencing by describing the intensity, frequency, location, and type of pain experienced. In addition to these verbal cues available to the patient’s environment as an indication of his or her pain, there is a myriad of nonverbal signs used to communicate pain experiences. These include grimaces, sighs, moans, limps, awkward or strained body positions, the use of a cane or crutch, and many other symbols associated in our society with discomfort or physical problems. 1435

Traditionally, in attempts to describe pain, the focus was only on the physiologic or structural mechanisms underlying the report of pain and not on other components such as behavioral indices and self-report. The reliance on strictly one component, such as structural measures, does not yield a valid or precise measure of an individual’s pain. Again, pain is a complex behavior and not purely a sensory event. One needs to consider multiple behavioral components in the assessment and treatment of this behavior.

OPERANT CONDITIONING AND CHRONIC PAIN: THE BASICS Sanders9 has provided an excellent overview of the key ingredients involved in the use of operant conditioning methods when managing chronic pain. Of course, as he appropriately points out, operant conditioning methods should not be viewed as the only technique to use in managing chronic pain. Rather, it is just one of a number of behavioral science methodologies that can be used in combination/unison with other methodologies. Operant techniques can be used to help significantly decrease many common overt pain behaviors, such as the following: • Verbal pain behaviors, such as overt expressions of hurting (e.g., moaning, sighing, complaining) • Nonverbal pain behaviors, such as limping, grimacing, overreliance on a cane or brace, rubbing the affected area, etc. • Overly sedentary activities, such as decreased activity level, sitting, and lying down • Overconsumption of medications and the sole reliance on other therapeutic devices to control pain Rather than engagement in the aforementioned maladaptive pain behaviors, the patient is encouraged and reinforced to engage in “well behaviors” that involve more positive activity and alteration away from the overfocusing on pain. Through a comprehensive approach, health care professionals, family members, and others reinforce and encourage these well behaviors, whereas other effective pain management techniques are learned by the patient, such as biofeedback, stress management, coping skills, and appropriate pharmacotherapy, which is closely maintained. The 1436

overall goal is to increase function which will then be accompanied by a decrease in pain.6

Classical Conditioning and Pain AVERSIVE CLASSICAL CONDITIONING AND PAIN As discussed earlier in this chapter, Pavlov conducted studies demonstrating that when an initially neutral stimulus (such as a bell) was presented just prior to the presentation of an aversive, painful stimulus (such as electric shock) which will, in turn, produce negative emotional responses (such as whimpering, fear, avoidance, etc.), the bell itself will produce the negative emotional response when presented by itself. We then may generalize this to a patient who developed a sudden painful back problem at work, which does not go away after several days, after which just the act of going to work and anticipating lifting a heavy object may produce a negative emotional response such as fear of lifting and possible avoidance of the workplace because of pain.

CLASSICALLY CONDITIONED FEAR/AVOIDANCE AND PAIN Figure 30.2 presents the conditioning sequence that a person may go through in the situation described earlier: (1) At first, before conditioning, there is no association between lifting an object at work and any avoidance of lifting because of fear of pain. (2) During conditioning, the individual now begins to experience some back pain while lifting objects at work. This pain becomes progressively worse over time, to the point that this person hesitates to lift anything because of fear of exacerbating the back pain he or she is already experiencing. (3) After conditioning, any prompting or requirement to lift an object automatically produces a fear response and active avoidance of any lifting to avoid pain. There is now a classically conditioned negative emotional response of lifting objects at work because of the fear of pain.

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FIGURE 30.2 Classically conditioned fear and pain during a work task (lifting an object). CR, conditioned reflex; CS, conditioned stimulus; UCR, unconditioned reflex; UCS, unconditioned stimulus.

How can the aforementioned classically conditioned association between lifting and a fear of pain response be broken? As Pavlov’s experiments have shown, just as a conditioned association can be learned, it can also be subsequently extinguished or broken under the right situations. One such method would be to initially teach patients how to correctly lift while keeping their back muscles relaxed. The weight they are then asked to lift is kept relatively light and then progressively made heavier as the individual is able to lift a certain weight while relaxed and not experiencing any pain. The person is also taught appropriate pacing skills so that enough time is given between lifts for his or her back muscles to recuperate before performing the next lift. Thus, fear of lifting becomes “deconditioned” or extinguished in this work situation.

Observational Learning and Pain Observational learning is defined simply as that learning which occurs without any apparent direct reinforcement.2 Many behaviors can be acquired if an individual merely sees the particular behavior displayed or modeled by another person. Examples of behaviors acquired by observational learning abound. For example, investigations of dental fears in children have revealed that the attitudes and feelings of a child’s family toward dental treatment are important in determining that child’s own 1438

anxiety toward dental treatment. In one such study, it was found that children with anxious mothers showed significantly more emotionally negative behaviors during a tooth extraction than did children of mothers with low anxiety.10 In our society, there is a great deal of potential observational learning that can negatively influence comprehensive pain management effects. We are constantly being bombarded by advertisements that certain medications or pills will make us feel better. This, in turn, produces an unfortunate iatrogenic effect on patients who assume that there is some magic “silver bullet” pill or procedure that will automatically make them feel better and take away their pain. Unfortunately, such expectations are often not realized. Thus, patient education is often initially needed to dissuade patients of the notion that there is an immediate magical cure for their pain, especially as it becomes more chronic in nature. Social norms can also influence an individual’s response to pain, often through the mechanisms of observational learning. These normative influences play a role in behaviors associated with the reporting of pain, seeking treatment for pain, and level of pain tolerance. A study by Sternbach and Tursky11 was among the earliest investigations that illuminated our further understanding of how normative factors influence responses to pain. In this study, the results implied that cultural differences associated with ethnicity played a role in an individual’s tolerance of painful electrical stimulation. Parallel results in terms of ethnic differences were also demonstrated when physiologic indices (such as heart rate and palmar skin resistance levels) were measured in response to painful electrical stimulation despite relatively large intraethnic group variation.12 Recent studies have also demonstrated the role played by ethnic differences. For example, ethnicity has been reported to account for differences in self-reported levels of pain, as well as for tolerance of induced ischemic pain, during a study on a sample of chronic pain patients.13,14 Cultural differences are also apparent in treatment preference and levels of health care utilization. A large population-based survey in the United States indicated that Caucasians had greater number of visits on average compared to African Americans and Hispanics and were more likely to have received complementary or alternative therapies for chronic 1439

pain.15 Early research on the association between gender and responses to pain also indicated that females had a lower tolerance level for experimentally induced pain16 and were also more likely to report pain within clinical settings.17 However, recent research has indicated that the extent of an individual’s identification with his or her own gender group norms moderates his or her tolerance of pain. Gender differences in the tolerance of experimentally induced pain are present only among individuals strongly identifying with social norms that dictate that men should tolerate more pain than women.18 Although it remains to be seen whether social norms also dictate gender differences in the probability of seeking treatment for pain, there is a demonstrable gender difference in health care utilization among chronic pain patients, with females being more likely to seek treatment for pain.19

Integrating Learning Principles in the Treatment of Pain COGNITIVE-BEHAVIORAL THERAPY AND PAIN As Turk20 has highlighted in his discussion of the cognitive-behavioral therapy (CBT) approach to pain, there are important behavioral learning theory principles that are part of this overall therapeutic perspective. Certainly, classical conditioning (a focus on eliminating conditioned fear avoidance), operant conditioning (such as not reinforcing pain behavior), and observational learning (such as education about the negative iatrogenic expectation of immediate pain relief) are all important components. However, in addition, Turk20 appropriately points out the fact that cognitive factors, in addition to behavioral factors, need to be considered: “The critical factor for the C–B model, therefore, is not that events occur together in time or are operantly reinforced but that people learn to predict them based on experiences and information processing. They filter information through their preexisting knowledge and organized representations of knowledge (e.g., cognitive scheme) . . . and react accordingly . . . Because interaction with the environment is not a static process, attention is given to the ongoing reciprocal relationships among 1440

physical, cognitive, affective, social, and behavioral factors” (p. 140). This perspective is in keeping with the biopsychosocial approach to pain,6 to be discussed later. With this aforementioned perspective in mind, there is no doubt that CBT is an effective treatment modality for the management of pain. Morley et al.,21 on the basis of their systematic review of the scientific literature and a meta-analysis of randomized controlled trials, found that CBT produced significantly greater changes in self-reported pain and cognitive coping, as well as reduced behavioral expressions of pain, relative to waiting list control patients and alternative treatment control conditions. In a more recent comprehensive review, Gatchel and Okifuji22 found comparable results. Table 30.1 provides a summary of some of the components of CBT, as delineated by Gatchel.6 TABLE 30.1 Summary of Some of the Major Components of Cognitive-Behavioral Therapy Educate patients about pain and their particular syndrome. Engender in patients a self-management and coping skills perspective to pain. Help patients focus on increasing physical functioning and management of their pain rather than expecting a sudden cure. Teach biofeedback, relaxation, and stress management techniques. Provide patients with coping skills in other areas, such as with interpersonal problems, workrelated problems, marital problems, etc. Emphasize to patients the importance of identifying, and then eliminating, maladaptive thoughts about pain. Provide patients with guidance about increasing activities of daily living (in order to distract them from pain), with appropriate pacing activities. Provide help to improve sleep. Review the appropriate use of potential adjunctive modalities, such as medications, exercise, and physical methods (e.g., cold and heat packs). Assist patients with appropriate goal setting for the future (e.g., when to return to work or other activities). Provide relapse prevention strategies in order to help cope with potential future relapses. Adapted from Gatchel RJ. Clinical Essentials of Pain Management. Washington, DC: American Psychological Association; 2005.

COGNITIVE-BEHAVIORAL THERAPY AS AN ESSENTIAL COMPONENT OF A COMPREHENSIVE INTERDISCIPLINARY APPROACH TO PAIN MANAGEMENT 1441

The biopsychosocial perspective of pain is now accepted as the most heuristic approach to the understanding and treatment of pain disorders.6,23 It views physical disorders, such as pain, as a result of a complex and dynamic interaction among physiologic, psychological, and social factors that perpetuate and may worsen the clinical presentation. Moreover, each individual experiences pain uniquely. Therefore, the range of psychological, social, and economic factors can interact with physical pathology to modulate a patient’s report of symptoms and subsequent disability. As a consequence, a comprehensive biopsychosocial approach to assessment and treatment must be employed with each patient because of the unique interactions as well as to tailor the treatment to the specific needs of the patient. This is why comprehensive interdisciplinary pain management programs have proven to be more therapeutic and costeffective than traditional unimodal treatment approaches.22 Within an interdisciplinary treatment program, there is a comprehensive treatment team that consists of the following: physician–nurse team to deal with medical issues, psychologist or psychiatrist to deal with the psychosocial issues of patients, a physical therapist to address any issues related to physiologic bases of pain as well as any issues related to physical progression toward recovery, and an occupational therapist who is involved in both physical and vocational aspects of the patient’s treatment. For such a program to be effective, constant and efficient communication among all treatment personnel is imperative, during which patient progress can be discussed and evaluated. This is important so that patients hear the same treatment philosophy and message from each of the treatment team members. The overall goal is to produce an increase of functioning and the ability to manage pain and disability. It is a major goal of the psychologist or psychiatrist to increase the patient’s understanding of pain as well as their coping skills required to manage the pain. This is where CBT plays a major role. Of course, in keeping with the biopsychosocial perspective, it is not a standalone treatment but must be integrated with the other components of therapy in order to yield the best long-term outcomes.6

Conclusion 1442

Pain is a complex behavior and is, therefore, subject to the general principles of learning and behavior change. The three major principles of learning include classical conditioning, operant conditioning, and observational learning. These principles play an important role in the development of pain behavior (e.g., social or environmental factors that can reinforce maladaptive pain behavior). However, these learning principles can also be effectively utilized in the treatment and management of pain. The biopsychosocial approach to the treatment and management of pain emphasizes interdisciplinary treatment modalities and eschews a “one-size-fits-all” approach in dealing with pain. Learning principles are therefore an important component in this approach due to its flexibility in addressing complex behavioral history at the individual level. CBT incorporates these learning principles and has been documented as an effective component of interdisciplinary pain management. References 1. Baum A, Gatchel RJ, Krantz DS, eds. An Introduction to Health Psychology. 3rd ed. New York: McGraw-Hill; 1997. 2. Bandura A. Principles of Behavior Modification. New York: Holt, Rinehart & Winston; 1969. 3. Turner JC. Social Influence. New York: Brooks/Cole; 1991. 4. Cialdini RB, Trost MR. Social influence: social norms, conformity, and compliance. In: Gilbert D, Fiske S, Lindsey G, eds. The Handbook of Social Psychology. New York: McGraw-Hill; 1998:151–192. 5. Bandura A, Ross D, Ross SA. Imitation of film-mediated aggressive models. J Abnorm Soc Psychol 1963;66:3–11. 6. Gatchel RJ. Clinical Essentials of Pain Management. Washington, DC: American Psychological Association; 2005. 7. Fordyce WE, Fowler RS Jr, Lehmann JF, et al. Some implications of learning in problems of chronic pain. J Chronic Dis 1968;21:179–190. 8. Fordyce WE, Steger JC. Chronic pain. In: Pomerleau OF, Brady JP, eds. Behavioral Medicine: Theory and Practice. Baltimore, MD: Williams & Wilkins; 1979:125–154. 9. Sanders SH. Operant conditioning with chronic pain: back to basics. In: Turk DC, Gatchel RJ, eds. Psychological Approaches to Pain Management: A Practitioner’s Handbook. New York: Guilford Press; 2002:128–137. 10. Weisenberg M. Cultural and racial reactions to pain. In: Weisenberg M, ed. The Control of Pain. New York: Psychological Dimensions; 1977:201–232. 11. Sternbach RA, Tursky B. Ethnic differences among housewives in psychophysical and skin potential responses to electric shock. Psychophysiology 1965;1(3):241–246. 12. Tursky B, Sternbach RA. Further physiological correlates of ethnic differences in responses to shock. Psychophysiology 1967;4:67–74. 13. Campbell CM, Edwards RR, Fillingim RB. Ethnic differences in responses to multiple experimental pain stimuli. Pain 2005;113(1–2):20–26. 14. Edwards RR, Doleys DM, Fillingim RB, et al. Ethnic differences in pain tolerance: clinical

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implications in a chronic pain population. Psychosom Med 2001;63(2):316–323. Portenoy RK, Ugarte C, Fuller I, et al. Population-based survey of pain in the United States: differences among white, African American, and Hispanic subjects. J Pain 2004;5(6):317– 328. Riley JL III, Robinson ME, Wise EA, et al. Sex differences in the perception of noxious experimental stimuli: a meta-analysis. Pain 1998;74(2–3):181–187. Unruh AM. Gender variations in clinical pain experience. Pain 1996;65(2–3):123–167. Pool GJ, Schwegler AF, Theodore BR, et al. Role of gender norms and group identification on hypothetical and experimental pain tolerance. Pain 2007;129:122–129. McGeary DD, Mayer TG, Gatchel RJ, et al. Gender-related differences in treatment outcomes for patients with musculoskeletal disorders. Spine J 2003;3:197–203. Turk DC. A cognitive-behavioral perspective on treatment of chronic pain patients. In: Turk DC, Gatchel RJ, eds. Psychological Approaches to Pain Management: A Practitioner’s Handbook. 2nd ed. New York: Guilford Press; 2002:138–158. Morley S, Eccleston C, Williams A. Systematic review and meta-analysis of randomized controlled trials of cognitive behaviour therapy and behaviour therapy for chronic pain in adults, excluding headache. Pain 1999;80:1–13. Gatchel RJ, Okifuji A. Evidence-based scientific data documenting the treatment and costeffectiveness of comprehensive pain programs for chronic nonmalignant pain. J Pain 2006;7(11):779–793. Turk DC, Monarch ES. Biopsychosocial perspective on chronic pain. In: Turk DC, Gatchel RJ, eds. Psychological Approaches to Pain Management: A Practitioner’s Handbook. 2nd ed. New York: Guilford Press; 2002:5–29.

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CHAPTER 31 Psychiatric Illness, Depression, Anxiety, and Somatic Symptom Disorder JOSEPH GREGORY HOBELMANN, MARK D. SULLIVAN, MICHAEL R. CLARK, and AJAY D. WASAN Chronic pain and psychiatric illness commonly occur together.1 Yet the high rates of psychiatric illness in patients with chronic cancer and noncancer pain are still poorly understood. Diagnostic hierarchies taught to physicians in medical school and residency, impairment rating strategies used by compensation systems, and the natural scientific method used by medicine that looks for objective causes for clinical symptoms force us into a mind–body dualism. George Engel2 helped develop our modern concept of “psychogenic pain.” Psychogenic pain has been defined as pain due to psychological factors in the absence of an organic basis for pain.3 If we cannot explain pain in terms of objective tissue pathology, Western biomedicine lures us to explain it in terms of patients’ psychopathology.4,5 This is not an evidence-based strategy but rather a reflection of what it means to explain a symptom in modern biomedicine. The majority of patients with chronic pain and psychiatric illness have a physical basis for pain in the body, whose perception is made worse by overlying psychiatric illness.6 Epidemiologic evidence supports the use of inclusive rather than exclusive models of psychiatric diagnoses in medical settings that allows for the presence of both medical disease and mental disorders (i.e., a comorbidity model). Medical illness in no way excludes the possibility of a clinically important psychiatric illness. Medically ill patients are much more likely to have psychiatric illness than patients without medical illness. Psychiatric illness in no way precludes the possibility of a clinically important medical illness. Psychiatric illness is, in fact, associated with health behaviors and psychophysiologic changes 1445

known to promote medical illness. The structure of our clinical settings makes the integrated delivery of mental and physical health care difficult. Nowhere is this more important than in the care of the patient with chronic pain. Psychotherapeutic interventions for chronic pain are rarely effective in isolation from somatic treatments, and the success of somatic treatments is diminished by cooccurring mental illness. Distress, disuse, and disability are important facets of a chronic pain problem, and all require clinical attention by the pain practitioner. Neglect of one of these components can result in treatment failure even in the presence of excellent care for the other components. Research has indicated that psychiatric comorbidity has an adverse impact on treatments for chronic pain, such as rehabilitation, spinal cord stimulation, or opioid therapy.3,7 Although the details of these interactions are quite relevant to understand, this chapter concentrates on the recognition and diagnosis of psychiatric illness in patients with chronic pain, a sizable task in and of itself. Similarly, psychiatric comorbidity has shown to be particularly prevalent in and salient to the outcomes of a range of noncancer pain disorders (e.g., chronic low back pain,8 fibromyalgia,9 temporomandibular joint disorder,10 chronic daily headache,11 and chronic pelvic pain12). However, the specific role that comorbid psychopathology plays in each of these disorders is beyond the scope of this chapter. This chapter first outlines an approach to psychiatric diagnosis and to categorizing psychiatric symptoms in patients with chronic pain. Because of the breadth of psychiatric symptoms in pain patients, this section is substantial in order to provide a framework for organizing symptoms into diagnostic and treatment categories. Then, this chapter discusses the main illness categories of depression, anxiety, personality, and somatoform disorders. It is beyond this chapter to discuss to what extent a pain practitioner should evaluate and treat psychiatric problems and when to refer to a psychologist or psychiatrist.

Psychiatric Nosology and Diagnostic and Treatment Approaches As noted, any discussion of psychiatric disorders in patients with chronic 1446

pain is haunted by the concept of psychogenic pain. We are drawn to the concept of psychogenic pain because it fills the gaps left when our attempts fail to explain clinical pain exclusively in terms of tissue pathology. Psychogenic pain, however, is often merely a diagnosis of exclusion made solely on the basis of the inability to identify an objective cause for pain. Positive criteria for the identification of psychogenic pain, mechanisms for the production of psychogenic pain, and specific therapies for psychogenic pain are lacking. Furthermore, neuroimaging studies indicate that anticipated pain, imagined pain, or empathizing with the pain of another are associated with activations of the same brain areas involved in processing a painful stimulus, such as applied noxious heat (the lateral and medial pain systems).13,14 Thus, there is a dynamic interaction between our mental states (mind) and brain function. The dichotomy between mind and body (including brain) underlying the concept of psychogenic pain is hollow. As discussed later in this chapter, it may be more useful to frame the contributions of the mind to pain perception in terms of a process of central sensitization. Psychiatric diagnosis of many disorders, such as depression, can be helpful to the clinician and patient by pointing to specific effective therapies. The Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5) lists the current diagnoses treated by psychiatrists and the specific symptoms that serve as descriptive criteria for each condition.15 However, DSM offers only consistency and reliability of symptoms and does not take into consideration course of illness, which is essential in recognizing mental illness.16 This is particularly true of psychiatric disorders in those with medical illness. Most psychiatrists tend to use the DSM as a guide to the major diagnoses, not as a definitive diagnostic method. As a descriptive tool, many of the symptom lists for DSM diagnoses are quite complete and will be referred to throughout this chapter. However, when patients with chronic pain are in need of psychiatric care, they want to know the generative nature of their conditions and how to differentiate them for the sake of receiving prognoses and treatments.17 Multidisciplinary pain treatment functions with the same limitations.18,19 Without the method to determine a set of unique causes and direct specific treatments, the patient receives 1447

symptomatic treatments with the expected “partial” response. Despite the involvement of more disciplines, the approach is clearly dualistic—cures for “organic” problems and management for “functional” problems. Cartesian dualism lives. The DSM, although it has limitations, provides a taxonomy that serves as the basis for psychiatrists and psychologists to communicate and further study disorders. This has been historically lacking for the classification of chronic pain conditions. However, the Analgesic, Anesthetic, and Addiction Clinical Trial Translations Innovations Opportunities and Networks (ACTTION) has partnered with the U.S. Food and Drug Administration and the American Pain Society (APS) to develop an evidence-based chronic pain classification system called the ACTTIONAPS Pain Taxonomy (AAPT).20 This classification incorporates available knowledge regarding both physiologic and biopsychosocial mechanisms contributing to pain conditions. It is important to recognize that psychological and social factors are not solely secondary consequences of chronic pain but rather play a complex role in the persistence and severity of pain conditions. These biopsychosocial factors can be risk factors, protective factors, and process variables within the dynamic system of forces that constitute a chronic pain condition.21 The AAPT classification system provides a framework that incorporates these complicated factors and could be very useful clinically if validated in future outcome studies. Patients with chronic pain come to or are referred to a psychiatrist because they are ill. In some way, they are considered a diagnostic dilemma.22,23 Despite the utilization of extensive health care resources to perform an exhaustive evaluation, the patients remain ill. A temptation emerges to diagnose them with a psychogenic problem because no “good” cause can be found for their persistent pain and the accompanying disability and suffering.24 The cause for their illness cannot be found until the investigation expands to include the domain of personal meaning.25 This realm contains not only the diseases of the brain (cerebral faculties) but also the disruptions of the motivational rhythms of behavior, the psychological constitution of the individual, and the personal chronicle of desire and relationships. All mental disorders are expressions of life under altered circumstances that affect characteristic mental capacities and 1448

generate particular expressions.26,27 These distinctions allow for independently informed perspectives about the nature of mental disorders and what may have happened to generate the disorder. Four perspectives (diseases, behaviors, dimensions, and life stories) represent classes of disorders that each have a common essence and logical implications for causation and treatment.28,29 In this approach to patient care, diseases are what people have, behaviors are what people do, dimensions are what people are, and life stories are what people encounter. The formulation of a patient with chronic pain should address the contributions from each perspective to the overall presentation and inform the design of a treatment plan that can address each component of the patient’s illness. Although the basis for a mental illness may be dominated by one perspective (i.e., the disease perspective in schizophrenia), generally, each psychiatric diagnosis has contributions from each perspective that are responsible for the onset and maintenance of the disorder. Diseases of the brain may manifest psychologically. The psychological faculties of the brain include, but are not limited to, consciousness, cognition, memory, language, affect, and executive functions. Abnormalities in the structures or their associated functions of these faculties are expressed in the symptoms typical of common diagnoses such as delirium, dementia, panic disorder, and major depression. However, the patient may describe deficits in these faculties with difficulty and rely on somatic symptoms (e.g., pain) as incomplete proxies for these criteria. The physical symptoms occur because the brain is malfunctioning and suggests pathology in the body. The unifying feature of diseases is a broken part within the individual that is causing the characteristic signs and symptoms typically manifested by the affliction.27 For the patient, only the symptoms and reduction of symptoms are of concern. Finding a cure may repair the broken part, prevent the initial damage from progressing, or compensate for the pathology through secondary compensatory measures. The perspective of behavior encompasses a wide range of actions and activities. The complex behaviors of human beings are designed with purpose to achieve goals. Human consciousness is characterized by the regular, rhythmic alterations of attention and perception produced by 1449

internal drives that increase a person’s motivation toward a particular activity.29,30 The drive pushes the individual into action. Then, after the actions, the drive is satisfied and a state of satiety emerges. Over time, drives reemerge with subsequent effects on the individual’s perceptual attitude toward his setting. In addition, personal assumptions or external opportunities increase the likelihood of certain behaviors. These present a choice to the person who must decide what action to take. After the choice is made and the behavior completed, external consequences emerge from the outcome and influence future actions. The person learns which choices are most effective. When aspects of choice and control over behavior become disrupted, physicians will be asked to address the distorted goals, excessive demands, damaging consequences, and a lack of responsiveness to negative feedback.31,32 Eating disorders and opioid use disorders are examples. Treatment of behavioral disorders begins with regaining temporary control of the situation by stopping the behavior.33 Restricting the patient’s actions and preventing these problematic behaviors eventually limits the chaos of destructive actions. This stable foundation is required for the patient to gain insight about and motivation toward appropriate choices that will result in less distress and more satisfaction.34 This is the basis for the effectiveness of behavioral approaches to chronic pain management as outlined in other chapters. In contrast, many mental disorders emerge not from a disease of the brain or some form of abnormal illness behavior but a patient’s personal affective or cognitive constitution.29,30 Each individual possesses a set of personal dimensions such as intelligence, extraversion, and neuroticism. These traits describe who a person is, and they are carried into the world as a set of innate capabilities of their psychological makeup. Which traits are relied on and how much of them a person possesses will determine his potential to cope with different situations. Some circumstances are overwhelming and provoke a person’s vulnerability to distress. The patient cannot manage the situation and what is required because of who he is. Borderline personality disorder is an example (Table 31.1). It is probably the most severe personality disorder and generally is evident prior to the onset of pain. Assessment of personality traits is discussed at greater length in the following text. Treatment for disorders of the dimensional 1450

type focuses on remediation of specific deficiencies and guidance about overcoming potential vulnerabilities through adaptations such as education about, assistance with, or modification of the particular stressors.19,33 TABLE 31.1 Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Diagnostic Criteria for Borderline Personality Disorder A pervasive pattern of instability of interpersonal relationships, self-image, and affects and marked impulsivity beginning by early adulthood and present in a variety of contexts, as indicated by five (or more) of the following: 1. Frantic efforts to avoid real or imagined abandonment (Note: Do not include suicidal or selfmutilating behavior covered in criterion 5.) 2. A pattern of unstable and intense interpersonal relationships characterized by alternating between extremes of idealization and devaluation 3. Identity disturbance: markedly and persistently unstable self-image or sense of self 4. Impulsivity in at least two areas that are potentially self-damaging (e.g., spending, sex, substance abuse, reckless driving, binge eating) (Note: Do not include suicidal or selfmutilating behavior covered in criterion 5.) 5. Recurrent suicidal behavior, gestures, or threats, or self-mutilating behavior 6. Affective instability caused by a marked reactivity of mood (e.g., intense episodic dysphoria, irritability, or anxiety usually lasting a few hours and only rarely more than a few days) 7. Chronic feelings of emptiness 8. Inappropriate, intense anger, or difficulty controlling anger (e.g., frequent displays of temper, constant anger, recurrent physical fights) 9. Transient, stress-related paranoid ideation, or severe dissociative symptoms Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric Association; 2013:325–326, with permission. Copyright © 2013 American Psychiatric Association. All rights reserved.

The life story perspective utilizes a narrative composed of a series of events that a person encounters and determines to be personally meaningful.29,30 These self-reflections are the means by which a person judges the value of his life as a whole. They impart a sense of self as the agent of a life plan unfolding in a social setting as well as the reflective subject experiencing and interpreting the outcome of such plans and commitments. If events are occurring as planned, then the person feels on track and successful. However, if the sequence of events results in an unexpected or disappointing outcome, the person will feel a sense of distress about this failure. Life story disorders are interpretive responses to life encounters such as grief from loss or anxiety due to expected threats.31,35,36 In patients with chronic pain, the demoralization resulting 1451

from the inability to work or perform normal duties is a good example. Treatment begins with the expectation to forge a narrative of setting and sequence that suggests some role of the patient in his life, and that illuminates the troubled state of mind as the outcome of that role and course of events.19,33 The effective treatment of life story disorders requires reframing and reinterpretation to remoralize the patient by transforming the story into one with the potential for success and fulfillment. The four perspectives provide a comprehensive yet flexible approach to the evaluation of a patient in distress with chronic pain and other somatic symptoms.29,37 The treatments prescribed are now designed from the individual formulation and relevant perspectives. If a patient’s symptoms and distress continue, the physician must consider other factors that may have been overlooked. Usually, these factors are within one of the perspectives initially thought to be less important. A new combination of therapies is then required to treat the patient successfully. Understanding the relevant contributions from each perspective is important to formulating treatment. In the discussion that follows, categories of psychiatric disorders as defined in the DSM-5 (2013) of the American Psychiatric Association are used as an organizing strategy. The DSM-5 is relatively new, and there are significant changes from the DSM (4th ed., DSM-IV), which was utilized for almost 20 years. As such, there is little research using the new criteria, so this chapter discusses concepts utilizing both DSM-IV and DSM-5.

Framework for Describing Psychiatric Symptoms Figure 31.1 illustrates common psychiatric symptoms in patients with chronic pain. However, Figure 31.1 does omit substance use disorders, which are beyond the scope of this chapter. It is important to note that substance abuse or addiction in patients with chronic pain is estimated to range from 3% to 48% depending on the population sampled, with most estimates around 15%.38 Psychiatry-based research and health psychology–based research have contributed important insights into characterizing the mental life of patients with chronic pain. The findings 1452

from these epistemologies overlap significantly, and although lacking until recently, the new AAPT classification system for pain is a model for integrating these results.39 Common terms to describe the psychological condition in pain patients are heightened emotional distress, high negative affect, and elevated pain-related psychological symptoms (i.e., those that are a direct result of chronic pain, and when the pain is eliminated, the symptoms disappear). These can all be considered forms of psychopathology and psychiatric comorbidity because they represent impairments in mental health and involve maladaptive psychological responses to medical illness. This approach melds methods of classification from psychiatry and behavioral medicine to describe the scope of psychiatric disturbances in patients with chronic pain. Psychiatry is the field of medicine that is concerned with someone’s mental life, such as their emotions, experiences, thoughts, and behaviors. It is focused particularly on disruptive, disordered, or pathologic psychological states. Thus, the constructs from pain psychology are situated in Figure 31.1 as psychiatric symptoms, which in themselves can be at pathologic levels, just as depression symptoms can rise to a level considered abnormal.

FIGURE 31.1 Common psychiatric symptoms in patients with chronic pain. DSM, Diagnostic and Statistical Manual of Mental Disorders; Gen, general; Rx, prescription; SUDs, substance use disorders. (Adapted from Wasan AD, Alpay M. Pain and the psychiatric co-morbidities of pain. In: Stern T, ed. Comprehensive Clinical Psychiatry. Philadelphia: Elsevier; 2008:1067–1080.)

In pain patients, the most common manifestations of psychiatric comorbidity involve one or more core psychopathologies in combination 1453

with pain-related psychological symptoms. For instance, poor pain selfefficacy or high levels of pain catastrophizing are most often found in conjunction with high levels of depression or anxiety symptoms.40 These categories interact, and some component of each are part and parcel of other psychopathologies. In other words, “lumping” (a diagnostic approach) and “splitting” (a construct-based approach) are both valid approaches to psychiatric phenomenology. As described in the previous section, not all patients and their psychiatric symptoms fit neatly into DSM categories of illness. This is true not just of those with chronic pain, and hence, looking beyond DSM to broader and more specific methods of illness description and diagnosis is more prudent. The pain-related psychological symptoms are described at length in other chapters, but it is important to understand how they interact with other psychiatric diagnoses. For example, pain-related anxiety (which includes state and trait anxiety-related to pain) is the form of anxiety most germane to pain.41 Elevated levels of pain-related anxiety (such as fear of pain) also meet DSM-5 criteria for an anxiety disorder due to a general medical condition. Because anxiety straddles both domains of core psychopathology and pain-related psychological symptoms, the assessment of anxiety in a patient with chronic pain (as detailed in the following discussion) must include a review of manifestations of generalized anxiety as well as pain-specific anxiety symptoms (e.g., physiologic changes associated with the anticipation of pain). As indicated on Figure 31.1, elevated pain-related psychological symptoms have a clear, negative predictive relationship to many outcome areas. Poor coping skills often involve passive responses to chronic pain (e.g., remaining bed-bound and mistakenly assuming that chronic pain is indicative of ongoing tissue damage as a reason for inactivity). Poor copers employ few active self-management strategies (such as using ice, heat, or relaxation strategies for 10 to 20 minutes before resuming activities). Pain catastrophizing (cognitive distortions that are centered around pain) and low self-efficacy (a low estimate by the patient of what he/she is capable of doing) are linked with higher levels of pain and disability and worse quality of life.39 A tendency to catastrophize predicts poor outcome and disability, often independent of other psychopathology, such as major 1454

depression. Duration of chronic pain and presence of psychiatric comorbidity are each independent predictors of pain intensity and disability. High levels of anger (which occur more often in men) can also explain significant variance in pain severity.42

Depression One must begin by distinguishing between depressed mood and the clinical syndrome of major depression. It is important to note, especially when working with chronic pain patients, that depressed mood or dysphoria is not necessary for the diagnosis of major depression. Anhedonia, the inability to enjoy activities or experience pleasure, is an adequate substitute. It is common for patients with chronic pain to deny dysphoria but to acknowledge that enjoyment of all activities has ceased, even those without obvious relation to their pain problem (e.g., watching television for a patient with low back pain). The DSM-5 criteria for major depressive episodes are listed in Table 31.2. These include psychological symptoms, such as worthlessness, and somatic symptoms, such as insomnia. The three core symptoms of major depression in patients with pain (which also holds true in those without pain) are low mood, impaired self-attitude, and neurovegetative signs.43 It is important to note that somatic symptoms count toward a diagnosis of major depression unless they are caused by “the direct physiologic effects of a general medical condition” or medication. The poor sleep, poor concentration, and lack of enjoyment often experienced by patients with chronic pain are frequently attributed to pain rather than depression. These should generally not be excluded as a direct physiologic effect of pain. Given the high rates of depression in chronic pain patients, in the context of low mood complaints, it is best to attribute these symptoms toward a diagnosis of depression. Indeed, studies of depression in medically ill populations have generally found greater sensitivity and reliability with “inclusive models” of depression diagnosis than with models that try to identify the cause of each symptom.44 Similarly, just as in those without pain, those with depression and pain are very likely to also have high levels of anxiety.45,46 1455

TABLE 31.2 Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Criteria for Major Depressive Episode A. Five (or more) of the following symptoms have been present during the same 2-wk period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure. Note: Do not include symptoms that are clearly attributable to another medical condition. 1. Depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feels sad or empty) or observation made by others (e.g., appears tearful). Note: In children and adolescents, can be irritable mood. 2. Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account or observation) 3. Significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight in a month), or a decrease or increase in appetite nearly every day. Note: In children, consider failure to make expected weight gains. 4. Insomnia or hypersomnia nearly every day 5. Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down) 6. Fatigue or loss of energy nearly every day 7. Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick) 8. Diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by others) 9. Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide B. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. C. The symptoms are not caused by the direct physiologic effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition (e.g., hypothyroidism). D. The occurrence of the major depressive episode is not better explained by schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional disorder, or other specified and unspecified schizophrenia spectrum and other psychotic disorders. E. There has never been a manic episode or hypomanic episode. Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric Association; 2013:94–95, with permission. Copyright © 2013 American Psychiatric Association. All Rights Reserved.

SUICIDAL IDEATION AND BEHAVIOR Suicide accounts for 1.4% of all deaths in the world, making it the 15th leading cause of death.47 In the United States, 4.6% of the population surveyed had made a suicide attempt, and 13.5% reported a history of suicidal ideation.48 The majority of suicide attempts occur within a year of the onset of suicidal ideation. The risk of suicidality is greatest in patients 1456

with affective disorders (e.g., depression and anxiety), personality disorders, substance use disorders, and chronic debilitating physical illnesses.49,50 Depression is the most consistent and strongest predictor of suicidal ideation.51 In one study of patients with major depressive disorder, 58% reported suicidal ideation during a current episode of illness.52 Suicide was attempted by 15% of these patients with 95% preceded by suicidal ideation. Hopelessness, low levels of function, perceptions of poor social support, and disorders of alcohol use predicted suicidal ideation. Medical illnesses and chronic pain particularly, increase the risk of suicide. In a study of suicide in the elderly, medical conditions such as congestive heart failure, chronic obstructive lung disease, seizure disorder, and urinary incontinence were significantly associated with suicide with treatment for multiple illnesses increasing the risk.53 Yet, except for bipolar disorder, the highest risk of suicide was found in patients with severe pain (odds ratio [OR] = 7.52). Pain has been studied as a contributory factor in episodes of deliberate self-harm involving patients with medical problems admitted to a general hospital.54 Multiple studies have shown that patients with chronic pain are at greater risk for suicidal ideation, suicide attempts, and suicide completions.55 Most clinical diagnoses of pain conditions have been associated with increased risk for suicide.56 A recent comprehensive review notes that the likelihood of death by suicide in patients with chronic pain is 2 to 3 times the rate described in the general population.50 The lifetime prevalence of suicide attempts in patients with chronic pain ranged from 5% to 14%, and the rate of suicide attempts is double that found in the general population. The lifetime prevalence of suicidal ideation associated with chronic pain is approximately 20%. The rate of suicidal ideation in patients with chronic pain is estimated between 5% and 24%. Although a number of methods are used to commit suicide, overdoses with medications are the most common. The relationship between chronic pain and suicidality is complex. Although the associations are consistent, the cause and effect pathways of transition from suicidal ideation to suicide attempt to suicide completion are more difficult to describe. At this time, no successful algorithm exists and only an in-depth and longitudinal evaluation of the patient with chronic pain offers the best strategy for detecting who is 1457

considering suicide as a personal option. Although understandable, it is not the norm to be suicidal even in those with severe pain. Most commonly, suicidality in a patient with chronic pain is indicative of an underlying psychiatric disorder.57 Thinking one is better off dead (a passive death wish) is not the same as actively trying or wanting to kill oneself (suicidality). It is important to bear this distinction in mind in evaluating any patient with thoughts about death. Part of the concern regarding the association between chronic pain and suicidality lies in whether chronic pain is an independent risk factor for suicidal behavior or the presence of depression completely explains this association. A thorough review described the evidence for eight painspecific risk factors of suicidality, which is defined as suicidal ideation, suicide attempt, or suicide completion.50 The studies available suffer from significant limitations including inadequate assessments, retrospective designs, limited control groups, and the failure to distinguish between the potential risk factors of pain versus pain-related disability. However, the existing pain literature coupled with the general knowledge of suicide supports the following as the strongest predictors of suicidality: family history of suicide, previous suicide attempts, and presence of comorbid depression. Evidence exists for other risk factors including pain characteristics (intensity, location, type, duration), female gender, comorbid insomnia, catastrophizing and avoidance, desire for escape, helplessness and hopelessness, and problem-solving deficits.58–60 The prevention of suicide should remain a priority for the care of patients with chronic pain.

WHICH CAME FIRST, DEPRESSION OR PAIN? Patients with chronic pain often dismiss a depression diagnosis, stating that their depression is a direct reaction to their pain problem. Psychiatry has long debated the value of distinguishing a reactive form of depression caused by adverse life events from an endogenous form of depression caused by biologic and genetic factors.61 Life events are important in many depressive episodes, although they play a less important role in recurrent and severe or melancholic or psychotic depressions.62 Determining whether a depression is a reasonable response to life’s stress 1458

may be important to patients seeking to decrease the stigma of a depression diagnosis and has been of interest to pain investigators (for a review, see Fishbain and colleagues6). It is not, however, important in deciding that treatment is necessary and appropriate. Indeed, no clinical benefit is gained from debating whether the depression caused the pain or the pain caused the depression, although such information may be useful in psychotherapy. If patients meet the diagnostic criteria outlined previously, it is likely that they can benefit from appropriate treatment. There is evidence that subsyndromal depression—depression symptoms not quite satisfying the threshold for major depression but debilitating nonetheless— also benefits from treatment and should be treated.63–65 Prospective studies of patients with chronic musculoskeletal pain have suggested that chronic pain can cause depression,66 that depression can cause chronic pain,67 and that they exist in a mutually reinforcing relationship.68 One fact raised to support the idea that pain causes depression is that the current depressive episode often began after the onset of the pain problem. The majority of studies appears to support this contention.69 However, it has been documented that many patients with chronic pain (especially those disabled patients seen in pain clinics) have often had episodes of depression that predated their pain problem by years.70 Among patients presenting to chronic pain clinics, one-third to more than one-half meet criteria for current major depression.71 Depression in patients with chronic pain is associated with greater pain intensity, more pain persistence, application for early retirement, and greater interference from pain, including more pain behaviors observed by others.72 This has led some investigators to propose that there may exist a common trait of susceptibility to dysphoric physical symptoms (including pain) and to negative psychological symptoms (including anxiety and depression).73,74 They conclude that “pain and psychological illness should be viewed as having reciprocal psychological and behavioral effects involving both processes of illness expression and adaptation.” It may be useful when initiating depression treatment to accept that the pain caused the depression because it builds rapport and is consistent with epidemiologic evidence about the current depressive episode. And most frequently, depression follows the onset of chronic pain and is not 1459

preceded by it.71

DIFFERENTIAL DIAGNOSIS When considering the diagnosis of depression in the patient with chronic pain, important alternatives include bipolar disorder, substance-induced mood disorder, and dysthymic disorder (particularly if accompanied by a severe personality disorder, such as borderline personality disorder). Patients with bipolar disorder have extended periods of abnormally elevated as well as abnormally depressed mood. These periods of elevated mood need to last more than one continuous day and include features such as inflated self-esteem, decreased need for sleep, and racing thoughts. A history of manic or hypomanic episodes predicts an atypical response to antidepressant medication and increases the risk of antidepressant-induced mania. Substance-induced mood disorders can also occur in those with pain. Patients with chronic pain may be taking medications such as opioids, corticosteroids, dopamine-blocking agents (including antiemetics), or sedatives (including muscle relaxants) that produce a depressive syndrome. Current medication lists should be scrutinized before additional medications are prescribed for any patient.

BIOLOGIC TESTS FOR DEPRESSION A variety of biologic tests for depression have been investigated.75 These tests have included the dexamethasone-suppression test, thyrotropinreleasing hormone stimulation test, clonidine-induced growth hormone secretion, and rates of imipramine binding to platelet membrane serotonin transporters. Forty percent to 50% of patients with major depression do not show normal suppression of morning plasma cortisol after receiving dexamethasone the night before. However, high false-positive rates for this dexamethasone-suppression test exist in patients who are pregnant; patients with dementia, alcoholism, anorexia nervosa, and other chronic debilitating diseases; and patients who are taking medications that induce microsomal enzymes, including barbiturates and opioids. This has limited the clinical value of this test.76 The serotonin transport mechanism on platelet membranes is similar to that on serotonergic neurons. 3Himipramine binding to this platelet receptor is reduced in patients with 1460

major depression. It appears to be further reduced in patients who have both pain and depression.77 Lower level of serotonin in the cerebral spinal fluid have found in depressed patients and have been linked to suicidal ideation.78 Although patients show significant differences on these tests, when considered as a group, substantial variation between individual patients limits the usefulness of these tests in the clinical setting. In the future, they may be able to provide a better understanding of the biochemical links between pain and depression.

DYSTHYMIC DISORDER Dysthymic disorder is a chronic form of depression lasting 2 years or longer. The symptoms are generally less severe than those during an episode of major depression. Individuals with dysthymia can develop major depression as well. This combined syndrome has often been called double depression.79 It is important to note dysthymia because it is frequently invisible in medical settings, often being dismissed as “just the way that patient is.” Dysthymia has been shown to respond to many antidepressants, including the selective serotonin reuptake inhibitors (SSRIs).80 Treatment of double depression can be particularly challenging because of treatment resistance and concurrent personality disorders.81 Psychiatric consultation should be considered when dysthymia or double depression is suspected.

EPIDEMIOLOGY OF DEPRESSION The prevalence of depression is much higher in medical settings and in patients with chronic illnesses than in the general population. It has been shown in studies using structured psychiatric interviews that a linear increase occurs in the prevalence of major depressive disorder when comparing community, primary care, and inpatient medical populations. Although 2% to 4% have major depression in the community, 5% to 9% of ambulatory medical patients and 15% to 20% of medical inpatients meet diagnostic criteria.82 Primary care patients with major depression have been found to have more severe medical illness than those who are not depressed.83 Even among community samples, the risk for depression appears to increase with worse perceived health status, number of chronic 1461

medical conditions, and number of medications taken.84 Depression is the most prevalent mood disorder associated with comorbid chronic pain.85 Prevalence rates of depression among patients in pain clinics have varied widely depending on the method of assessment and the population assessed. Rates as low as 10% and as high as 100% have been reported.86 The reason for the wide variability may be attributable to a number of factors, including the methods used to diagnose depression (e.g., interview, self-report instruments), the criteria used (e.g., DSM-5, cutoff scores on self-report instruments), the set of disorders included in the diagnosis of depression (e.g., presence of depressive symptoms, major depression), and referral bias (e.g., higher reported prevalence of depression in studies conducted in psychiatry clinics compared with rehabilitation clinics). The majority of studies report depression in more than 50% of chronic pain patients sampled.87,88 There is a direct relationship between the duration of pain and the incidence of major depression. Certain chronic painful conditions are associated with higher rates of depression than others. For example, fibromyalgia, chronic daily headache, and chronic pelvic pain, each are associated with higher rates than arthritis.45,89 Studies of primary care populations (in which generalization is less problematic) have revealed a number of other factors that appear to increase the likelihood of depression in patients with chronic pain. Dworkin and colleagues90 reported that patients with two or more pain complaints were much more likely to be depressed than those with a single pain complaint. Number of pain conditions reported was a better predictor of major depression than pain severity or pain persistence.90 Von Korff and colleagues91 developed a four-level scale for grading chronic pain severity based on pain disability and pain intensity: (1) low disability and low intensity; (2) low disability and high intensity; (3) high disability, moderately limiting; and (4) high disability, severely limiting. Depression, use of opioid analgesics, and doctor visits all increased as chronic pain grade increased. Engel and colleagues92 showed that depression was associated with high total health care costs but not high back pain costs among health maintenance organization patients with back pain. When dysfunctional primary care back pain patients are studied for a year, those 1462

whose back pain improves also show improvement of depressive symptoms to normal levels.93 These epidemiologic studies provide solid evidence for a strong association between chronic pain and depression but do not address whether chronic pain causes depression or depression causes chronic pain. As indicated previously, this question has more importance in medicolegal contexts than clinical contexts. Overall, in most instances, depression follows the onset of pain.93

PAIN AND DEPRESSION: MECHANISMS OF ASSOCIATION Beyond documenting the association of chronic pain and depression lies the question concerning mechanisms by which they may interact. Biologic, psychological, and social mechanisms have been proposed to explain the high co-occurrence of chronic pain and depression. There is also substantial evidence (beyond the scope of this chapter to recount) that the following mechanisms underlie the other psychiatric comorbidities of pain, such as anxiety disorders.

Biologic Theories Pain Sensitivity It is well documented that patients with major depression, or even depressive symptoms, have more pain complaints than those without depression. Studies have shown that 30% to 60% of depressed patients complain of pain.94 These findings raise the possibility that depressed patients may have a greater sensitivity to noxious stimuli. In other words, depressed patients may have a reduced pain threshold. But many studies have shown that depressed patients and patients with other psychiatric disorders have an elevated, not reduced pain threshold.95,96 Depression appears to elevate pain threshold more for exteroceptive (e.g., cutaneous) stimulation than interoceptive (e.g., ischemic) stimulation, but there is significant heterogeneity in findings among different patient populations and stimulus modalities.97 Psychiatric patients with dissociation such as borderline personality disorder have reliably shown elevated pain thresholds to external noxious stimuli.98,99 Patients with posttraumatic 1463

stress disorder (PTSD) show complex responses with higher pain thresholds and higher pain ratings to noxious stimuli than controls. Elevated pain thresholds were associated with dissociation levels, whereas elevated experimental and clinical pain ratings were associated with anxiety and anxiety sensitivity.100 Thus, there is an unexplained discrepancy between the higher experimental pain thresholds and the higher clinical pain complaints among patients with depression and other psychiatric disorders. But it is clear that the increased pain complaints of patients with psychiatric disorders cannot be explained by changes in pain thresholds. Biogenic Amines, Cytokines, and Neural Pathways The highly variable relationship between injury severity and pain severity has been known since Beecher’s studies of the soldiers at Anzio beach in World War II. Since the 1970s, great strides have been made in identifying the central nervous system mechanisms of endogenous pain modulation. Opioid and nonopioid branches to this system have been identified. Stimulation of the rostral ventromedial medulla or the dorsolateral pontine tegmentum produces behavioral analgesia in animals and inhibition of spinal pain transmission. The rostral ventromedial medulla is the principal source of serotonergic neurons that project to the spinal dorsal horn. The dorsolateral pontine tegmentum is the major source of noradrenergic neurons that project to the dorsal horn. Both neurotransmitters (serotonin and norepinephrine) inhibit nociceptive dorsal horn neurons when locally applied.101 The descending inhibitory system is modulated by serotonin and norepinephrine, which are also thought to modulate mood. This is perhaps best illustrated by the effects of selective serotonin norepinephrine reuptake inhibitors (SNRIs) on depression and pain. The two drugs approved for use in this class are duloxetine and venlafaxine. Both are FDA-approved antidepressants that have analgesic properties independent of their effects on mood.102,103 These medications enhance serotonergic and noradrenergic neurotransmission. Additional studies indicate that opioid analgesia is enhanced in the presence of antidepressant treatment104 and decreased after serotonin and norepinephrine depletion.105 Therefore, it appears that biogenic amines play a critical role in endogenous pain 1464

modulation. To the extent that depletion or impaired function of amines such as serotonin and norepinephrine occurs in depression, this may contribute to the pain experienced and reported by those with major depression. Just as cytokine responses are important to the initiation and maintenance of chronic pain,106 they have also been implicated in the pathogenesis of depression.107 Depressed patients without pain have been found to have higher levels of proinflammatory cytokines and acute phase proteins. Administration of the cytokine interferon-α leads to depression in up to 50% of patients. Proinflammatory cytokines affect neurotransmitter metabolism, neuroendocrine function (particularly the hypothalamicpituitary-adrenal axis), and synaptic plasticity. Cortical Substrates for Pain and Affect Advances in neuroimaging have linked the function of multiple areas in the brain which process pain and mood simultaneously, described at length in a previous chapter. This system is often termed the medial pain system or spinolimbic pain system.108 These cortical areas (e.g., the anterior cingulate cortex [ACC], the insula, amygdala, and the dorsolateral prefrontal cortex [DLPFC]) form functional units through which psychiatric comorbidity may amplify pain and disability (Fig. 31.2). They are also laden with opioid receptors.109 The ACC, insula, and DLPFC are less responsive to endogenous opioids in pain-free subjects with high negative affect (e.g., depression, anxiety, and anger symptoms).110 Thus, high negative affect may diminish the effectiveness of endogenous and exogenous opioids through direct effects on supraspinal opioid binding. The medial pain system runs parallel to the spinothalamic tract and receives direct input from the dorsal horn of the spinal cord. The interactions among the function of these areas, pain perception, and psychiatric illness are still being investigated. But the spinolimbic pathway is involved in descending pain inhibition, whose function may be negatively affected by the presence of psychopathology. This, in turn, could lead to heightened pain perception. Coghill and colleagues111 have shown that differences in pain sensitivity between patients can be correlated with differences in activation patterns in the ACC, the insula, and the DLPFC. The anticipation of pain—a form of anxiety for pain—is 1465

also modulated by these areas, suggesting a mechanism by which anxiety about pain can amplify pain perception. Ploghaus and colleagues13 have demonstrated that anticipation for an acute painful stimulus in healthy volunteers is marked by brain activation patterns throughout the medial pain system.

FIGURE 31.2 Supraspinal pathways of pain perception. ACC, anterior cingulate cortex; Amyg, amygdala; BG, basal ganglia; HT, hypothalamus; PAG, periaqueductal grayPB, parabrachial nucleus; PCC, posterior cingulate cortex; PF, prefrontal cortex; SMA, supplementary motor area. (From Apkarian AV, Bushnell MC, Treede RD, et al. Human brain mechanisms of pain perception and regulation in health and disease. Eur J Pain 2005;9:463–484; Price DD. Psychological and neural mechanisms of the affective dimension of pain. Science 2000;288[5472]:1769–1772.)

Sleep Disturbance Depression produces well-documented disturbances to sleep architecture. Polysomnographic recordings have documented reduced slow wave sleep, early onset of the first period of rapid eye movement (REM) sleep, and increased phasic REM sleep in patients with major depression.112 Sleep continuity disturbances and increased phasic REM sleep tend to normalize with depression remission, even with psychotherapeutic treatment. However, reduction of REM latency and decreased slow wave sleep tend to persist despite clinical recovery. In sum, there appear to be state and trait elements to the sleep disturbance associated with depression. Studies have also demonstrated that sleep disturbance may be a result of chronic pain, which, in turn, can make it worse.113 Fibromyalgia patients who were sleep deprived reported worsening pain and were found to be hyperalgesic (beyond their baseline pain) on pressure sensitivity testing.114 Thus, whether depression or pain precipitated or worsened a sleep disturbance, 1466

its presence makes pain worse and is an important link between the two conditions.

Psychological Theories Psychodynamic Theory In classic psychoanalytic theory,115 depression is postulated to be derived from anger unconsciously turned inward, excessive dependence on others for self-esteem, and feelings of helplessness in achieving one’s goals. Some have suggested that the depression in some chronic pain patients is a manifestation of a personality style that draws from early developmental conflicts of guilt, anger, and masochism.116,117 From this perspective, chronic pain may be a symptom of depressive disorder.118 Psychoanalytic theory stresses the fundamental parallelism between mental and physical pain and the possible displacement from the former to the latter. Intrapsychic links between pain and depression suggest that pain may function as a hysterical or conversion symptom that may prevent the breakthrough of more severe depression. These intrapsychic links largely correspond with the dynamics of pain proneness that were originally described by Engel2 and, in a further elaboration, connected with the concept of masked depression by Blumer and Heilbronn.116 Blumer and Heilbronn116 proposed a new psychological disorder, the “pain-prone” disorder, building on Engel’s2 notion of the pain-prone patient. In this view, pain should be considered as a variant of depressive disease. The central explanation is unconscious core conflicts. Core issues include “strong needs to be accepted and to depend on others as well as marked needs to receive affection and to be cared for.” Pain in the absence of organic pathology is considered by Blumer and Heilbronn116 to be a depressive spectrum disorder. According to this model, pain and depression are viewed as manifestations of a single, common disease process. Specifically, the pain-prone disorder is viewed as a masked “depressive equivalent . . . the prime expression of a muted depressive state.” No empiric research has supported the psychoanalytic formulation as presented by Blumer and Heilbronn.116,119,120 A more modern variant of this theory sees chronic pain as an expression of repressed anger and rage toward others. This was initially advanced by 1467

John Sarno, MD, a physiatrist practicing in New York City.121,122 This theory has not been thoroughly investigated empirically, but there is preliminary evidence of a significant relationship between forgiveness and pain, anger, and psychological distress in patients with low back pain.123 Behavioral (Operant Conditioning) Theory The behavioral model of depression concentrates on the most obvious symptom of depression, the motivational deficit characterized by a reduction in active behavior. A central feature of the behavioral model is response-contingent reinforcement (i.e., the responses from significant others to the individual’s behavior). From this perspective, depressive behavior and depression are associated with low rates of positive reinforcement from the environment. Lack of positive reinforcement leads to a decrease in the frequency of the individual engaging in these behaviors, and ultimately, they may be extinguished completely. These low rates of reinforcement may occur because (1) positive reinforcers in the environment may become less available, or aversive events in the environment may have become more prevalent; (2) the positive effect of previous reinforcers may have declined, or the negative impact of aversive events may have increased; or (3) the individual may lack the skills either to attain the available positive reinforcers or to cope with aversive aspects of the environment. When individuals experience low rates of positive reinforcement, they reduce the performance of those behaviors, unless they are self-reinforcing. The reduction of behavior decreases further opportunities to receive positive reinforcement. In the case of chronic pain, the individual may reduce his or her behavior because of physical impairments or because of fear of additional pain or further injury. Thus, by the restriction in behavior and social contacts, chronic pain patients may reduce the opportunity to achieve positive reinforcement and to engage in previously rewarding activities and consequently become depressed. The family can also reinforce maladaptive behavior. Although many families of patients with chronic pain are supportive with the best of intentions, excessive catering to the patient at the expense of maintaining function can perpetuate illness behavior, leading to depression. In other words, patients can occupy the

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sick role for reasons other than causal disease. Cognitive Theory According to Beck,124 people may be vulnerable to depression because, from an early age, they have possessed negatively biased conceptualizations (schemas) of themselves and their experiences. When they are challenged by stressful life events, these schemas become activated, which, in turn, elicits negative thoughts about themselves, the world, and the future (the negative cognitive triad). These patients view themselves as hopeless, hapless, and helpless (i.e., “my life is not going to get better, no one can help me, and I can’t help myself”). The latter can also be termed poor self-efficacy, or the belief that one is incapable of doing things to improve his or her life. Poor pain self-efficacy is the related belief that a patient cannot do anything to improve his or her pain or function. In depressed patients, Beck124 suggests that the cognitive triad serves as a filter for incoming information. This filter creates a negative bias that serves to put a pessimistic light on information and reinforces the depressed state. It also creates low expectations about their ability and thus may lead to lack of effort. Moreover, these people tend to discount their performance, underestimating their accomplishments. Beck’s124 cognitive theory of depression emphasizes the importance of peoples’ appraisal processes. In particular, it is believed that depressed persons show faulty information processing reflected by errors of logic. Through these cognitive errors (collectively referred to as cognitive distortions), depressed persons systematically misinterpret or distort the meaning of events so as to consistently construe themselves, their world, and their experiences in a negative way (the negative cognitive triad). According to this perspective, differences in cognitive errors and cognitive distortions, in general, should differentiate depressed and nondepressed patients. One of the most common cognitive distortions is catastrophizing, a tendency to view the most negative possible outcome as the only likely outcome. Pain catastrophizing (discussed at length in previous chapters) is the extension of this concept to patients viewing their pain as unbearable, uncontrollable, and leading to tissue damage. It has a significant co1469

occurrence and conceptual overlap with other depression and anxiety symptoms in pain patients. In other words, when pain patients with depression or anxiety catastrophize, they most often catastrophize over their pain. Cognitive-Behavioral Perspective The cognitive-behavioral perspective is based on five central assumptions: (1) People are active processors of information and not passive reactors. They attempt to make sense of information and determine what constitutes positive reinforcers. (2) Thoughts (e.g., appraisals, expectancies, beliefs) can elicit and influence mood, affect physiologic processes, have social consequences, and serve as impetuses for behavior; conversely, mood, physiology, environmental factors, and behavior can influence the nature and content of thought processes. (3) Behavior is reciprocally determined by both the individual and environmental factors. (4) People can learn more adaptive ways of thinking, feeling, and behaving. (5) Individuals should be active collaborative agents in changing their maladaptive thoughts, feelings, and behaviors.125 From the cognitive-behavioral model, the way in which one thinks about pain and behaves in response to pain affects the extent of depression experienced. Like Beck’s cognitive theory, its essential difference from the purely behavioral model is its view of patients as active interpreters of their environment. Depression in chronic pain patients is postulated to result from patients’ interpretations of the meaning and effect of their symptoms and their inability to exert any control over their symptoms. It is only when patients interpret their pain as interfering with important life activities and believe that they (or anyone) can do little to control the symptoms that they become depressed (i.e., they become depressed when they feel helpless and hopeless to exert any control, overwhelmed by the disruption of their lives, and unable to attain significant positive reinforcement from previous activities).68 Thus, the cognitive-behavioral approach integrates the principles of operant conditioning and behavioral techniques with the emphasis of cognitive theory on the patients’ appraisals, beliefs, and attributions.126 Diathesis-Stress Model 1470

This is discussed at length in other chapters but should be restated here because it is the dominant model for understanding the interactions between pain and comorbid psychopathology, including depression.3,127 This model frames the biologic and psychological mechanisms discussed earlier as diatheses or vulnerabilities. Under a condition of mental or physical stress, such as pain, the diatheses interact to produce the conditions of chronic pain and depression.128,129 One can rephrase this notion such that in any given person, genetic susceptibilities to chronic pain and/or mental illness interact with the environment (e.g., physical experience of acute pain, reinforcement from the family, inability to work) leading to changes in the functioning of mental processes (mind, such as negative cognitive schema) and brain (such as neurotransmitter systems and endogenous opioid response), resulting in chronic pain and psychiatric comorbidity.130

Anthropologic Theories Traditional and industrial societies appear to hold individuals less responsible for somatic symptoms than psychological symptoms. This difference may be especially prominent in modern Western biomedicine, in which symptom complexes are validated or invalidated through their correspondence with objective disease criteria.131 A somatic “idiom of distress” may become the favored means for communicating distress of any origin that is overwhelming or disabling.5,132 In other words, complaints about pain may be indicative of depression rather than a pain syndrome of a somatic origin. In many cultures including Western nations, pain is a more acceptable reason for disability than depression. Therefore, cultural incentives exist for translation of depression into pain. Because depressed patients have many physical symptoms, these can become the focus of clinical communication and concern. Giving patients with chronic pain permission to talk of distress in the clinical setting, using nonsomatic terms, can facilitate treatment as long as they do not feel that the somatic elements of their problem are being neglected or discounted. This is one of the bedrock principles of narrative medicine,133,134 which through the patient’s description of their illness experience helps them to articulate the interrelationships between their physical symptoms, 1471

psychological states, and their roles among family, coworkers, and within society. The physical symptoms of chronic pain and the pathophysiology underlying them can be thought of as the disease of chronic pain. Although the constellation of disease, a patient’s psychological state, and their experience of suffering can be termed, the illness of chronic pain.133 Questions from the practitioner, such as “What have you lost as a result of your pain?” “How do you manage with your pain?” and “Is it a lot of work to stay well despite having pain?” are important to evoking an illness narrative and describing these interrelationships.135

DEPRESSION TREATMENT Just as in the treatment of major depression in patients without chronic pain, the best quality treatment of depression in pain patients is to combine psychotherapy with medication management.136,137 One of the most effective psychotherapy modalities in chronic pain patients is cognitivebehavioral therapy (CBT), discussed in the following text and in further detail in other chapters.

Pharmacologic Agents In choosing an antidepressant agent in a patient with chronic pain, an important principle is that the medication should have independent analgesic properties. This means that the medication can be helpful for pain independent of its effect on mood (i.e., it works as an analgesic in those with and without depression). The two main classes with this property are the tricyclic antidepressants (TCAs) and the selective SNRIs. In the United States, duloxetine, venlafaxine, desvenlafaxine, and milnacipran are the SNRIs currently available. The monoamine oxidase inhibitors (MAOIs) (such as selegiline or tranylcypromine) are excellent antidepressants which do also have analgesic properties. But they are rarely used anymore except by psychiatrists (due to their side effect profile and medication interactions), and their use is confined to a third- or fourthline agent in treatment resistant depression. Antidepressant medication can effectively treat depression in the presence of chronic pain, but there is some evidence that depression with comorbid pain is more resistant to treatment.138 When depression accompanies chronic pain, as when it 1472

accompanies other chronic medical disorders, there may be some extra hurdles for depression treatment to overcome. These include aversive physical symptoms, severe deactivation, vocational dysfunction, marital conflict, social isolation, and concurrent medications. Comprehensive assessment of these issues and formulation of a treatment plan that takes them into account increase the likelihood of successful depression treatment in the chronic pain patient. If depression can be relieved, many other aspects of rehabilitation, such as physical therapy, are often much more easily accomplished. Pain often subsides with improvement in depressive symptoms.139 Patients will typically report that they may still have pain but that “it doesn’t bother me anymore.” This statement is very telling that the affective component of pain has significantly improved. All currently marketed antidepressants are equally effective for the initial treatment of depression. However, there is some evidence that medications with effects on dual neurotransmitter systems, such as serotonin and norepinephrine (the TCAs and SNRIs), are associated with a faster rate of improvement and lower rates of depression relapse.140 Overall, whatever differences may exist among antidepressants in efficacy for neuropathic pain do not appear to affect their ability to treat depression. The clinical art of depression treatment for those with chronic pain consists of establishing a solid therapeutic alliance around the problem of depression and finding a medication regimen with independent analgesic properties and a side effect profile that the patient can tolerate. Because patients with chronic pain can be vigilant and catastrophic in thinking about somatic symptoms, care must be taken to educate them about antidepressant side effects. Sometimes, it becomes necessary to initiate an antidepressant regimen at the lower doses used for geriatric patients to ease habituation to side effects. Because of their analgesic properties, the SNRIs and TCAs are the treatments of choice for patients with chronic pain and depression. Although the TCAs are considered first line, their side effect profiles and the slower rate of titration needed to reach a therapeutic dose limit their usefulness compared to SNRIs. The TCAs have more side effects (anticholinergic) and more therapeutic effects (sleep continuity and anxiolysis) than the SNRIs. However, because the TCAs are used 1473

frequently in the management of neuropathic pain, it is very common to encounter a patient on lower doses of TCAs (10 to 75 mg). Typically, these patients have acclimated to many of the side effects, and gradual escalation of the dose to antidepressant ranges (approximately 100 to 300 mg, depending on the compound) can easily be performed in the pain management setting. In monitoring their use for depression, it is possible to obtain serum blood levels of TCAs to make sure that they are in the therapeutic range, but it is also appropriate to titrate to clinical effect. Disadvantages of TCAs include a wide range of adverse effects, including anticholinergic effects, orthostatic hypotension, effects on the cardiac conduction system, weight gain, sedation, sexual dysfunction, restlessness, “jitteriness,” heightened anxiety on initial dosing, and cardiotoxicity in overdose. Before starting a TCA, in those over 45 years or in any patient with a history of cardiac disease, the QTc interval on an electrocardiogram (ECG) should be checked to see if it is 450 ms places them at a greater risk of developing torsades de pointes arrhythmia, even when lower doses of TCAs are used (10 to 75 mg), as is common in pain medicine. Of the TCAs, nortriptyline has the lowest incidence of side effects and thus is the preferred TCA for use in chronic pain patients, either for treatment of pain or depression. Although nortriptyline is more sedating than desipramine, it has a lower incidence of orthostatic hypotension and dizziness. Nortriptyline also has a comparable rate of analgesia to amitriptyline, despite the latter perhaps having broader effects on multiple analgesic mechanisms, such as sodium channel blockade. Nortriptyline is also twice as potent as amitriptyline, so it is much easier to get patients to therapeutic doses and to sustain use at these doses. The SSRIs (those available in the United States include citalopram, escitalopram, fluoxetine, fluvoxamine, sertraline, and paroxetine) have become the most popular antidepressants because of their favorable side effect profiles but are more useful as second-line agents in a pain population because they do not have significant analgesic properties. Bupropion has effects on dopamine-norepinephrine reuptake inhibitors (DNRIs). Because of its energizing effects, it is very useful in those with chronic pain because many experience fatigue and poor concentration, 1474

either due to the pain itself or as side effects from pain medications. One study has shown that bupropion has analgesic properties in neuropathic pain.141 Another study showed equivocal results in back pain.142 More detailed information on prescribing antidepressants is available in one of the standard psychopharmacology manuals.143–145 In situations of treatment-resistant depression, studies have indicated that electroconvulsive therapy can be useful for treatment of depression and pain, across a variety of painful disorders.146,147 However, no carefully controlled studies demonstrate the effectiveness of electroconvulsive therapy for treatment of chronic pain. Chronic pain is frequently associated with insomnia and anxiety. It is, therefore, common that patients are treated with benzodiazepines or other sedatives (e.g., the muscle relaxers). Some patients begin taking these medications during the acute phase of the pain problem and then continue to take them for many months or years. Assessing chronic pain patients who take benzodiazepines for depression is important. These medications mask some symptoms of depression (e.g., initial insomnia, agitation), but they are not adequate treatments for depression. Indeed, dangerous levels of depression can develop under the cover of benzodiazepines. It has been suggested that benzodiazepines can induce depression with chronic use, but the evidence for this is not strong.148 More important is the masking of depression by benzodiazepines. Nearly, all patients with chronic pain should be tapered off benzodiazepines. Few conditions exist for which chronic benzodiazepines are the treatment of choice.149 Many patients with chronic pain are treated with opioids, and the combination of opioid and benzodiazepine therapy is associated with large increases in mortality risk.150,151 The Centers for Disease Control and Prevention (CDC) opioid guideline strongly recommends against simultaneous use of opioids and benzodiazepines in the treatment of patients with chronic pain.152 The treatment of choice for chronic anxiety disorders, which are almost always accompanied by depressive symptoms, is antidepressant medication.153 Buspirone (a 5HT1a partial agonist) is marketed as an anxiolytic but is more similar to the antidepressants in its pharmacology and side effect profile. It is a reasonable alternative to the benzodiazepines for the treatment of 1475

breakthrough anxiety, particularly for those who experience agitation on the antidepressants.

PSYCHOTHERAPY Psychodynamic Psychotherapy In general, psychodynamic theory emphasizes the long-term predisposition to depression rather than the losses that occur in the short term. Treatment of depression from the classical psychoanalytic perspective tries to help the patient achieve insights into the repressed conflict and often encourages outward release of hostility turned inward. In the most general terms, the goal of therapy is to uncover latent motivations for the patient’s depression. The psychodynamic approach to the depressed individual with chronic pain emphasizes the importance of individual differences in patients based on their developmental history, intrapsychic conflicts, interpersonal difficulties, and the subsequent failure to adapt to chronic illness. Patients’ premorbid characteristics are hypothesized to color their adaptation to their current situation and affect their vulnerability to depression. Psychodynamic therapy emphasizes the need for patients to address unconscious conflicts that may contribute to and maintain the depression and makes use of the therapeutic relationship, assuming that the patient will transfer or project his or her feelings onto the therapist.154 This approach can be contrasted with treatment based on operant conditioning, in which it is assumed that the basic principles of learning apply to all individuals and the environmental contingencies of reinforcement can influence the reports of pain, distress, and suffering. As a treatment for depression, there is no good standardization of psychodynamic therapy, and thus, it is difficult to evaluate the studies of its effectiveness.

Behavioral Model As noted, the behavioral model of depression concentrates on the reduction in active behavior that is a central feature of depression. Behavioral therapy for depression focuses on physical and social reactivation of patients.155 As long as avoidance behaviors are targeted, it has efficacy equal to that of CBT, without any focus on cognitions.156 The 1476

focus of treatment for depression is on the shaping of behavior through the use of graded task assignments and response-contingent reinforcement. Depressed individuals are encouraged to engage in more activities and to behave in ways that are likely to be regarded more positively by others. In some instances, it is believed that depressed patients are deficient in certain skills necessary to achieve positive reinforcement. Social skills training may also be included when the therapist determines that the patient is deficient in specific skills (e.g., communication skills). Attention may also be given to assisting the patient in planning pleasant events that the patient will find reinforcing.

Cognitive Model From the cognitive perspective, therapy is based on the rationale that an individual’s affect and behavior are largely determined by the ways in which he or she construes the world, and the therapeutic techniques were designed to identify, test, and correct distorted conceptualizations and the dysfunctional beliefs (schemas) underlying these cognitions. Beck’s124 therapy for depression is based on the assumption that the affected people engage in faulty information processing and reasoning and subscribe to schema that are self-defeating. In particular, depressed people are subject to the negative cognitive triad, in which they have feelings of pessimistic helplessness about themselves, the world, and their future. The aim of the cognitive therapist is to identify and then help patients to correct these distorted ideas and also to improve their information processing and reasoning. In contrast to psychodynamic therapy, the focus is on the here and now. Thus, attention to the origin of dysfunctional schemas in the cognitive model is limited. The therapeutic procedures are highly structured and time limited and begin with the recognition of the connections between cognitions and affect, careful recording of these connections, collection of evidence for and against the ideas, followed by substitution of more adaptive and realistic interpretations. The cognitive approach is most frequently combined with behavioral techniques to treat patients with chronic pain, even though some debate exists about the compatibility of these approaches.124,125 1477

Cognitive-Behavioral Model No one cognitive-behavioral model exists but rather sets of models that share a perspective and incorporate some common features, namely (1) an interest in the nature and modification of patients’ thoughts, feelings, and beliefs, as well as behaviors, and (2) some commitment to behavior therapy procedures in promoting change (e.g., graded practice, use of homework, training in relaxation, coping skills training, problem solving, and relapse prevention).126 Depressed people may focus attention selectively on and become preoccupied with somatic symptoms and their potentially ominous significance for their health and future. They may view themselves as helpless and their situation as hopeless and beyond their control. In depressed patients with chronic pain, the cognitive distortions often center around their pain, such as excessive fear of pain or fear of movement. To break this vicious circle, the cognitive-behavioral therapist applies a comprehensive approach to treatment that combines physical, psychological, behavioral, and social interventions. Coping skills training, problem-solving strategies, communications skills training, and directing patients to attend to their appraisals, interpretations, and beliefs surrounding pain are commonly used techniques. One of the most effective CBT methods in pain patients is to combine coping skills training focusing on fear of pain, reinjury, and movement with gradual activity and movement-based physical therapy.157 The cognitive-behavioral therapist attempts to assist patients to try new behaviors and to adopt more adaptive modes of thinking. Alterations in behavior become information that the patients are encouraged to use as the basis for changing their views of their situation and themselves from being helpless, hopeless, and out of their control to being resourceful and capable of exerting at least some control over their plights. Changing the cognitive schema by cognitive and behavioral means is designed to result in different interpretations of information about themselves and their futures. Thus, changing behaviors and thoughts may be reciprocally related and mutually reinforcing. Neither attending exclusively to behavior, as in the behavioral model, nor only attending to patients’ thinking, as in the cognitive model, is adequate to alleviate depression.125 1478

The cognitive-behavioral approach has become a central component for treating depression in many multidisciplinary pain rehabilitation and functional restoration programs. All of the psychological therapies emphasize patients’ active role in alleviating depression. In contrast to the psychodynamic model, in which the therapist plays a relatively passive role, in behavioral, cognitive, and CBTs, the therapist takes an active, directive role, attempting to guide patients into changing their behavior and reorganizing their thinking and actions. The behavioral, cognitive, and CBTs are all centered in the present, compared with psychodynamic therapy, which focuses on the past.

Anxiety Disorders It is not unusual for patients with symptoms of pain to be anxious and worried. Up to 30% of chronic pain patients meet criteria for an anxiety disorder such as generalized anxiety disorder (GAD), panic disorder, agoraphobia, and PTSD.158 There may be stronger data for anxiety disorders preceding the onset of chronic pain than mood disorders.159 This is especially true when the symptoms are unexplained, as is often the case for chronic pain syndromes. For example, in a large-scale, multicenter study of fibromyalgia patients, between 44% and 51% of patients indicated that they were anxious.160 In other clinic samples, rates of an anxiety disorder ranged from 16% to 29% among pain patients.161,162 Most researchers agree that the prevalence of anxiety disorders in patients with chronic pain is underestimated by these data.1,55 Anxiety and concern about symptoms are not synonymous with a psychiatric diagnosis of an anxiety disorder, necessarily. When anxiety is debilitating, it may meet criteria for an anxiety disorder. Anxiety disorders are a broad spectrum of disorders which include GAD, PTSD, obsessivecompulsive disorder, and panic disorder. As noted earlier in this chapter, pain anxiety is the most prevalent and salient form of anxiety in pain patients.163 Although distinct in some respects, there is significant overlap of pain anxiety symptoms with the constructs of fear of pain, fear of movement, and pain catastrophizing.164 High levels of pain anxiety (which 1479

are impairing, maladaptive, and predictive of higher pain levels165) also meet DSM-5 criteria for anxiety due to a general medical condition.15 Although this diagnosis was intended originally for anxiety secondary to chronic hypoxemia or steroid use, for example, chronic pain is a medical condition primarily and falls within the scope of this diagnostic category. Fears, worries, and preoccupations about pain are all secondary to having pain, and if the pain resolves, so do these psychological symptoms. Anxiety disorders frequently accompany other affective disorders, such as major depression, so clinicians should remain alert to the possibility of a mood disorder when patients complain of severe anxiety.1 In general, the approach is to diagnose and treat initially the most prominent mood disorder in a patient, whether it be depression or anxiety. For instance, in a patient with significant depression and anxiety symptoms, if the depression symptoms seem to be greater or more debilitating than the anxiety symptoms, the diagnosis is major depression with anxious features. In these situations, addressing the depression will also improve the anxiety symptoms. In a major depression with significant overlying anxiety, clinicians will often choose an antidepressant with significant antianxiety properties, such as the SNRIs or SSRIs.

GENERALIZED ANXIETY DISORDER Table 31.3 outlines the criteria for GAD. GAD is characterized by excessive anxiety and worry (apprehensive expectation) and difficulty controlling the worry for at least 6 months, accompanied by at least three of the following symptoms: restlessness or feeling keyed up, being easily fatigued, difficulty concentrating, irritability, muscle tension, or sleep disturbance.1 There is significant debate whether a 6-month duration of symptoms is necessary to make the diagnosis, and many psychiatrists contend that this is unnecessarily lengthy.85 Often, there are significant associated depression symptoms, but they do not rise to the level of a major depressive disorder. It is very common for patients with GAD to also have panic attack symptoms or posttraumatic stress symptoms. There are trait and state (situational) components to anxiety disorder presentations in patients with pain. The trait components include excessive worry and concern, often about routine matters. The amount of worry and 1480

anxiety is out of proportion to the likelihood of the negative consequences occurring, and the patient has great difficulty controlling worry. In making a diagnosis of GAD, trait anxiety in this context does not imply that the symptoms or the tendency toward these symptoms have been present since the beginning of adulthood. TABLE 31.3 Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Criteria for Generalized Anxiety Disorder A. Excessive anxiety and worry (apprehensive expectation), occurring more days than not for at least 6 mo, about a number of events or activities (such as work or school performance) B. The person finds it difficult to control the worry. C. The anxiety and worry are associated with three (or more) of the following six symptoms (with at least some symptoms present for more days than not for the past 6 mo). Note: Only one item is required in children. 1. Restlessness or feeling keyed up or on edge 2. Being easily fatigued 3. Difficulty concentrating or mind going blank 4. Irritability 5. Muscle tension 6. Sleep disturbance (difficulty falling or staying asleep, or restless unsatisfying sleep) D. The anxiety, worry, or physical symptoms cause significant distress or impairment in social, occupational, or other important areas of functioning. E. The disturbance is not attributable to the physiologic effects of a substance (e.g., a drug of abuse, a medication) or another medical condition (e.g., hyperthyroidism). F. The disturbance is not better explained by another mental disorder (e.g., anxiety or worry about having panic attacks in panic disorder, negative evaluation in social anxiety disorder [social phobia], contamination or other obsessions in obsessive-compulsive disorder, reminders of traumatic events in posttraumatic stress disorder, gaining weight in anorexia nervosa, physical complaints in somatic symptom disorder, perceived appearance in flaws in body dysmorphic disorder, having a serious illness in illness anxiety disorder, or the content of delusional beliefs in schizophrenia or delusional disorder). Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric Association; 2013:122–123. Copyright © 2013 American Psychiatric Association. All Rights Reserved.

The situational (state) anxiety is often centered on the pain itself and its negative consequences (pain anxiety). Patients may have conditioned fear, believing that activities will cause uncontrollable pain, causing avoidance of those activities. Pain may also activate thoughts that a person is seriously ill.41 Questions such as the following can be helpful: “Does the 1481

pain make you panic? If you think about your pain, do you feel your heart beating fast? Do you have an overwhelming feeling of dread or doom? Do you experience a sense of sudden anxiety that overwhelms you when you feel more pain?” The best quality of treatment for GAD is CBT plus medications. The CBT is pain based as in major depression treatment. Psychotherapy alone is highly effective for anxiety disorders.166 Successful CBT in patients with obsessive-compulsive disorder has been shown on neuroimaging studies to correlate to changes in the functioning of frontal lobe limbic areas.167 As discussed, the most frequently chosen medication classes are the SNRIs or SSRIs. Unlike depression treatment and despite their lack of analgesic properties, in anxiety disorders, the SSRIs are considered first line because of their efficacy over most other antidepressant classes. The TCAs can be effective, but higher doses are often needed which are difficult for patients to tolerate. Benzodiazepines should almost always be avoided, especially in patients on opioid therapy. Breakthrough anxiety can be addressed with buspirone, hydroxyzine, or low-dose antipsychotics (which is beyond the scope of this discussion).

PANIC DISORDER Panic disorder is a common, disabling psychiatric illness associated with high medical service use and multiple medically unexplained symptoms. The diagnosis of panic disorder requires recurrent, unexpected panic attacks (Table 31.4) followed by at least 1 month of worry about having another panic attack, the implications or consequences of the panic attacks, or behavioral changes related to the attacks. These attacks should not be the direct physiologic consequence of a substance or other medical condition. The panic attacks should not be better accounted for by another mental disorder, such as PTSD (see following discussion) or obsessivecompulsive disorder. At least two unexpected attacks are required for the diagnosis, although most patients have many more. TABLE 31.4 Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Criteria for Panic Attack Specifier An abrupt surge of intense fear or intense discomfort that reaches a peak within minutes and during which time four (or more) of the following symptoms occur.

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Note: The abrupt surge can occur from a calm state or an anxious state. 1. Palpitations, pounding heart, or accelerated heart rate 2. Sweating 3. Trembling or shaking 4. Sensations of shortness of breath or smothering 5. Feeling of choking 6. Chest pain or discomfort 7. Nausea or abdominal distress 8. Feeling dizzy, unsteady, lightheaded, or faint 9. Chills or heat sensations 10. Paresthesias (numbness or tingling sensations) 11. Derealization (feelings of unreality) or depersonalization (being detached from oneself) 12. Fear of losing control or “going crazy” 13. Fear of dying Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric Association; 2013:120–121. Copyright © 2013 American Psychiatric Association. All Rights Reserved.

One of the most common problems with panic disorder is the fear of an undiagnosed, life-threatening illness. Patients with panic disorder can receive extensive medical testing and treatment for their somatic symptoms before the diagnosis of panic disorder is made and appropriate treatment initiated.

EPIDEMIOLOGY Lifetime prevalence of panic disorder throughout the world is estimated to be 1.5% to 3.5%. One-year prevalence rates are from 1% to 2%. Panic disorder is 2 to 3 times more common in women than in men. Age of onset is variable, but most patients typically start between late adolescence and the mid-30s. Of all common mental disorders in the primary care setting, panic disorder is most likely to produce moderate to severe occupational dysfunction and physical disability.168 It was also associated with the greatest number of disability days in the past month. In some studies in pain patients, it has a prevalence of 5% to 8%, significantly higher than the general population.1,169 The most common complication of panic disorder is agoraphobia, or fear of public places. Patients with panic disorder learn to fear places where escape might be difficult or help not available in case they have an attack. One-half to two-thirds of patients with panic disorder also suffer 1483

from major depression. These patients are the most disabled panic disorder patients. The differential diagnosis of patients presenting with panic symptoms in the medical setting includes thyroid, parathyroid, adrenal, and vestibular dysfunction; seizure disorders; cardiac arrhythmias; and drug intoxication or withdrawal. Patients with panic disorder typically present in the medical setting with cardiologic, gastrointestinal, or neurologic complaints. These include chest pain, abdominal pain, and headaches.170 Chest pain is one of the most common complaints presented to primary care physicians, but a specific medical etiology is identified in only 10% to 20% of cases. From 43% to 61% of patients who have normal coronary arteries at angiography and 16% to 25% of patients presenting to emergency rooms with chest pain have panic disorder. A number of these patients eventually receive the diagnoses of vasospastic angina, costochondritis, esophageal dysmotility, or mitral valve prolapse. High rates of psychiatric disorders have been found in some of these groups as well.171 Many of these patients remain symptomatic and disabled 1 year later despite reassurance concerning coronary artery disease.172 Patients with documented coronary disease also have elevated rates of panic disorder. A number of studies have found nearly identical rates of panic disorder in chest pain patients with and without coronary disease. Increased mortality has been noted in those with anxiety and coronary disease. These data point to the importance of remaining alert to both medical and psychiatric diagnoses in those presenting with chest pain. Patients with unexplained chest pain who were given low-dose imipramine (50 mg per day) reported significant reductions in pain regardless of whether they had increased anxiety symptoms or another psychiatric disorder. This has been postulated to be caused by a visceral analgesic effect of imipramine.173 It is possible, however, that imipramine was treating subthreshold anxiety and depressive symptoms, because 63% of the sample had a history of these disorders at some point in their lives. Approximately 11% of primary care patients present the problem of abdominal pain to their physician each year. Less than one-quarter of these complaints are associated with a definite physical diagnosis in the following year. Among the most common reasons for abdominal pain is 1484

irritable bowel syndrome. It is estimated that irritable bowel syndrome accounts for 20% to 52% of all referrals to gastroenterologists. Various studies have found that 54% to 74% of these patients with irritable bowel syndrome have associated psychiatric disorders. Walker and colleagues174 determined that patients with irritable bowel syndrome have much higher current (28% vs. 3%) and lifetime (41% vs. 25%) rates of panic disorder than a comparison group with inflammatory bowel disease. This suggests that the psychiatric disorder was not simply a reaction to the abdominal distress. Among 10,000 persons assessed in a community survey who consulted their physicians for headache, 15% of female and 13% of male subjects had a history of panic disorder. Further studies have suggested that migraine headache is most strongly associated with panic attacks.175 Often, anxiety symptoms precede the onset of the headaches, whereas depressive symptoms often have their onset after the headaches. Some authors have suggested that a common predisposition exists with headaches (especially migraines and chronic daily headache), anxiety disorders, and major depression.

TREATMENT Psychopharmacologic and psychotherapeutic treatments for panic disorder have been proven effective. The American Psychiatric Association has released a “Practice Guideline for the Treatment of Patients with Panic Disorder.”176 Panic-focused CBT and four classes of medications (SSRIs, TCAs, MAOIs, and benzodiazepines) have demonstrated effectiveness. These drugs may be used in combination with CBT. Panic-specific CBT includes psychoeducation, continuous panic monitoring, development of anxiety management skills, cognitive restructuring, and in vivo exposure. As discussed previously with depression, the SSRIs likely are the easiest antidepressants to use for panic disorder. However, starting doses should be halved to avoid any initial exacerbation of agitation or anxiety. TCAs and MAOIs are now reserved for those patients who do not respond to the SSRIs. Benzodiazepines should be avoided. It is possible to use them for early symptom control in conjunction with one of the other classes of effective medication, but subsequent tapering can be difficult. 1485

Posttraumatic Stress Disorder DIAGNOSIS At the time of initial physical trauma, patients who develop chronic pain may also experience overwhelming psychological trauma. George Crile, a surgeon and experimental physiologist, laid the foundation for our modern concept of psychological trauma. He suggested that fear is the memory of pain. This fear holds an adaptive advantage in directing individuals to anticipate and avoid injury. Freud added anxiety to our modern conceptualization. Anxiety is the capacity to imagine pain and not merely to remember it. In other words, anxiety is memory of pain set loose.177 After direct personal exposure to an extreme traumatic event, some individuals develop a syndrome that includes reexperiencing the event, avoidance of stimuli associated with the event, and persistent heightened arousal. PTSD was originally described after exposure to military combat but is now recognized to occur after sexual or physical assault, natural disasters, accidents, life-threatening illnesses, and other events that induce feelings of intense fear, hopelessness, or horror. Persons may develop the disorder after experiencing or just witnessing these events. DSM-5 diagnostic criteria are shown in Table 31.5. TABLE 31.5 Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Diagnostic Criteria for Posttraumatic Stress Disorder Note: The following criteria apply to adults, adolescents, and children older than 6 y. A. Exposure to actual or threatened death, serious injury, or sexual violence in one (or more) of the following ways: 1. Daily experiencing the traumatic event(s) 2. Witnessing, in person, the event(s) as it occurred to others 3. Learning the traumatic event(s) occurred to a close family member or close friend. In cases of actual or threatened death of a family member or friend, the event(s) must have been violent or accidental. 4. Experiencing repeated or extreme exposure to aversive details of the traumatic event(s) (e.g., first responders collecting human remain, police officers repeatedly exposed to details of child abuse) Note: Criterion A4 does not apply to exposure through electronic media, television, movies, or pictures, unless this exposure is work related. B. Presence of one (or more) of the following intrusive symptoms associated with the traumatic event(s), beginning after the traumatic event(s) occurred:

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1. Recurrent, involuntary, and intrusive memories of the traumatic event(s) Note: In children older than 6 y, repetitive play may occur in which themes or aspects of the traumatic event(s) are expressed. 2. Recurrent distressing dreams in which the content and/or affect of the dream are related to the traumatic event(s) Note: In children, there may be frightening dreams without recognizable content. 3. Dissociative reactions (e.g., flashbacks) in which the individual feels or acts as if the traumatic event(s) were recurring (Such reactions may occur on a continuum, with the most extreme expression being a complete loss of awareness of present surroundings.) Note: In children, trauma-specific reenactment may occur in play. 4. Intense or prolonged psychological distress at exposure to internal or external cues that symbolize or resemble an aspect of the traumatic event(s) 5. Marked physiologic reactions to internal or external cues that symbolize or resemble an aspect of the traumatic event(s) C. Persistent avoidance of stimuli associated with the traumatic event(s), beginning after the event(s) occurred, as evidenced by one or both of the following: 1. Avoidance of or efforts to avoid distressing memories, thoughts, or feelings about or closely associated with the traumatic event(s) 2. Avoidance of or efforts to avoid external reminders (people, places, conversations, activities, objects, situations) that arouse distressing memories, thoughts, or feelings about or closely associated with the traumatic event(s) D. Negative alterations in cognitions and mood associated with the traumatic event(s), beginning or worsening after the traumatic event(s) occurred, as evidenced by two (or more) of the following: 1. Inability to remember an important aspect of the traumatic event(s) (typically due to dissociative amnesia and not to other factors such as head injury, alcohol, or drugs) 2. Persistent and exaggerated negative beliefs or expectations about oneself, others, or the world (e.g., “I am bad,” “no one can be trusted,” “the world is completely dangerous,” “my whole nervous system is permanently ruined”) 3. Persistent, distorted, cognitions about the cause or consequences of the traumatic event(s) that lead the individual to blame himself/herself or others 4. Persistent negative emotional state (e.g., fear, horror, anger, guilt, shame) 5. Markedly diminished interest or participation in significant activities 6. Feelings of detachment or estrangement from others 7. Persistent inability to experience positive emotions (e.g., inability to experience happiness, satisfaction, or loving feelings) E. Marked alterations in arousal and reactivity associated with the traumatic event(s), beginning or worsening after the traumatic event(s) occurred, as evidenced by two (or more) of the following: 1. Irritable behavior and angry outbursts (with little or no provocation) typically expressed as verbal or physical aggression toward people or objects 2. Reckless or self-destructive behavior 3. Hypervigilance 4. Exaggerated startle response 5. Problems with concentration 6. Sleep disturbance (e.g., difficulty falling or staying asleep or restless sleep) F. Duration of the disturbance (criteria A, B, C, D, and E) is more than 1 month.

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G. The disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning. H. The disturbance is not attributable to the physiologic effects of a substance (e.g., medication, alcohol) or another medical condition. Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric Association; 2013:143–146. Copyright © 2013 American Psychiatric Association. All Rights Reserved.

EPIDEMIOLOGY OF POSTTRAUMATIC STRESS DISORDER IN CHRONIC PAIN PATIENTS Approximately 13% of all veterans returning from service in Iraq and Afghanistan receive diagnoses of PTSD. These constitute about half of all mental health diagnoses received.178 Up to 80% of Vietnam veterans with PTSD report chronic pain in limbs, back, torso, or head.179 Increased physical symptoms, including muscle aches and back pain, are also more common in Gulf War veterans with PTSD than in those without PTSD.180 The prevalence of PTSD in medical populations has been shown to be quite high. For example, a number of patients presenting at medical clinics with myocardial infarctions181 and cancer182,183 often meet the criteria for PTSD. Averaging the prevalence rates of PTSD across a number of studies reveals that after motor vehicle accidents sufficient to require medical attention, 29.5% of patients meet the criteria for PTSD.184 For more than one-half of these patients, the symptoms resolve within 6 months. In one study, 15% of idiopathic facial pain patients seeking treatment were found to have PTSD.185 In another study, 21% of fibromyalgia patients were found to have PTSD.186 Case reports have associated reflex sympathetic dystrophy (complex regional pain syndrome) with PTSD. Other studies suggest that 50% to 100% of patients presenting at pain treatment centers meet the diagnostic criteria for PTSD.186,187 Among adult urban primary care patients, 23% had PTSD, of whom 11% had it noted in the medical record. The prevalence of PTSD, adjusted for demographic factors, was higher in participants with chronic pain, major depression, and anxiety disorders.188 Pain patients with PTSD have been shown to have more pain and affective distress than those without PTSD,189 so it is not surprising that PTSD rates among pain patients increase as treatment settings become 1488

more specialized.

POSTTRAUMATIC STRESS DISORDER AND ASSOCIATIONS WITH PAIN The relationship between pain and PTSD is multifaceted, as suggested by the early thinking by Crile and Freud discussed previously. Pain and PTSD may result from a traumatic event. Sometimes, acute pain can constitute the traumatic event, as described in a case of traumatic eye enucleation.190 In a nationwide survey of patients admitted after trauma, 23% of injury survivors had symptoms consistent with a diagnosis of PTSD 12 months after their hospitalization.191 PTSD symptoms have been significantly associated with greater levels of pain, emotional distress, interference, and disability.192 Greater levels of early postinjury emotional distress and physical pain were associated with an increased risk of symptoms consistent with a PTSD diagnosis. Pain may also be a consequence of PTSD or a manifestation of it. In a sample of patients admitted to an orthopedic hospital, back pain after major trauma was not associated with measures of injury severity or demographic factors but was significantly associated with the presence of PTSD, the use of a lawyer, the presence of chronic illnesses, and lower education levels.193 Compared with accidentrelated factors, PTSD symptoms and other psychological factors were the strongest predictors of the development of chronic pain in people who had severe accidents 3 years earlier.194 Functional brain imaging studies suggest altered processing of noxious signaling in the brain of patients with PTSD. In one study, patients with PTSD revealed increased activation in the left hippocampus and decreased activation in the bilateral ventrolateral prefrontal cortex and the right amygdala.195 Much research remains to be done on the relative contributions of physical trauma and psychological trauma to chronic pain problems.

TREATMENT It is best to institute treatment for PTSD as close in time to the trauma as possible. Acute crisis intervention may reduce the development of chronic PTSD and other complications, including, possibly, chronic pain. This treatment should establish support, promote acceptance of what happened, 1489

provide education and information about symptoms, and attend to general health needs. Beyond the acute phase, the CBT treatment described for panic disorder earlier has been shown to be effective with PTSD as well. The most evidence-based therapies for PTSD are prolonged exposure (PE) and cognitive processing therapy (CPT).196 Stress-inoculation training, implosive therapy, and systematic desensitization have also been reported to have some efficacy185,197 as have complementary and alternative techniques such as recreational therapy, yoga, acupuncture, and alternative delivery methods of psychotherapy.198 Medications are rarely adequate as the sole treatment for PTSD. Controlled trials of TCAs, SSRIs, and MAOIs have demonstrated some benefit by 8 weeks at reducing core intrusive features. These benefits appear to be in addition to the antidepressant and antianxiety effects of these medications.199 Recent PTSD treatment trials have demonstrated effectiveness of venlafaxine ER200 and prazosin,201 but these trials have not specifically monitored the effects on pain. Propranolol has been shown to attenuate traumatic memory in primary and tertiary use.202

Personality Disorders EPIDEMIOLOGY Several studies have reviewed the personality characteristics and disorders of patients with chronic pain.161,162,203–205 The prevalence of personality disorders among clinic populations ranges from 31% to 81% and is greater than in the general population or in populations with either medical or psychiatric illnesses. The Minnesota Multiphasic Personality Inventory (MMPI) is the most widely used personality assessment tool of patients with chronic pain but is probably not purely a personality trait measure.206–208 Previous studies have identified profiles defined by MMPI scale elevations that are proposed to be characteristic of chronic somatic symptoms such as pain.209 The hypochondriacal reaction, conversion “V,” and neurotic triad profiles exhibit different multivariate relationships between other constructs such as somatization, coping strategies, depression, pain severity, and activity level.210 However, although patients with chronic pain differ from nonchronic pain controls in their scale 1490

profiles on the MMPI, there is no single personality trait or disorder associated with medically unexplained chronic pain or chronic pain from “organic” diseases.

OVERVIEW OF PERSONALITY DISORDERS Personality pathology is best thought of along a continuum of traits present to greater or lesser degrees. Personality disorders described in the DSM represent the pathologic extreme of personality traits. Patients with personality disorders are one type of “difficult patient” characterized by an inflexible, pervasive, and maladaptive inner experience and set of behaviors.15,135 Traits have been conceptualized as dimensional aspects of individual variation, whereas personality disorders are represented as categorical aberrations within the realm of psychopathology. This section presents an overview of personality pathology and not a discussion of the criteria for each specific personality disorder. Analytic approaches undertaken to understand the features of temperament have described several core factors. The five-factor model is one of the most popular and characterized by the trait dimensions of neuroticism, extraversion, openness, agreeableness, and conscientiousness as described by the revised NEO Personality Inventory.211–213 In contrast, the Temperament and Character Inventory (TCI) is composed of four heritable and stable dimensions of temperament (harm avoidance [HA], novelty seeking, reward dependence, persistence) that represent individual differences in associative learning and three dimensions of character (selfdirectedness [SD], cooperativeness [C], self-transcendence) that develop over time as a function of social learning and maturation of interpersonal behavior.214 This psychobiologic model defines personality as the interaction of temperament and character. Studies have described three dimensions (HA, SD, C) as a core feature of all personality disorders.215 However, this profile has also been associated with other constructs such as depressive and anxiety disorders.216,217 Only a portion of the variance in the factors or dimensions characterizing personality disorders is explained by core personality traits.218 Personality traits are generally considered to be enduring features of an individual. The stability of personality after age 30 years has been 1491

consistently documented with long-term follow-up studies.219 Longitudinal studies also demonstrate that dimensional models of personality disorders may represent a manifestation of personality traits interacting with life events or illness consistent with the diathesis-stress model.220,221 Caution should be exercised in making the diagnosis of a personality disorder in the presence of any illness. Personality traits should be appreciated as sustaining or modifying factors that have the potential to complicate the treatment process rather than as causes of or the sole explanation for illnesses such as chronic pain.203 Personality vulnerabilities contribute to the degree of potential disability that individuals experience by modifying their response to pain. Although these patients are more likely to be “difficult” because of their complexity, their prognosis should not be viewed as hopeless or unresponsive to treatment. The diathesis-stress model may partly explain the high rates of personality pathology but also the decreases in these rates that have been observed with chronic pain treatment.204,205 A comprehensive review of the effect of pain on the measurement of personality characteristics found substantial evidence that trait inventories are not pain state independent.222 Pain treatment resulted in improvement in trait scores across the majority of studies that utilized the MMPI and measures of trait anxiety, coping/self-efficacy, and somatization/illness behavior. In a significant number of the studies reviewed, the trait changes could be attributed to improvements in pain. This state–trait interaction contradicts the notion that personality inventories catalog only enduring aspects of the individual. Instead, there is increasing evidence that a state disorder (psychiatric, medical, stress-related pain) may distort the measurement of traits and that treatment of that condition will decrease the presumed trait disorder.223–226 Just as personality pathology may improve with adequate pain treatment, personality disorders may emerge in the context of chronic pain, even if prior to pain, there was no evidence of maladaptive personality traits. The explanation for this change may include several mechanisms or confounders including that trait measurements are being contaminated by state-specific questions; pain treatments (medications, CBT) directly alter traits; and pain treatments improve state disorders which were previously affecting trait measurement, test–retest-related problems; and that 1492

standardized tests are actually measuring both states and traits.

PERSONALITY AND PAIN TREATMENT OUTCOME Current research has focused on how personality relates to treatment outcome, the transition from acute to chronic pain, and the persistence of pain-related disability. However, results have been inconsistent and more likely to detect emotional distress and psychopathology. Recently, a disability profile based on elevations of four or more clinical scales of the MMPI-II has been proposed as more common than those described earlier.1 In a prospective investigation of almost 1,500 patients with chronic occupational spinal disorders, this disability profile was associated with 5 times the likelihood of having a personality disorder and 14 times the likelihood of having an Axis I disorder. Although associated with high levels of psychopathology, patients with the disability profile compared to those with neurotic triad, conversion V, and normal profiles showed no significant differences in response to treatment with an interdisciplinary rehabilitation program. In a 30-year longitudinal study of healthy college students, elevations on MMPI scales 1 and 3 were associated with increased reports of chronic pain conditions at midlife.227 However, the magnitude of this association was small, and the clinical significance was unclear. In a similar study, patients with chronic pain due to nonspecific musculoskeletal disorders exhibited higher levels of HA and lower levels of SD on the TCI.228 This trait profile would characterize patients as cautious, insecure, pessimistic, lacking self-esteem and long-term goals, failing to accept responsibility, and struggling with their identity. Another study of patients with chronic pain of all types identified the same profile plus low levels of C.162 Low levels of SD have been associated with learned helplessness, poor self-efficacy, and an external locus of control. High levels of HA overlap with the construct of fear-avoidance behavior, fearful cluster C personality disorders, and the development of pain-related disability. The fear-avoidance model and expectancy model of fear provide explanations for the initiation and maintenance of chronic pain disability, proposing that anxiety sensitivity amplifies reactions such as avoidance of specific activities.229–232 Anxiety sensitivity is a significant predictor of 1493

fear of and anxiety about pain.233 Fear of pain, movement, reinjury, and other negative consequences that result in the avoidance of activities promote the transition to and sustaining of chronic pain and its associated disabilities such as muscular reactivity, deconditioning, and guarded movement.234 Fear-avoidance beliefs have been found to be one of the most significant predictors of failure to return to work in patients with chronic low back pain.235 Operant conditioning reinforces disability if the avoidance provides any short-term benefits such as reducing anticipatory anxiety or relieving the patient of unwanted responsibilities. In a study of patients with chronic low back pain, improvements in disability following physical therapy were associated with decreases in pain, psychological distress, and fear-avoidance beliefs but not specific physical deficits.236,237 Decreasing work-specific fears was a more important outcome than addressing general fears of physical activity in predicting improved physical capability for work among patients participating in an interdisciplinary treatment program.238 These studies suggest that certain personality traits or profiles should alert the clinician to the presence of psychological problems and psychiatric disorders that would benefit from more specific treatments as opposed to defining a group of patients with chronic pain who should be condemned to no treatment because of an expected poor outcome.

Somatic Symptom Disorders, Illness Behavior, and Sick Role DEFINITIONS Sickness is a complicated psychological and social state that has been understood from a variety of perspectives over the years. We consider those of sick role, illness behavior, and somatic symptom disorder (SSD). The concept of the sick role was first introduced by Talcott Parsons239 in 1951 and was formulated more concretely 12 years later.240 The sick role is granted to an individual provided that he or she regards his or her condition as undesirable and is not held responsible for it (i.e., under his or her control and able to be reversed voluntarily). If granted, the individual is allowed exemption from his or her usual obligations to a greater or 1494

lesser extent and is considered to be deserving of care and attention. Associated with the sick role are the obligations of seeking the advice and assistance of a person regarded as competent to diagnose and treat the condition and of cooperating with that person. The basic concept of illness behavior was introduced by Mechanic and Volkart241 and later fully formulated by Mechanic.242 Mechanic’s242 concept of illness behavior complements the sick role because it delineates the contribution of the patient to the role-granting process. Illness behavior was originally defined as the ways in which individuals differentially perceive, evaluate, and respond to their symptoms. This concept proved to be an extremely useful one because it has facilitated the empiric study of behaviors that are of considerable importance to clinicians and other health care providers as well as to the individual’s family and society. Although useful as it stands, health care providers find Mechanic’s242 definition restrictive because it refers to symptoms as the focus of behavior and consequently deemphasizes actions directed toward avoidance of the illness. A slightly modified definition describes illness behavior as “the ways in which individuals experience, perceive, evaluate, and respond to their own health status.” This definition recognizes the possibility that a person may be concerned about illness in the absence of symptoms. Illness behavior is a concept more easily applied to individual patients than sick role and has therefore seen more use in clinical settings. However, it is dependent on social definitions of what constitutes legitimate illness. Although medical science determines what qualifies as disease based on objective changes in anatomy and physiology, society determines what qualifies as illness. These often follow each other quite closely, but there can be interesting discrepancies. Essential hypertension is a disease usually without symptoms. It has taken a concerted educational effort on the part of the medical profession to convince the public that it is an illness that should be monitored and treated. Chronic fatigue syndrome and fibromyalgia are illnesses increasingly recognized and accepted by the public. Because the medical profession has not been able to identify objective changes in physiology with these illnesses, many physicians question whether they qualify as legitimate diseases. Physicians, insurance companies, and compensation systems can find themselves in 1495

disagreement with patients experiencing chronic pain about whether a legitimate disease or illness is causing the pain. Pilowsky243 introduced the concept of abnormal illness behavior for those situations in which physician and patient disagree about the applicability of the sick role to the patient’s condition. He contends that patients with truly abnormal illness behavior have extreme difficulty accepting the advice of any physician if it does not agree with their own appraisal of their health status. He cautions that misdiagnoses of abnormal illness behavior can occur when physician and patient do no share a common culture. We might add that it is also important to keep in mind the limitations of current diagnostic tests and disease criteria when diagnosing the patient’s disagreement with his or her physician as pathologic.

OVERVIEW OF SOMATOFORM DISORDERS AND SOMATIC SYMPTOM DISORDERS Current psychiatric thinking frames the diagnoses of abnormal illness behavior or misuse of the sick role as SSDs. The categorization of these disorders has been significantly modified in the DSM-5. In the DSM-5, SSD appears in a new section, somatic symptoms, and related disorders. This section replaces the somatoform disorders of the DSM-IV. SSD is a single diagnostic entity that replaces three of the DSM-IV somatoform disorders: somatization disorder, pain disorder, and undifferentiated somatoform disorder. The DSM-5 criteria for SSD are listed in Table 31.6. Currently, there is scant available research about SSD as it was fairly recently adopted. TABLE 31.6 Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Diagnostic Criteria for Somatic Symptom Disorder A. One or more somatic symptoms that are distressing or result in significant disruption of daily life B. Excessive thoughts, feelings, or behaviors related to the somatic symptoms or associated health concerns as manifested by at least one of the following: 1. Disproportionate and persistent thoughts about the seriousness of one’s symptoms 2. Persistently high level of anxiety about health or symptoms

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3. Excessive time and energy devoted to these symptoms or health concerns C. Although any one somatic symptom may not be continuously present, the state of being symptomatic is persistent (typically more than 6 mo). Specify if: With predominant pain (previously pain disorder): This specifier is for individuals whose somatic symptoms predominantly involve pain. Specify if: Persistent: A persistent course is characterized by severe symptoms, marked by impairment and long duration (more than 6 mo). Specify current severity: Mild: Only one of the symptoms specified in criterion B is fulfilled. Moderate: Two or more of the symptoms specified in criterion B are fulfilled. Severe: Two or more of the symptoms specified in criterion B are fulfilled, plus there are multiple somatic complaints (or one very severe symptom). Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric Association; 2013:161–162. Copyright ©2013 American Psychiatric Association. All Rights Reserved.

The essential feature of the somatoform disorders is the presence of physical symptoms that suggest a general medical condition but are not fully explained by a general medical condition. The DSM-5 diagnosis of SSD eliminated the requirement that somatic symptoms be medically unexplained. In either case, these symptoms must cause impairment in social and occupational functioning. These disorders are distinguished from factitious disorders and malingering in that the symptoms are not intentionally or voluntarily produced in the somatoform disorders or SSD. Malingering is the deliberate feigning of symptoms for a clear gain, often financial. In factitious disorder, although there is a feigning of symptoms, the patient is only partially aware that they are doing so, and their gain or benefit is much less clear. In factitious disorder, the maintenance of symptoms is for the psychological benefits of the sick role, similar to the gain in somatoform disorders. In the majority of patients with pain and somatoform illness, there is a physical basis (including functional or structural pathology, such as neuropathic pain) for at least a portion of the pain complaints, in which symptom reporting is magnified by somatizing. Somatization is best thought of as a process (vs. somatization disorder, discussed in the following text). The spectrum of somatization includes amplification of symptoms, which entails “focusing on the symptoms, racking with intense 1497

alarm and worry, extreme disability, and a reluctance to relinquish them.”244 Pain-related psychological symptoms amplify pain perception and disability. Hence, there is a tremendous overlap between the somatoform component of a chronic pain syndrome and other psychiatric comorbidities. In other words, in a patient with pain and any psychiatric comorbidity, somatization is a ubiquitous, mediating process by which pain and disability are worsened. It has psychological and physiologic bases, which are still being elucidated. Similarly, pain complaints may become an “idiom of distress”132 in which psychological distress or needs are communicated through the proxy of pain reporting. In the DSM-IV, four somatoform disorders may involve pain: somatization disorder, conversion disorder, hypochondriasis, and pain disorder (with or without a physical basis for pain). In the DSM-5, three somatic symptoms and related disorders involve pain: SSD, illness anxiety disorder, and conversion disorder (functional neurologic symptom disorder). Somatoform disorders without any physical basis for pain are estimated to occur in 5% to 15% of patients with chronic pain who receive pain treatment.245

Somatic Symptom Disorder The DSM-IV somatoform disorders were criticized for two main reasons: (1) the questionable importance of medically unexplained pain in pain disorder associated with psychological factors and (2) the lack of a definition of psychological factors or a description of when they are of sufficient importance to have a role in the experience of pain in the presence of a general medical condition, which made it a diagnosis of exclusion.246 If a medical cause for pain is discovered, it means the SSD diagnosis is discarded regardless of the evidence previously considered supportive of it. However, somatic symptoms that are not attributable to a medical condition are a substantial problem in primary care and pain specialty practice. It is estimated that 20% of visits to medical doctors are for this type of complaint.247 However, because somatoform disorders were restrictively defined, and many clinicians felt that giving patients a somatoform diagnosis could be interpreted as “everything is just in the 1498

mind,” the diagnostic category was rarely used in the United States and Europe.248 The DSM-5 Somatic Symptoms Disorders Work Group tried to address these issues when developing the criteria for the new diagnostic group. The new category was named Somatic Symptoms and Related Disorders with SSD as the prototype. The common feature of this category is that individuals have “somatic symptoms associated with significant distress and impairment.” The major advance in the DSM-5 is that it uses positive criterion, namely, maladaptive reaction to a somatic symptom, rather than the earlier negative criterion, namely, that the symptoms should be medically unexplained. The new diagnosis of SSD is designed to cover not only patients with somatization but also patients with chronic pain conditions, most patients with hypochondriasis, and many patients with medical conditions that are accompanied by psychological features.248 The diagnostic criteria for SSD includes one or more physical symptoms lasting 6 months or longer that are associated with excessive thoughts, feeling, or behaviors. There are three specifiers that describe the nature, duration, and severity of the symptoms. Despite these advances in the DSM-5, criticisms have emerged. The main criticism is the high probability of misdiagnosing a medical illness, such as a chronic pain condition, as a mental illness.249 The conditions that qualify for a diagnosis are highly variable and include patients with medically unexplained symptoms, medical patients with emotional stress, patients with typical chronic pain conditions, and patients with healthrelated anxiety.248 This results in a classification with high sensitivity but low specificity. Several authors have proposed modified criteria that reduce the likelihood of diagnostic inflation and this misdiagnosis of a medical illness as a mental disorder and suggested that adjustment disorder may be a safer and more accurate diagnosis when one is needed for someone who is medically ill and troubled by symptoms.246

Conversion Disorder (Functional Neurologic Symptom Disorder) The essential feature of conversion disorder is an alteration in voluntary 1499

motor or sensory function that suggests a neurologic or general medical disorder. Classic examples include hysterical paralysis, blindness, or mutism. Psychological factors must be associated with the initiation or exacerbation of this deficit. The name “conversion disorder” refers to a hypothesis based on a psychological etiology that has little supportive empirical evidence.250 As such, the DSM-5 has added the bracketed term, functional neurologic symptom disorder, to give a more proper and respectable definition to these symptoms. Diagnostic DSM-5 criteria are displayed in Table 31.7. In the new criteria, there is less emphasis on psychological and emotional events prior to the development of symptoms and emphasis on the need for positive diagnostic signs and symptoms.251 These changes may lead to a more collaborative approach between psychiatrists and neurologists and be more acceptable to patients. TABLE 31.7 Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Diagnostic Criteria for Conversion Disorder (Functional Neurologic Symptom Disorder) A. One or more symptoms of altered voluntary motor or sensory function B. Clinical findings providing evidence of incompatibility between the symptom and recognized neurologic or medical conditions C. The symptom or deficit is not better explained by another medical or mental disorder. D. The symptom or deficit causes clinically significant distress or impairment in social, occupational, or other important areas of functioning or warrants medical evaluation. Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric Association; 2013:163. Copyright © 2013 American Psychiatric Association. All Rights Reserved.

Despite these changes, great caution must be exercised in making the diagnosis of conversion disorder because the presence of relevant psychological factors does not exclude the possibility of a concurrent organically caused condition. In “Psychogenic Pain and the Pain-Prone Patient,” George Engel2 proposed that psychogenic pain arose from guilt and an intolerance of success. He indicated that it functioned as a substitute for loss or a replacement for aggression. He further stated that “ . . . patients with conversion hysteria constitute the largest percentage of the pain-prone population.” Others have also contended that pain is probably the most 1500

common conversion symptom encountered clinically.252 However, only case reports exist to support this contention. Pain is not a classic conversion disorder symptom, and it is controversial whether chronic pain can ever qualify as a conversion disorder by itself. Some, for example, have contended that reflex sympathetic dystrophy (complex regional pain syndrome) can be understood as a conversion reaction; however, this is highly controversial.253 Some elements of conversion disorders appear to be present in reflex sympathetic dystrophy/complex regional pain syndrome patients (e.g., indifference or neglect toward the affected body part), although it is highly unlikely that the condition is entirely psychogenic. Rather than labeling some chronic pain problems as conversion reactions and others as not, it may be more useful to understand what components of conversion reaction may be present in chronic pain problems. Again, the emphasis should be on thinking about somatoform illnesses as a process. Being ill surely creates problems in living for those affected, but it can also solve problems in living. For example, being ill provides an excuse for not being at school or not meeting a deadline at work. These interpersonal advantages of illness were originally recognized by Freud and termed secondary gain. The term secondary gain has been distorted and misunderstood in the care of chronic pain, probably because of medicolegal pressures. A number of corrections are in order. First, all illnesses are characterized by some secondary gain, not just illnesses considered to be psychogenic. Being sick always has advantages as well as disadvantages. Second, secondary gain includes all potential interpersonal benefits of illness, not just monetary advantages. Many of the advantages of illness are quite subtle and individualized. Third, secondary gain must be understood in the context of primary gain, the intrapersonal advantages of illness. For example, focusing on pain rather than depression may allow patients to avoid self-blame and thereby achieve primary gain. This is a common phenomenon in chronic pain. Indeed, blame avoidance has been hypothesized by some to be one of the main functions of somatization.254 Thus, traditional elements of conversion disorder may be present in many chronic pain problems without many pain problems qualifying as 1501

conversion disorders per se. Purely psychogenic or conversion models of chronic pain have some questionable implications for diagnosis and therapy of chronic pain disorders. Interview of the patient with a suspected conversion disorder with the aid of a sodium amobarbital (Amytal) infusion has been a standard tool in psychiatric diagnosis.255 More recently, lorazepam interviews have been substituted. It is more common that motor and sensory deficits than pain resolve under sodium amobarbital (Amytal) or benzodiazepine sedation. Furthermore, some patients have had violent or suicidal reactions to abrupt resolution of their somatic symptoms under sodium amobarbital (Amytal), possibly caused by loss of face-saving primary gain aspects of the illness. Psychodynamic theories of the origin of conversion symptoms imply that psychological treatments alone will be effective. Psychodynamic treatments for chronic pain, however, have little documented success. The most effective psychological treatments, such as CBT, include a reactivation component that addresses the profound disuse and deconditioning found in many patients with chronic pain.

ILLNESS ANXIETY DISORDER Many patients with chronic pain resist their physician’s reassurance that “nothing is wrong” or that the “tests reveal nothing.” These patients know that they hurt and cannot accept that a bodily cause cannot be identified for their pain. This has been described as disease conviction in the chronic pain literature. Disease conviction has been measured with the Illness Behavior Questionnaire, and hypochondriasis is assessed with the MMPI. In DSM-IV, there also exists a disorder called hypochondriasis, which was changed to illness anxiety disorder in the DSM-5. The major change to the DSM-5 criteria was the addition, in criterion B, that somatic symptoms should not be present, and if they are present, they are only mild in intensity. This will lead to some patients with previously diagnosed hypochondriasis now being diagnosed with SSD. Otherwise, hypochondriasis and illness anxiety disorder are essentially the same in concept, that is, a persistent fear in having a medical illness. The prevalence of hypochondriasis in primary care has been reported to 1502

be 4% to 9%.256 The prevalence of hypochondriasis in pain clinic populations is difficult to determine but is likely to be high if patients are not excluded by qualifying for pain disorder because of the likelihood of disagreement between patient and physician about the cause of the pain problem. Treatments of hypochondriasis have attempted to shift patient focus from cure of the disease causing the symptoms to strategies of symptom management.257 These strategies are common components of multidisciplinary pain treatment programs as well. It is indeed critical to achieve early in treatment some agreement with the patient about the cause of the pain that acknowledges the reality of the pain and yet points away from invasive attempts to cure disease or repair broken parts. The task is not to convince the patient that “nothing serious is wrong” because his or her pain may be severe and persistent. The task is to convince the patient that the appropriate treatment is different than the treatment he or she thought necessary.

Conclusion: Pain and Suffering and Psychiatry Psychiatric diagnosis and treatment can add an essential and often neglected component to the conceptualization and treatment of chronic pain problems. The high rates of psychiatric comorbidity and the negative impact they have on chronic pain necessitate that a psychiatric assessment be part of any comprehensive pain evaluation. The expanse of psychiatric symptoms in patients with pain is broad and deep, and thus, a comprehensive framework for describing psychiatric symptoms and the relationships between them is essential to thorough diagnosis and treatment. Advances in neuroimaging have elucidated some of the interrelationships between pain perception and psychological states, underscoring that most painful conditions have an affective component to the pain experience. It is this disordered affective experience of pain and, consequently, suffering that form a key interaction between pain and overlying psychiatric disorders. It is absolutely critical to avoid a dualistic model that postulates that pain is either physical or mental in origin. This model 1503

alienates patients who feel blamed for their pain. It is also inconsistent with modern models of pain causation. Since the gate control theory of pain, multiple lines of evidence suggest that pain is a product of efferent as well as afferent activity in the nervous system. Tissue damage and nociception are neither necessary nor sufficient for pain. Indeed, it is now widely recognized that the relationship between pain and nociception is highly complex and must be understood in terms of the situation of the organism as a whole. We are only beginning to understand the complexities of the relationship between pain and suffering. Pain usually, but not always, produces suffering. Suffering can, through somatization, produce pain. We have traditionally understood this suffering, as we have understood nociception, as arising from a form of pathology intrinsic to the sufferer. Hence, the traditional view that pain is caused by either tissue pathology (nociception) or psychological states (suffering). Psychiatric comorbidity represents an additional layer of suffering, which also magnifies the perception on pain. Yet this is still somewhat dualistic; an alternative model is to think of pain as a transdermal process with causes outside as well as inside the body. For humans, social pathology can be as painful as tissue pathology. We can investigate the physiology and the psychology of this sociogenic pain without losing sight of its origins in relations between people. Psychiatric care for patients with chronic pain should occur within the medical treatment setting whenever possible. This is the most effective way to reassure patients that the somatic elements of their problems are not neglected. It also allows integration of somatic and psychological treatments in the most effective manner.1 The success of multidisciplinary approaches to pain underscores the value of psychiatric assessment and treatment by the pain medicine provider. References 1. Dersh J, Gatchel DJ, Mayer T, et al. Prevalence of psychiatric disorders in patients with chronic disabling occupational spinal disorders. Spine (Phila PA 1976) 2006;31(10):1156– 1162. 2. Engel GL. Psychogenic pain and the pain-prone patient. Am J Med 1959;26:899–918. 3. Dersh J, Polatin PB, Gatchel RJ. Chronic pain and psychopathology: research findings and theoretical considerations. Psychosom Med 2002;64:773–786.

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227. Applegate KL, Keefe FJ, Siegler IC, et al. Does personality at college entry predict number of reported pain conditions at mid-life? A longitudinal study. J Pain 2005;6:92–97. 228. Malmgren-Olsson EB, Bergdahl J. Temperament and character personality dimensions in patients with nonspecific musculoskeletal disorders. Clin J Pain 2006;22:625–631. 229. Greenberg J, Burns JW. Pain anxiety among chronic pain patients: specific phobia or manifestation of anxiety sensitivity? Behav Res Ther 2003;41:223–240. 230. Lethem J, Slade PD, Troup JD, et al. Outline of fear-avoidance model of exaggerated pain perceptions. Behav Res Ther 1983;21:401–408. 231. Reis S. Expectancy theory of fear, anxiety, and panic. Clin Psychol Rev 1991;11:141–153. 232. Vlaeyen JW, Linton SJ. Fear-avoidance and its consequences in chronic musculoskeletal pain: a state of the art. Pain 2000;85:317–332. 233. Zvolensky MJ, Goodie JL, McNeil DW, et al. Anxiety sensitivity in the prediction of painrelated fear and anxiety in a heterogeneous chronic pain population. Behav Res Ther 2001;39:683–696. 234. Asmundson GJ, Norton PJ, Norton GR. Beyond pain: the role of fear and avoidance in chronicity. Clin Psychol Rev 1999;19:97–119. 235. Waddell G, Newton M, Henderson I, et al. A Fear-Avoidance Beliefs Questionnaire (FABQ) and the role of fear-avoidance beliefs in chronic low back pain and disability. Pain 1993;52:157–168. 236. Mannion AF, Müntener M, Taimela S, et al. A randomized clinical trial of three active therapies for chronic low back pain. Spine (Phila PA 1976) 1999;24:2435–2448. 237. Mannion AF, Junge A, Taimela S, et al. Active therapy for chronic low back pain: part 3. Factors influencing self-rated disability and its change following therapy. Spine 2001;26:920– 929. 238. Vowles KE, Gross RT. Work-related beliefs about injury and physical capability for work in individuals with chronic pain. Pain 2003;101:291–298. 239. Parsons T. Social Systems. London: Routledge and Kegan Paul; 1951. 240. Parsons T. Social Structure and Personality. New York: Free Press; 1964. 241. Mechanic D, Volkart EH. Stress, illness behavior, and the sick role. Ann Soc Rev 1961;26(1):51–58. 242. Mechanic D. The concept of illness behavior. J Chron Dis 1962;15:189–194. 243. Pilowsky I. The diagnosis of abnormal illness behavior. Aust NZ J Psychiatry 1971;5:136– 141. 244. Barsky AJ III. Patients who amplify bodily sensations. Ann Intern Med 1979;91(1):63–70. 245. Cloninger CR, Sigvardsson S, von Knorring AL, et al. An adoption study of somatoform disorders. II. Identification of two discrete somatoform disorders. Arch Gen Psychiatry 1984;41(9):853–859. 246. Katz J, Rosenbloom BN, Fashler S. Chronic pain, psychopathology, and DSM-5 somatic symptom disorder. Can J Psychiatry 2015;60(4):160–167. 247. Steinbrecher N, Koerber S, Freiser D, et al. The prevalence of medically unexplained symptoms in primary care. Psychosomatics 2011;52:263–271. 248. Rief W, Martin A. How to use the new DSM-5 somatic symptom disorder diagnosis in research and practice: a critical evaluation and proposal for modifications. Annu Rev Clin Psychol 2014;10:339–367. 249. Frances A. The new somatic symptom disorder in DSM-5 risks mislabeling many people as mentally ill. BMJ 2013;346:f1580. 250. Stone J, LaFrance WJ Jr, Levensen JL, et al. Issues for DSM-5: conversion disorder. Am J Psychiatry 2010;167(6):626–627. 251. Demartini B, D’Agostino A, Gambini O. From conversion disorder (DSM-IV-TR) to

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252. 253. 254. 255. 256. 257.

functional neurological symptom disorder (DSM-5): when a label changes the perspective for the neurologist, the psychiatrist and the patient. J Neurol Sci 2016;360:55–56. Ziegler FJ, Imboden JB, Meyer E. Contemporary conversion reaction: a clinical study. Am J Psychiatry 1960;116:901–910. Ochoa JL, Verdugo RJ. Reflex sympathetic dystrophy. A common clinical avenue for somatoform expression. Neurol Clin 1995;13(2):351–363. Bridges K, Goldberg D, Evans B, et al. Determinants of somatization in primary care. Psychol Med 1991;21(2):473–483. Fackler SM, Anfinson TJ, Rand JA. Serial sodium Amytal interviews in the clinical setting. Psychosomatics 1997;38:558–564. Barsky AJ, Wyshak G, Klerman GL, et al. The prevalence of hypochondriasis in medical outpatients. Soc Psychiatry Psychiatr Epidemiol 1990;25:89–94. Barsky AJ. Hypochondriasis. Medical management and psychiatric treatment. Psychosomatics 1996;37:48–56.

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CHAPTER 32 Treatment of Pain in Patients with Addiction PEGGY COMPTON, FRIEDHELM SANDBRINK, and MARTIN D. CHEATLE Substance use disorder (SUD), formerly called substance abuse, dependence, or addiction, is a prevalent chronic disease in our society, not only with implications for the health and quality of the life of the sufferers but also with often devastating consequences for the families and communities in which they live and for society. Perhaps unlike any other chronic illness, SUD has meaningful effects on all aspects of the pain experience, ranging from its perception to its management. Specifically, the neurologic and behavioral states associated with the disease tend to worsen the pain presentation and mitigate the efficacy of therapeutic interventions. These complications become particularly apparent in the case of opioid use disorder (OUD), where the abused substance is also a primary analgesic used to treat moderate to severe pain. The development of opioid tolerance, physical dependence, hyperalgesia, and/or relapse are all challenges clinicians face when attempting to manage the pain of persons with OUD. This chapter provides a brief overview of SUD, conceptualizing it as a chronic, relapsing neurologic disease for which evidence-based treatments exist, however, with access to these treatments limited in part due to negative societal perceptions of the illness. The overlap in neurobiologic systems in pain and SUD is considered, and how the presence of an SUD in general, and OUD specifically, can affect the experience of pain is discussed. Finally, principles of acute and chronic pain management for the patient with SUD is outlined, differentiated by whether the patient is actively using, on medication-assisted therapy (MAT; i.e., methadone, buprenorphine, naltrexone), or in drug-free recovery. Evident in these 1517

recommendations is the understanding that effectively and thoughtfully treating pain in the patient with SUD concomitantly benefits the recovery process regardless of the state of disease progression.

Substance Use Disorder Misusing and abusing drugs and alcohol is endemic in the United States. The most recent national surveys suggest that approximately 8% (or 20 million) of Americans older than 12 years met diagnostic criteria for an SUD in the past year.1 Being legal and readily available, not surprisingly, three quarters of these individuals meet criteria for alcohol use disorder (AUD). Among those with an illicit drug use disorder, the most common drug is marijuana (4 million people), followed by an estimated 2.1 million people with an OUD, which includes 1.8 million people with a prescription pain reliever use disorder and 0.6 million people with a heroin use disorder.1 There is good evidence to suggest that the prevalence of SUD is higher in patients seeking medical care secondary to the toxic effects of the drugs themselves and/or the risky behaviors associated with the disorder.2–5 Like chronic pain, addiction is an extremely complex human condition, with strong behavioral and social components, that cannot be entirely understood by analyzing its physiology. SUD is defined as a chronic, relapsing disorder that is characterized by (1) a compulsion to seek and take drugs, (2) loss of control over drug intake, and (3) emergence of strong negative emotional states (e.g., dysphoria, anxiety, and irritability) when access to the drug is prevented (Table 32.1).6 The occasional, limited, recreational use of a drug is clinically distinct from the loss of control over drug intake and the emergence of compulsive drug-seeking behavior that characterize SUD.7 Because the disorder is primarily evident in behaviors, it is one of the few conditions in which the sufferer is the disease, as reflected in the pejorative labels ascribed to him or her (i.e., “drunk,” “druggie,” “addict,” “lush”). TABLE 32.1 Indicators of Substance Use Disorder Indicators of Substance Use Disorder

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More substance (drug, alcohol) is used than intended or planned. Inability to cut down or control substance use Much of time obtaining, using, or recovering from substance Craving or a strong desire to use substance Inability to fulfill role obligations at work, school, or home Continued substance use despite accumulating consequences Reduced participation in social, occupational, or recreational activities due to substance use Substance use in situations in which it is physically hazardous Continued substance use despite health problems caused or exacerbated by substance Need for increased amounts of substance to achieve desired effect (tolerance) Characteristic withdrawal syndrome for substance when not used (physical dependence) Adapted from the American Psychiatric Disorder. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Publishing; 2013.

Like all chronic disorders, SUD is never “cured,” but it can be effectively managed with lifestyle changes and, in some cases, medication. Similar to other chronic conditions, there are demonstrable pathophysiologic changes underlying the disorder, which, in the case of addiction, reside in subcortical and cortical neural pathways underlying reward and memory and, ultimately, the prefrontal cortex, driving behavior (Fig. 32.1). Without treatment, the disease will predictably progress and result in disability and ultimately death. Known risk factors for SUD in both patients with pain and in those without pain include a prior history of alcohol and/or illicit drug abuse (including nicotine addiction), a family history of substance abuse or SUD, a history of mood or anxiety disorder, early onset (age

×

Liebmann et al.189 Prosser et al.190

—

×

>

×

—

×

>

×

Pud et al.186 Ren et al.125

×

Triester et al.183

×

×

60% saturation of total iron binding capacity or a markedly elevated ferritin. Ochronosis is a rare disorder caused by a hereditary deficiency of homogentisic acid oxidase, leading to accumulation of homogentisic acid in connective tissue. Deposits of homogentisic acid impart a blue-black hue to the sclerae and external cartilage of the ears. Arthritis appears in middle age and involves most often the knees, shoulders, hips, and spine.19 1630

These patients frequently have calcified intervertebral disks. Approximately 60% of patients with acromegaly develop OA, which most often involves the spine, knees, hips, shoulders, and, occasionally, ankles.20 The increased growth of articular cartilage causes joint surface incongruity and abnormal wear.

Laboratory Findings Routine laboratory work is normal in patients with primary OA. The synovial fluid in OA is straw-colored and has good viscosity. The cell count is usually less than 2,000 white cells per cubic millimeter, and the cells are predominantly mononuclear. Radiographs in early OA are usually normal, but as the disease progresses joint space narrowing, subchondral bone sclerosis, subchondral cysts, and osteophytes are observed (Fig. 34.4). Erosive OA is characterized by erosions on the joint surface, sclerosis of subchondral bone, and later by bony ankylosis. Radiographic abnormalities do not always correlate with clinical symptoms.

FIGURE 34.4 Osteoarthritis of the hip. The features of osteoarthritis are well illustrated in this xray including joint space narrowing, subchondral cysts, osteophytes, and subchondral sclerosis (thickening of the bone where cartilage has been lost).

Treatment Think about the treatment of OA as a program especially when the weight1631

bearing joints are involved. Basically, the program consists of three parts: physical modalities, medications, and surgery. The goal in OA should not necessarily be 100% pain relief, as absence of pain in a biomechanically abnormal joint may not be a good thing. The goal should be to reduce pain to a level that promotes quality of life and activity. Physical modalities include education, weight loss if needed, joint protective aerobic exercises, range of motion exercises especially focusing on reduction of contractures, muscle-strengthening exercises, assistive devices such as a cane, and attempts to affect alignment with off-loading knee braces or patellar taping, if needed. The Arthritis, Diet, and Activity Promotion Trial demonstrated the benefit of promoting both exercise and weight loss in an 18-month-long program that examined both together versus either one alone.21 The control group was healthy lifestyle. The combination group lost more weight than the weight loss group alone (5.7% of body weight vs. 4.9%), and the combination group had a 24% improvement in physical functioning and a 30% decrease in knee pain over the study period. The exercise group only showed improvement in walk time while the weight loss group showed no significant improvement in any of the variables related to the arthritis. Correct use of a cane can offload a joint by up to 24% and has been shown to reduce pain in OA of the hip or knee. There is evidence for a modest benefit with the use of an offloading knee brace designed to realign either a varus or valgus knee misalignment.22 The first-line pharmacologic therapy for OA is over-the-counter analgesics (e.g., acetaminophen, 1,000 mg four times a day or even less if it is effective). If the patient remains symptomatic after 2 to 4 weeks, lowdose ibuprofen or nonacetylated salicylates are indicated. If the response is still inadequate after 2 to 4 weeks, the patient should be placed on a full dose of a nonsteroidal drug. In the patient with risk factors for upper gastrointestinal bleeding or ulcer disease, a proton pump inhibitor should also be provided. There is one cyclooxygenase-2 (COX-2) inhibitor currently on the market, celecoxib, which could be used for patients as significant risk of gastrointestinal bleeding if other options do not work. Because of a concern for cardiac toxicity from the COX-2 agents, use the recommended dose of no more than 200 mg per day. There was for a time 1632

some excitement about glucosamine based on a European trial (sponsored trial) published in the Lancet in 2001.23 The data suggested not only a clinical benefit over placebo but also a possible disease modification of OA. A publicly funded U.S. five-arm trial (glucosamine, chondroitin, combination, nonsteroidal anti-inflammatory drug [NSAID], and placebo) did not demonstrate an impressive effect of either nutraceutical in OA, although the placebo response was impressive.24,25 In the 2012, American College of Rheumatology (ACR) treatment guidelines for OA includes a recommendation that these not be used.26 Intra-articular corticosteroid injections are effective in OA and can be used as part of the overall program. How often can injections be given? For many years, these were limited due to the concern about the development of Charcot joints. Again, the comments about not being too effective in controlling pain should be remembered. Data suggested that corticosteroid injections can be given every 3 months for at least 2 years with clinic benefit without structural change. In the absence of data, injections should probably not be given more frequently than this.27 Injectable hyaluronic acid is approved for use on OA of the knee. A metaanalysis of data on hyaluronic acid injections in knee OA suggests a small benefit especially for the higher molecular weight compounds.28 Treatment with hyaluronic acid requires three to five injections and can be used in patients who fail more conservative therapy. Other options in the 2012 ACR guidelines include use of topical NSAIDs for hands and knees such as diclofenac and tramadol. When a joint is severely damaged and painful, joint replacement should be considered. Total hip replacement has provided dramatic relief of pain and improvement of function. Placement of a knee or shoulder can also be quite helpful. Correction of a valgus or varus deformity by osteotomy of the knee improves weight distribution and extends the functional life of the joint. Rebuilding the first CMC joint and replacement of the PIP joint with a prothesis are now possible. Surgery is generally suggested for patients with a level of pain that is not controlled with physical modalities or medications and the patient is willing to endure a period of hospitalization and physical therapy.

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RHEUMATOID ARTHRITIS Rheumatoid arthritis is an inflammatory polyarthritis of unknown etiology that involves peripheral joints in a symmetric distribution. The worldwide prevalence varies from 0.097 to 2.900 per 1,000.29,30 In the United States, the prevalence is 1% to 2%. Women are more commonly affected: The average ratio is 3:1. Certain Native American populations in the United States can have prevalence rates as high as 7%.31

Etiology and Pathophysiology Even though the etiology of rheumatoid arthritis remains unknown, significant advancements have been made in the understanding of the inflammatory events leading to joint injury and extra-articular manifestations. It is a disease process where genes and environment interact in pathologic dance that leads to autoimmune disease. The genetic contribution is polygenic, and currently, there are 100 or so risk genes identified. It is estimated that 40% to 65% of the risk in rheumatoid arthritis is associated with genetic factors.29 The strongest genetic association exists with the HLA-DR4 antigen that is present on the surface of cells of the immune system. The so-called shared epitope (SE), which is carried by the vast majority of people with rheumatoid arthritis, is a fiveamino acid sequence found on the third allelic hypervariable region of the HLA-DRβ chain of the HLA DR4 molecule. The presence of the SE confers not only disease risk but also severity. One of the earliest events in the development of rheumatoid arthritis is the appearance of anticitrullinated antibodies. These antibodies appear as a result of inflammation causing the deamination of the amino acid arginine and the formation of the amino acid citrulline. Citrulline is not a normally occurring amino acid in the human body and its appearance in human proteins constitutes neoantigen formation to which the immune system responds. The HLA-DR4 molecule with its HLA-DRβ on T cells interacts with processed antigen (i.e., proteins that contain citrulline) from antigenpresenting cells, and if the HLA-DRβ happens to contain the SE, it is perfectly shaped or charged to interact with citrullinated peptides. The active T cells then produce inflammatory cytokines and also interact with B cells to produce antibodies against the citrulline-containing peptides 1634

(anti-CCP antibodies). There is typically a period of time when only the anti-CCP antibodies are present with no articular symptoms. This may be as long as 14 years.32 Then, at some point, the anti-CCP antibodies, joined often by rheumatoid factor, gain access to the joint and lead to inflammation. Rheumatoid factor is produced in the setting of immune complex disease and may serve as a protective mechanism to remove these from circulation. The hallmark of rheumatoid arthritis is the proliferation of synovium, which spreads over the articular surface as a pannus and damages cartilage, bone, and joint capsule. This process leads to eventual joint damage/destruction with the classic changes on examination. The environmental exposure that may lead to lung inflammation and production of citrullinated peptides is smoking. An interesting piece of evidence in this light is the fact that rheumatoid arthritis was rare in the Old World before European exploration of the New World and seems to have appeared in Europe after this period.33 Rheumatoid arthritis has been diagnosed via skeletal remains in certain Native American population antedating the age of exploration, leading some to speculate that the disease is a New World phenomenon that was transmitted back to the Old World. One of the New World products taken back to Europe was tobacco. There is a very strong relationship between smoking and the development of and severity of rheumatoid arthritis.34

Symptoms and Signs The typical patient with rheumatoid arthritis is a young to middle-aged woman who presents to her physician with a history of 2 to 3 months of joint pain and stiffness in her hands. Constitutional symptoms of fatigue, weight loss, and low-grade fever might also be present. The hands and other involved joints are stiff on arising in the morning. Stiffness might last from 30 minutes to 2 hours or longer. In severe disease, the patient might remain stiff most of the day. Patients with involvement of the hands and wrists might have difficulty performing tasks such as lifting pots, washing their hair, and opening jars or doors. A firm handshake can be quite painful. Tingling and numbness of the thumb and index and middle fingers, which often occur at night, indicate compression of the median nerve by synovial tissue in the carpal 1635

tunnel (carpal tunnel syndrome). At times, the carpal tunnel syndrome produces pain radiating up the forearm and down into the hand. Rheumatoid arthritis can begin in the feet in the MTP joints. It is not unusual for a patient to attribute metatarsalgia to improperly fitting shoes before seeking medical attention. On physical examination, the joints are swollen, tender to palpation, and warm but not hot. The combination of synovial proliferation and fluid gives the joint a boggy sensation on palpation (Fig. 34.5). Synovial proliferation in the flexor tendons of the fingers fills in the palm, giving it a flat appearance. The skin over the small joints often has a bluish discoloration resulting from venous engorgement. The hands may be cool and clammy. The range of joint motion is initially limited by pain and later by contractures. Ulnar deviation of the fingers at the MCP joint is a common deformity in established disease and results from radial deviation of the wrist and slippage of the extensor tendons to the ulnar side of the MCP joints. Another common deformity of the hand that develops in chronic disease is the swan-neck deformity. This appearance results from flexion of the DIP joint and MCP joint with hyperextension of the PIP joint. The boutonniere deformity is caused by avulsion of the extensor hood over the PIP joint, leading to a flexion deformity of this joint and hyperextension of the DIP joint. In advanced disease, subluxation and flexion deformities are common and involve the knees, ankles, elbows, wrists, shoulders, hands, and feet.

FIGURE 34.5 Example of rheumatoid arthritis of the hands. Distal interphalangeal joints are spared, whereas the metacarpophalangeal and proximal interphalangeal joints are swollen. There is

1636

beginning to be some early ulnar deviation on the left hand.

The natural history of rheumatoid arthritis is highly variable. Fifteen percent of patients may go into complete remission, whereas 10% or less go on to destructive disease that responds poorly to all forms of therapy. Most patients fall between these two groups with variable periods of remission and relapse. Some patients experience significant disability, whereas others respond to treatment and function quite well throughout their lifetimes. Prognostic factors for more severe disease include the presence of high titers of rheumatoid factor, elevated anti-CCP antibodies (see discussion later), presence of HLA-DR4, and more joints initially involved. Patients with seronegative rheumatoid arthritis (negative for anti-CCP and rheumatoid factor) are a different disease genetically and risk factor–wise and generally have a better prognosis that seropositive rheumatoid arthritis.

Laboratory Findings Patients often have a normocytic normochromic anemia and an elevated erythrocyte sedimentation rate (ESR). Approximately 80% of patients have a positive rheumatoid factor test result. In the last several years, the anti-CCP has emerged as an important diagnostic and prognostic test. It detects the presence of antibodies to citrullinated peptides and is 75% sensitive and 96% specific for rheumatoid arthritis. The higher levels are correlated with more erosive disease and may appear before overt arthritis has appeared.35 Radiography in early disease reveals only juxta-articular osteopenia and soft tissue swelling. In more advanced disease, one finds narrowing of joint spaces, erosions at the margins of the joint, and eventually subluxation (Fig. 34.6). The synovial fluid usually has a white blood cell count that varies from 5,000 to 25,000 cells per cubic millimeter (most of the cells are neutrophils), decreased viscosity, and a low glucose level, although this is rarely measured anymore (see Table 34.4).

1637

FIGURE 34.6 X-ray of rheumatoid arthritis of the right hand. Note the erosions and joint space narrowing at the second and third metacarpophalangeal joints.

Treatment Philosophy The treatment of rheumatoid arthritis has undergone considerable rethinking over the years. The time-honored approach to the treatment of rheumatoid arthritis has been based on the pyramid, in large part because of the philosophy that rheumatoid arthritis was a disabling but otherwise benign disease. Following the treatment pyramid philosophy, patients would receive NSAIDs or salicylates along with education and physical and occupational therapy, and as the disease progressed, more aggressive therapy with immunomodulating drugs known as disease-modifying antirheumatic drugs (DMARDs) of increasing toxicity would be used. In 1965, up to 120 months would pass before a DMARD would be started.36 Because a majority of patients with rheumatoid arthritis develop erosions by 2 years of disease and it has been found not to be the benign disease it was once thought to be, it has been suggested that we invert the pyramid; that is, begin with aggressive therapy up front to prevent erosive changes to joints that are generally not reversible and thus prevent the disability and potentially the mortality caused by unchecked rheumatoid arthritis.37,38 There has been a dramatic change in the level of disability and prognosis of rheumatoid arthritis in the last 10 to 20 years with the philosophy of early aggressive therapy and treating to target to prevent joint damage.29,39 Most patients who accept therapy will never know how 1638

sick they can be. Currently, rheumatologists start a DMARD as soon as the diagnosis of rheumatoid arthritis is made and medication-induced remission rates in rheumatoid arthritis are now approaching 50% with the combination of methotrexate and biologic agents that will be discussed later.

Current Management of Rheumatoid Arthritis Disease-Modifying Agents Current therapy of rheumatoid arthritis is early diagnosis and early aggressive therapy especially for patients who have factors indicative of a poor prognosis, namely, high titer rheumatoid factor or CCP and a high number of joints involved at presentation.29,40–42 Disease activity scores are routinely monitored and therapy changed to lower rheumatoid arthritis disease activity into remission or low disease activity level. Patients with features that suggest more severe disease are typically started on methotrexate or even combination therapy from the outset, whereas patients with features or low disease activity may be started on less-potent DMARDs such as hydroxychloroquine or sulfasalazine. If after 3 to 6 months of therapy, if there is incomplete control of the disease, other agent(s) are added to the regimen. These can include triple therapy which is a combination of methotrexate, sulfasalazine, and hydroxychloroquine or methotrexate plus a biologic especially one of the anti-TNF agents. Patients with early mild synovitis could be started on hydroxychloroquine. This agent takes 8 to 12 weeks before it begins to affect the synovitis. Its mechanism of action is thought to be on the basis of increasing the pH of the vacuoles in antigen-presenting cells and gently disrupting the interaction of the major histocompatibility complex with antigen, thus affecting the way antigen is presented to T cells. Hydroxychloroquine is dosed by weight at 6.5 mg/kg/day in divided doses. Doses higher than this increase the risk for ocular toxicity. Common side effects include diarrhea, gastrointestinal upset, and rash. Serious side effects are listed in Table 34.5 as well as a monitoring schedule. Improvement in morning stiffness and pain, as well as a decrease in the number of tender and swollen joints, and a reduction in acute-phase reactants (i.e., ESR or C-reactive protein [CRP]) are measures of success. 1639

Patients with more significant synovitis may be candidates for either sulfasalazine or methotrexate as single agents. TABLE 34.5 Immunomodulating Drugs Used in Rheumatology Medications

Dosage Range

Route

Hydroxychloroquine

200–400 mg/d

PO

Sulfasalazine

1,000–3,000 mg/d

PO

Methotrexate

5–25 mg/wk

PO, SC

Leflunomide

10–20 mg/d

PO

TNF inhibitors Etanercept Infliximab Certolizumab Adalimumab Golimumab Rituximab (anti–B cell)

Several

SC, IV

1,000–2,000 mg every 6 mo

IV

Abatacept (anti–T cell)

125 mg SC weekly or 500–1,000 mg IV monthly

SC, IV

Anti–IL-6 agents Tocilizumab Sarilumab Tofacitinib (JAK inhibitor)

Several

SC, IV

10 mg/d

PO

Important Side Effects Retinopathy, neuromyopathy, skin discoloration Rash, hepatitis, bone marrow suppression Hepatitis, bone marrow suppression, pneumonitis Hepatitis, bone marrow suppression Reactivation of TB and hepatitis B, serious infections, drug-induced lupus

Reactivation of hepatitis B, serious infection Reactivation of TB, serious infection, COPD exacerbation Reactivation of TB, serious infection, elevation of lipids Reactivation of TB

COPD, chronic obstructive pulmonary disease; IL, interleukin; IV, intravenous; JAK, janus kinase; PO, by mouth; SC, subcutaneous; TB, tuberculosis; TNF, tumor necrosis factor.

Sulfasalazine is another DMARD used for less severe disease. It is a combination of sulfapyridine and 5-aminosalicylic acid, which is cleaved by gut bacteria into two compounds. It is thought that the sulfapyridine moiety is the active one in rheumatoid arthritis. It is dosed generally at 1640

2,000 mg in two divided doses. It takes 4 to 8 weeks for an effect to be apparent in most patients and in some may be up to 12 weeks. Common side effects include gastrointestinal upset, diarrhea, and rash. Severe agranulocytosis can occur and is idiosyncratic. Drug cessation resolves the cytopenias in most cases, but there have been a few cases requiring granulocyte colony-stimulating factor therapy. Glucose-6-phosphate dehydrogenase (G6PD) deficiency may lead to severe anemia in affected patients and should be checked before starting therapy if suspected. Methotrexate is the current “workhorse” drug for rheumatoid arthritis. It is used by itself or more and more frequently in combination with other agents. In rheumatoid arthritis in particular, methotrexate plus something else seems to work better than either agent alone. The dose range and other characteristics are presented in Table 34.5. Methotrexate is a dihydrofolate reductase inhibitor. Its mode of action is uncertain but may be caused by an increase in adenosine, an anti-inflammatory compound.42 Methotrexate has the advantage of being given once a week and can be given both orally and subcutaneously. Methotrexate begins to be effective generally in 3 to 8 weeks after initiation of therapy. Common side effects include stomatitis, nausea, gastrointestinal upset, and mild hair thinning. Stomatitis in particular might respond to the addition of 1 mg of folic acid daily without affecting its activity in rheumatoid arthritis. Leflunomide is a newer DMARD. The usual dose is 10 to 20 mg per day. Data indicate that it is similar to methotrexate in efficacy as well as toxicity. It has had, if you would, the misfortune to come to market at the same time as the anti-TNF biologic agents and thus somewhat overshadowed by the impressive results of these agents. Biologic Disease-Modifying Antirheumatic Drugs There are currently five anti-TNF DMARD on the market. Etanercept, infliximab, adalimumab, certolizumab, and golimumab are anti-TNF agents that have been shown to be quite effective in not only controlling inflammation in rheumatoid arthritis but also preventing joint damage. In fact, data from the early anti-TNF studies for rheumatoid arthritis called the TEMPO trial indicated that the combination of methotrexate plus etanercept can prevent new erosion in 76% of patients over 3 years and

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even lead to filling in of previous erosions.29,40,43 In addition to anti-TNF therapy, there is anti–T cell therapy with abatacept, anti–B cell therapy with rituximab, anti–IL-6 therapy with tocilizumab, and the first of likely many oral agents that affect cytokine activity, tofacitinib, a janus kinase inhibitor. Table 34.5 has a list of DMARD therapies, including name, mechanism of action, dose, and common side effects. Glucocorticoids The anti-inflammatory mechanisms of glucocorticoids include altering leukocyte traffic and function, stabilizing lysosomal membranes of neutrophils and monocytes, and inhibiting the secretion of destructive enzymes including collagenase and elastase.44 They also inhibit the products of arachidonic acid metabolism including prostaglandins and leukotrienes. A 2012 study of methotrexate plus 10 mg of prednisone compared to methotrexate alone for 2 years showed the combination therapy had less joint damage, needed less methotrexate to control disease activity, and needed to change therapy less often than those on methotrexate alone.45 The study reported no more side effects in the combination group compared to the methotrexate alone group. Low-dose prednisone treatment can be especially beneficial during initiation of treatment with a DMARD. Glucocorticoids are often used as bridge agents for patients diagnosed with rheumatoid arthritis (i.e., 5 to 10 mg per day until the DMARD begins to work). In patients on corticosteroids, it is important to give calcium in the range of 1,000 to 1,500 mg per day and vitamin D 400 units a day. Patients should be monitored closely for evidence of hypercalcemia and hypercalcinuria. A bisphosphonate (e.g., alendronate) may also reduce the bone loss of calcium in patients on corticosteroids. Judicious intra-articular administration of corticosteroids can be quite useful in the treatment of rheumatoid arthritis. In a badly damaged joint or one that is soon to be replaced by a prosthetic joint, corticosteroids should probably not be injected within 6 weeks of surgery. Surgery Indications for orthopedic surgery in rheumatoid arthritis are twofold: pain unresponsive to medical management and loss of function. Synovectomy 1642

of selected joints provides alleviation of symptoms and improvement of function in the first year after operation but may not provide a long-term effect. Removal of synovial tissue from the wrist and dorsal tendon sheath and resection of the ulnar head might prevent rupture of the extensor tendon. Patients with severely deformed hands can benefit from MCP arthroplasty. Patients with severe pain and loss of function can benefit from total joint replacement, especially the knee or hip. Metatarsal head resection can be of tremendous help in patients with painful metatarsal heads. Intermittent splinting of selected joints is beneficial.

Important Complications of Rheumatoid Arthritis Presenting with Pain Carpal Tunnel Syndrome Carpal tunnel syndrome is a common problem in rheumatoid arthritis caused by wrist synovitis that can lead to median nerve compression. Therapy is generally directed at the rheumatoid synovitis with DMARDs and anti-inflammatory agents. A wrist injection with corticosteroids may be helpful in many cases. Carpal tunnel release may be necessary in some cases. Rheumatoid Vasculitis This is a potentially life-threatening complication. Patients with longstanding, seropositive, erosive rheumatoid arthritis are generally at risk for this small to medium vessel vasculitis similar to polyarteritis nodosa.46 Patients may present with digital gangrene or symptoms of mononeuritis multiplex (i.e., foot drop). More serious complications include intestinal perforation or cardiac involvement. Kidneys are less commonly involved than in polyarteritis nodosa. Treatment is traditionally with cyclophosphamide and high-dose prednisone, but even with aggressive therapy, historical survival rates were only 60% at 5 years. More recently, there has been some experience with rituximab in rheumatoid vasculitis with reported high rates of success in induction and maintenance, although the data is at the level of retrospective case series and case reports.47 Fortunately, with the current approach to early aggressive treatment of rheumatoid arthritis, complications such as rheumatoid vasculitis are now 1643

relatively rare. Cervical Spine Disease The synovial portions of the cervical spine can be involved in rheumatoid arthritis. This can lead to C1–C2 instability or subaxial instability. Symptoms may be caused by cord or vascular compression and may include neck pain, shock-like sensation up or down the spine, and intermittent loss of consciousness when vertebral artery compression occurs. Before surgery, all patients with long-standing rheumatoid arthritis should have a set of lateral flexion and extension views of the cervical spine taken to evaluate the cervical spine for C1–C2 subluxation. Septic Arthritis Patients with rheumatoid arthritis are at increased risk of septic arthritis caused by abnormal joint architecture, use of immunosuppressive drugs, and skin breakdown over high-pressure, biomechanically abnormal sites such as the feet. Patients often present with one joint out of proportion to the others in terms of pain or swelling and may have a paucity of systemic symptoms typical in non–rheumatoid arthritis patients. Detection is imperative because of the high mortality in such patients (i.e., 20% mortality if a single joint is infected and over 50% in patients with multiple joints involved).48

THE SPONDYLOARTHROPATHIES Ankylosing Spondylitis Ankylosing spondylitis is an inflammatory arthritis involving sacroiliac joints and the spine. Inflammation also occurs at sites of tendon and ligament insertions (enthesitis). Hips and shoulders are the most common peripheral joints involved, but rarely, the joints of the hands and feet can be affected as well. Onset of disease is usually in the second or third decade, and men are predominantly affected. The histocompatibility antigen HLA-B27 is found in 90% or more of patients.49 The normal frequency of HLA-B27 in the white population is approximately 7%. Pathophysiology Synovitis occurs in the apophyseal and costovertebral joints of the spine 1644

and peripheral joints and is characterized by synovial hyperplasia with focal accumulation of lymphoid and plasma cells. Inflammation also involves cartilaginous joints, which include the intervertebral disks, manubriosternal joint, and symphysis pubis. With progression, ossification of the outer layers of annulus fibrosus of the disk and the inner layers of the longitudinal ligaments forms syndesmophytes that eventually interconnect to give the spine the appearance of bamboo. In recent years, the enthesis (insertion of tendons, ligaments, and joint capsule to bone) has become an important tissue in the understanding the pathophysiology of spondyloarthropathies.50 These are common sites of inflammation, and it appears that inflammation may begin on the bone side at areas rich in fibrocartilage such as enthesis and extend to surrounding tissues. The knee has some 32 entheses alone, and the concept of enthesitis explains the clinic finding of dactylitis or sausage digits in the spondyloarthropathies (Fig. 34.7).

FIGURE 34.7 Classic example of dactylitis, a.k.a. “sausage digit,” in a patient with a spondyloarthropathy (psoriatic arthritis in this case).

Symptoms and Signs The patient initially notes low back pain and stiffness, especially at night when trying to sleep and on arising in the morning. The stiffness of the back lasts for several hours in the morning and occurs after periods of inactivity during the day. The pain might radiate into either buttock, extend down the back of the leg to the knee, and can be mistaken for the pain caused by herniated disk. The pain might alternate from side to side. 1645

The back symptoms can be continuous or may be episodic. Involvement of the hips and shoulders causes pain, stiffness, and decreased motion. Costovertebral joint arthritis can cause chest pain similar to that of angina pectoris or pleurisy. Spine ankylosis typically develops insidiously over 10 years or more of disease activity. The extent of involvement varies among patients and ranges from bilateral sacroiliitis to complete ankylosis of the spine. The spondylitis sometimes skips segments of the back. Atlantoaxial subluxation (with the potential danger of spinal cord compression) can occur, but this is observed less often in ankylosing spondylitis than in rheumatoid arthritis. The fused spine, especially the neck, is susceptible to fractures with even limited trauma. Acute iritis occurs in approximately one-third of the patients. It is typically unilateral and episodic and can rarely lead to vision-altering changes. A rare manifestation of ankylosing spondylitis is fibrosis of the upper lobes of the lung, which occurs late in the course of the disease. Also with long-standing disease, dilatation of the proximal aorta may lead to insufficiency of the aortic valve and inflammation of the atrioventricular bundle can produce cardiac conduction abnormalities. Patients occasionally have significant constitutional symptoms of fever and weight loss. On physical examination, sacroiliac tenderness is elicited by direct palpation or by maneuvers that stress the joint. A loss of normal lumbar lordosis occurs, giving the lumbar area an ironed-out appearance. Flexion is limited and can be documented by performing a modified Schober test. The test is performed marking the midpoint between the posterior superior iliac spines and measuring and marking 10 cm vertically. When the patient bends forward to touch toes with the knees straight the top, mark should move 5 cm or now measure 15 cm total. Tenderness can be present over costovertebral joints, iliac crests, greater trochanter, and heels. Chest expansion is limited. In advanced disease, the spine becomes rigid, fusing in varying degrees of flexion. Laboratory Findings The sedimentation rate or CRP can be elevated, and a mild hypoproliferative anemia can occur. The rheumatoid factor test result is negative, and one would rarely mistake rheumatoid arthritis and 1646

ankylosing spondylitis. The synovial fluid is inflammatory (see Table 34.4). Radiography of the sacroiliac joints in early disease shows blurring and irregularity of the joint margins, followed later by subchondral erosions, sclerosis, and eventually fusion (Fig. 34.8). Bony spurs appear at tendinous insertions such as the sites of attachment of the Achilles tendon and plantar fascia. Radiography shows a straight lumbar spine, squared vertebrae, and syndesmophytes. Syndesmophytes extend along the outer aspect of the intervertebral disk and eventually form a bridge between adjacent vertebrae (bamboo spine).

FIGURE 34.8 Ferguson view of the pelvis showing reactive bone changes around the sacroiliac joints as well as an indistinctness to the joints caused by erosions.

Treatment Nonsteroidal Anti-inflammatory Drugs. NSAIDs are especially useful in reducing inflammation and relieving pain, and there is some evidence of mild disease-modifying behavior for high-dose NSAIDs.51 It is speculated that NSAIDs may encourage the patient to be more mobile and possibly lessen the chance of spine fusion, but NSAIDs also influence bone metabolism. Preferred agents include indomethacin or a once-a-day agent such as piroxicam because of their anti-inflammatory activity. Any antiinflammatory agent chosen usually needs to be dosed at an antiinflammatory level (i.e., upper limit of dosing range) for benefit. Disease-Modifying Antirheumatic Drugs. Sulfasalazine has been shown to be beneficial for the peripheral joint in ankylosing spondylitis but not the spine.52 Methotrexate may also be helpful for peripheral joint disease. 1647

The anti-TNF agents have a significant impact on disease symptoms and also diminish both bone edema and enthesitis by serial magnetic resonance imaging (MRI) scan.53,54 Anti-TNF agents may have disease-modifying activity if used early in the course of the illness. Once the patient has some degree of ossification, the anti-TNF agents may not halt further ossification. The newest agent for treatment of ankylosing spondylitis is secukinumab, an anti–IL-17 agent. It is given by subcutaneous injection every week for 1 month and then monthly thereafter. Anterior uveitis or iritis can be treated with topical or intraocular corticosteroids, and in severe cases, methotrexate or the monoclonal anti-TNF agents such as adalimumab (officially approved for treating uveitis) or infliximab can be used. Etanercept, a fusion protein, is not effective for uveitis. Physical Therapy and Surgery. Physical therapy is directed at maintaining the erect posture of the patient. Patients should be encouraged to sleep in the prone position and to avoid using a pillow when sleeping on their backs. Patients with severe hip or shoulder disease can benefit from total shoulder replacement, and in extreme cases, vertebral osteotomies with rod placement may change someone who can only look at the feet to someone in an upright forward looking position. Important Complications of Ankylosing Spondylitis Presenting with Pain Cauda Equina Syndrome. Patients with cauda equina syndrome generally have long-standing ankylosing spondylitis. The patient generally presents with progressive lower extremity weakness, pain, and loss of sensation in the lower extremities and perineum. Impotence and overflow incontinence are also frequently occurring problems. Radiographically, large dorsal diverticula are seen on myelography or MRI.55 Electromyography demonstrates multi-root involvement. Neurosurgery needs to be involved with the treatment of these patients. Data regarding appropriate therapy is sparse.

Spondylodiskitis Spondylodiskitis is a rare complication of long-standing ankylosing spondylitis. Patients have persistent mechanical-type back pain (pain with activity) rather than inflammatory low back pain (pain in the morning or

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with rest). It is caused by a mobile vertebral segment surrounded by fused segments. The focus of activity at the one segment may lead to significant inflammation and damage to the adjacent vertebral bodies, simulating infection. Infection generally needs to be ruled out, and treatment is directed to immobilizing the segment either via brace and allowing it to fuse or refuse; occasionally, it may need to be surgically fused.56 Vertebral Fracture Vertebral segments connected by syndesmophytes are subject to fracture with even minor trauma.56 The usual location for such fractures is the C5– C7 vertebral segments; the fractures are typically caused by a hyperextension injury. Patients suspected of fracture should be evaluated by computed tomographic scan or bone scan to try to identify a potential fracture site, as plain radiography may not be able to demonstrate the fracture. Patients with such fractures have a relatively high morbidity and mortality even if identified because of surgery or prolonged immobilization usually required for treatment. Only 40% of such patients return to their former level of activity. Chronic Enthesitis Enthesitis of the Achilles tendon, plantar fascia, and, occasionally, the ribs can be a chronic source of pain and may be more resistant than spondylitis to usual therapies. In such cases, indomethacin at maximum dose or use of a DMARD such as methotrexate, sulfasalazine, anti-TNF therapy, or anti– IL-17 agent may be warranted.

REACTIVE ARTHRITIS Reactive arthritis (formally Reiter’s syndrome) is defined as an asymmetric arthropathy involving predominantly joints of the lower extremities plus one or more of the following: urethritis or cervicitis, dysentery, mucocutaneous lesions, and inflammatory eye disease. It is also defined as an episode of arthritis lasting longer than 1 month that is associated with urethritis or cervicitis. The histocompatibility antigen HLA-B27 is present in approximately 80% of patients.57 The reasons for the change in nomenclature for Reiter’s to reactive arthritis is due to the involvement of Hans Reiter with the Nazi regime and the fact that the 1649

same syndrome had been described previously by others. There appears to be a relationship between certain infections and a specific genetic background. Reactive arthritis can follow infections with Shigella, Salmonella, Campylobacter, or Yersinia.58,59 An association also exists with urethritis associated with Chlamydia or Mycoplasma infections. In addition, reactive arthritis has been associated with HIV infection. Reactive arthritis develops in patients without these infections, however, and most patients with nonspecific urethritis do not develop this syndrome. The risk of an individual who has a positive result for HLAB27 with nonspecific urethritis developing reactive arthritis is in the range of 20%. Up to 3% of individuals with nonspecific urethritis have been shown to develop a reactive arthritis. Reactive arthritis has a worldwide distribution and occurs more often in men. In post dysenteric reactive arthritis, the gender distribution is equal.

Symptoms and Signs Arthritis affects several joints in an asymmetric fashion; knees and ankles are most often involved.59 Patients also experience pain in the feet and ankles secondary to inflammation at the insertion of the Achilles tendon and plantar fascia. Joints can remain swollen for several months. Swelling of two adjacent interphalangeal joints and adjoining tendon sheath results in a sausage digit or dactylitis. In approximately 20% of patients, spinal involvement occurs. Sacroiliitis is usually unilateral, and spine involvement mild. Patients can also experience chest pain caused by inflammation at the tendinous insertions of the intercostal muscles. The mucocutaneous lesions of reactive arthritis include oral ulcers, balanitis, and keratoderma blennorrhagica. The oral ulcers are shallow and irregular and have a slightly erythematous base. These lesions are only present for several days. Balanitis usually begins as small painless vesicles on the glans penis that become hyperkeratotic. These lesions are painless and remain crusted in the circumcised patient. In the uncircumcised patient, lesions are moist and can become secondarily infected. Keratoderma blennorrhagica consists of hyperkeratotic lesions/plaques that may coalesce and most commonly involves the feet soles of the feet. It can also involve the palms of the hands and rarely the trunk. 1650

Conjunctivitis involves one or both eyes. Uveitis also occurs and again is unilateral and self-limited. Urethritis can precede or accompany the arthritis, and prostatitis may be an issue. As with ankylosing spondylitis, some patients may develop dilatation of the proximal aorta, leading to aortic valve insufficiency. The course of reactive arthritis is recurrent or persistent, with some patients experiencing a single transient, self-limited bout of disease.

Laboratory Findings Routine laboratory test results are usually normal. The sedimentation rate is quite variable and does not correlate with disease activity. Synovial fluid shows an elevated white cell count ranging from 5,000 to 50,000 white blood cells per cubic millimeter, predominantly neutrophils. Radiography shows juxta-articular osteopenia, joint space narrowing, and bone erosions. Periostitis is present adjacent to the involved joints and at the insertion of tendons and fasciae. Erosions, sclerosis, and irregularity of the sacroiliac joint can be present and are usually unilateral. Changes of spondylitis are usually asymmetric, occur at various levels of the spine, and are similar to those seen in psoriatic arthritis. Testing for HLA-B27 is not necessary for diagnosis.59 This test should be reserved for patients who have asymmetric arthritis without other evidence of reactive arthritis.

Treatment Treatment of reactive arthritis is similar to that of ankylosing spondylitis. NSAIDs are first-line therapy followed by sulfasalazine in refractory cases. Methotrexate or azathioprine can be used in more severe disease. Intra-articular corticosteroid can also be useful. The anti-TNF agents are less well studied but are reported to be effective in case series and case reports. Combination antibiotic therapy with doxycycline, rifampin, and azithromycin was reported to be efficacious in patients with chronic reactive arthritis due to Chlamydia.60

Complications of Reactive Arthritis Associated with Chronic Pain Rare patients may have more persistent inflammatory eye disease 1651

requiring continuous ophthalmology care. Enthesitis can be severe in some cases of reactive arthritis. Chronic foot involvement can lead to erosive disease at the MTP joints.

PSORIATIC ARTHRITIS Arthritis appears in up to 30% of outpatients with psoriasis depending on the population studied.61,62 Genetics play a role as an increased prevalence of psoriatic arthritis occurs in first-degree relatives with psoriasis. An association with HLA-B27 is seen in psoriatic arthritis with spondylitis but not in patients with peripheral arthritis. Onset of psoriatic arthritis is usually in the third or fourth decade, and the gender ratio is approximately equal. In most patients, psoriasis precedes the arthritis by several years, but arthritis may be the presenting manifestation. Most patients with psoriatic arthritis have oligoarthritis, and overall, the prognosis tends to be better than in rheumatoid arthritis.

Symptoms and Signs Several patterns of arthritis are observed in patients with psoriasis. The majority of patients have an asymmetric oligoarthritis that can involve the proximal joints of the hands and feet, the knees, the wrist, and ankles. In approximately 10% of patients, arthritis affects predominantly the DIP joints and is usually accompanied by psoriatic changes of the adjacent nail. Other patients have a symmetric polyarthritis similar to that seen in rheumatoid arthritis. These patients usually have negative results for rheumatoid factor. If the rheumatoid factor test or the CCP result is positive, the patient may have both rheumatoid arthritis and psoriasis. Patients can also have sacroiliitis and variable degrees of spine involvement. A few patients have a severe, destructive, and deforming polyarthritis referred to as arthritis mutilans. Joints are swollen, warm, and tender, and a digit may have the appearance of a sausage. Contractures and ankylosis of joints occur with long periods of persistent joint inflammation. In most cases, there appears to be no definite correlation between the degree of skin involvement and joint disease.

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Laboratory Findings Laboratory findings include an elevated sedimentation rate and a hypoproliferative anemia. The rheumatoid factor test result is negative. The synovial fluid shows evidence of inflammation with elevated white cell counts; the cells are predominantly polymorphonuclear. A somewhat characteristic radiographic finding is that of the pencil-in-cup deformity caused by osteolysis, or whittling of the distal end of the middle phalanx, which produces a pencil point that projects into a widened cup-like erosion in the adjacent surface of the distal phalanx (Fig. 34.9). Radiography shows joint space narrowing, erosions, osteolysis, and ankylosis, depending on the degree of clinical severity. The radiographic findings of the spine are similar to those found in patients with reactive arthritis.

FIGURE 34.9 X-ray of the left foot in psoriatic arthritis demonstrating fusion of the fourth metatarsophalangeal joint and a developing pencil-in-a-cup deformity of the fifth metatarsophalangeal joint.

Treatment Initial treatment of psoriatic arthritis with one to two joints involved and little impairment may be an NSAID alone. In patients with progressive disease, methotrexate, cyclosporine, leflunomide, hydroxychloroquine, and sulfasalazine have been used successfully for peripheral arthritis.61,62 Only 1653

methotrexate and cyclosporine are useful for the skin as well. None of these medications address spine involvement with present. Low-dose oral corticosteroids as well as intra-articular corticosteroids can also be used. Placing a patient on moderate- to high-dose prednisone and then tapering may exacerbate the skin disease. Prednisone doses if needed should be kept to 10 mg or less, if possible. There are a variety of biologic agents that are now available to use to treat psoriatic arthritis. The anti-TNF agents have an impressive effect on both skin and joints, including the spine.62 Ustekinumab is an IL-12/IL-23 inhibitor that has effects on skin and joint disease as does secukinumab, a newer anti–IL-17 agent, and apremilast, an oral phosphodiesterase-4 inhibitor.

ARTHRITIS ASSOCIATED WITH INFLAMMATORY BOWEL DISEASE Both ulcerative colitis and regional enteritis (Crohn’s disease) are associated with peripheral arthritis spondylitis and enthesitis.63 Peripheral arthritis occurs in approximately 10% to 20% of patients with inflammatory bowel disease. Type I peripheral arthritis affects one to five joints typically large weight-bearing joints and/or the MTP joints. This arthritis is present with active bowel disease and is acute, lasts several days to several weeks, and leaves no residual damage. In some cases, the arthritis may precede obvious bowel involvement. The knees and ankles are most frequently affected. Type II peripheral arthritis is a polyarthritis that affects the small joints, and MCP joints are commonly involved and may mimic rheumatoid arthritis. Spondylitis is also associated with inflammatory bowel disease and is seen in 5% to 12% of patients with inflammatory bowel disease. The gender distribution is 3:1 male to female. The majority (70%) of patients with spondylitis associated with inflammatory bowel disease has positive results for HLA-B27. Asymptomatic bilateral sacroiliitis can be found in up to 15% of patients with inflammatory bowel disease. Frequency of HLA-B27 is not increased in patients with only peripheral arthritis. Enthesitis typically occurs at the heel (plantar fasciitis, Achilles tendonitis) or the knee. Calcification may be seen at tendon insertions.

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Treatment Peripheral joint symptoms if mild can be managed with NSAIDs. NSAIDs, however, may lead to an exacerbation of the inflammatory bowel disease. Peripheral arthritis often in ulcerative colitis can disappear after colectomy. Many of the drugs used to treat inflammatory bowel disease also affect peripheral arthritis such as sulfasalazine, azathioprine, or methotrexate. The TNF agents, with the exception of etanercept, are useful for the bowel disease, peripheral arthritis, and spondylitis.

ARTHRITIS CAUSED BY CRYSTALS Calcium Pyrophosphate Deposition Disease Deposition of calcium pyrophosphate (CPP) dihydrate in the joint produces both an acute and chronic form of joint disease. The acute or subacute form is historically referred to as pseudogout because of its similarity to gout, but the suggested term for such arthritis is acute CPP crystal arthritis.64 Chondrocalcinosis refers to CPP crystal deposits in articular tissue that are detectable radiographically. It is thought that the presence of the crystals can lead to low-grade inflammation and joint damage. If the crystals are recognized by the innate immune system, an attack of acute arthritis can occur. Acute CPP crystal arthritis affects persons over the age of 40 years and in men predominately. The knee is the most frequent site of acute arthritis, but the hip, shoulder, ankle, wrists, and bursae can be affected. It affects approximately 4% to 7% of the adult population in Europe and the United States. Three forms of calcium pyrophosphate deposition disease (CPPD) are recognized: a hereditary form, CPPD associated with metabolic and other diseases, and an idiopathic form. The frequency of OA in CPPD varies from 40% to 70%. CPPD occurs in 41% of patients with hemochromatosis and in 5% to 15% with hyperparathyroidism.65 An association is suspected in patients with diabetes mellitus, hypophosphatemia, Wilson’s disease, ochronosis, and hypothyroidism.

Pathophysiology The initial site of crystal formation is in articular cartilage. In idiopathic CPPD, it is not clear whether the primary event is deposition of crystals in 1655

cartilage or whether the crystals develop as a consequence of disturbed cartilage metabolism. Increased inorganic pyrophosphate is found in the synovial fluid and probably reflects a local disorder of pyrophosphate metabolism possibly due to overactivity of the ANKH membrane protein leading to deposition of CPP crystals in the joint.64,66 Elevated levels are also found in patients with OA. Acute arthritis is brought on by shedding of crystals into the joint space. The mechanism for crystal shedding is the lowering of either calcium or pyrophosphate ions in synovial fluid. The decreased concentration of ionized calcium results in movement of crystals from cartilage into synovial fluid. Crystals can also be shed into the synovial fluid as a consequence of mechanical disruption of cartilage. Attacks can follow trauma. In addition, crystals can be released as a result of degradation of cartilage by enzymes from neutrophils during episodes of bacterial arthritis or other forms of inflammatory arthritis.

Symptoms and Signs Several patterns of joint disease are recognized.64 In approximately 25% of patients, CPPD presents as an acute arthritis (pseudogout) involving a single joint or a few joints at any given time. The clinical picture mimics that of acute gout in intensity. The onset of joint swelling and pain is abrupt and severe and usually reaches a peak within 24 to 36 hours. An attack can last up weeks to months as opposed to gout that typically last a few days to a week.64 The joint is swollen, red, and tender. The most common site of involvement is the knee, but attacks can involve other large joints such as the ankles, wrists, elbows, or hips. Also, the lumbar and cervical spine can be involved. Trauma, surgery, or severe medical illness can precipitate an attack. The same joint is often involved in subsequent attacks. Radiographic evidence of chondrocalcinosis is usually present in affected joints. Approximately 5% of patients with CPPD have a form of disease that mimics rheumatoid arthritis (pseudorheumatoid disease). Involvement of multiple joints, synovial proliferation, limitation of joint motion, and joint deformity can develop. Patients experience fatigue and morning stiffness. To further confuse the issue, CPP deposition can occur in rheumatoid arthritis. 1656

CPPD also occurs in a chronic form that is similar to OA. Multiple joints are involved and include the knees, wrists, MCP joints, hips, shoulders, elbows, and ankles. The disease involves middle-aged to elderly patients, predominantly women. CPPD can mimic neuropathic arthropathy (pseudo-Charcot) with a more severe joint destructive pattern. The diagnosis of CPP disease is established by identification of CPP crystals in synovial fluid, both free and in neutrophils. The crystals appear as short rods, rhomboids, and cuboids, and they have a sign of weakly positive birefringence under compensated polarized light. X-rays show calcification in articular hyaline cartilage that is parallel to and separated from the subchondral bone. Calcifications in fibrocartilage are thick and irregular densities and are found in the menisci of the knee, symphysis pubis, annulus fibrosus, and the triangular cartilage of the wrist. Calcifications also occur in the Achilles, supraspinatus, and triceps tendons but can involve any tendon. Changes in the joint are similar to those seen in OA with sclerosis of subchondral bone, joint space narrowing, and large subchondral cysts.

Treatment The NSAIDs are effective in the treatment of acute and chronic joint disease. An NSAID is given for 10 to 14 days in patients with acute CPP crystal arthritis.64 The drug can be continued indefinitely in patients with chronic CPP disease associated with OA. When an NSAID is contraindicated, another method of treatment for an acute attack is prednisone, starting with 40 mg the first day and gradually tapering over a 7-day period. Colchicine, 0.6 mg twice a day, is started on day 3 or 4 and continued for several weeks to avoid a flare of arthritis after prednisone is discontinued. An IL-1 inhibitor, anakinra, can be given subcutaneous for 1 to 3 days and will also treat an acute attack in patients who cannot use the aforementioned agents.67 Anakinra is not approved for this indication yet but has been effective in case series and case reports. Colchicine, 0.6 mg twice a day, can also be given prophylactically to reduce the number and length of attacks (see colchicine in section on gout). Aspiration of the involved joint followed by an injection of glucocorticoids reduces pain and swelling. 1657

URATE GOUT Urate gout is characterized by elevated serum urate levels, recurrent attacks of acute arthritis involving a single joint or a few joints at any given time, and deposition of monosodium urate dihydrate (tophi) in and around joints, leading in some patients to a deforming and crippling arthritis. Monosodium urate can serve as a nidus for calcium oxalate to form renal stones or form renal stone in their own right. Recognized since ancient times, gout has been depicted in caricatures as affecting well-fed aristocrats overindulging in rich foods and wines. The disease has been referred to as the king of diseases and the disease of kings.68 Currently, it is estimated that 6.1 million adults in the United States have gout.69 The normal serum urate concentration depends on several factors including age (increases with maturity), gender (women generally have lower levels than men), body habitus (those with metabolic syndrome will generally have higher levels), and genetic background. As noted, the upper limit of urate level is 6.8 mg/dL, but with the “super size” of the population in the United States, normative data which take the mean plus two standard deviations on either side has upper limit of normal as high in some labs as 8.5 mg/dL, which is above the level of urate solubility. Both genetic and environmental factors play a role in the expression of hyperuricemia and gout. For example, higher serum urate levels are found in Filipinos living in the United States compared with racially identical persons living in the Philippines. These persons are unable to excrete the greater uric acid load resulting from the higher purine content of the diet eaten in the United States.70

Etiology and Pathophysiology Uric acid is a product of purine metabolism.68 The serum urate concentration depends on the rate of uric acid production and excretion. Approximately two-thirds of uric acid is excreted in the urine and onethird into the gastrointestinal tract. Normally, uric acid is completely filtered through the glomeruli and completely reabsorbed in the proximal tubule. Secretion of uric acid occurs in the proximal tubule, followed by a second reabsorption in the proximal tubule. 1658

Primary gout is defined by the absence of other diseases or conditions such as drugs that lead to hyperuricemia and gout. Approximately 90% of patients with primary gout have decreased renal clearance of uric acid resulting from reduced glomerular filtration, increased tubular reabsorption, reduced tubular secretion, or combinations of these factors. Evidence for a molecular renal defect is still lacking in the majority of patients. Approximately 10% of patients are overproducers of uric acid. Overproduction is defined as the urinary excretion of more than 800 to 1,000 mg of uric acid in 24 hours while the patient is on a regular purine diet. Two inborn errors of purine metabolism make up a small number of primary gout patients who are overproducers of uric acid. The first disorder is caused by a partial deficiency of the enzyme hypoxanthineguanine phosphoribosyltransferase, which catalyzes conversion of hypoxanthine to inosinic acid and guanine to guanylic acid.68 The second disorder is caused by increased 5-phosphoribosyl-1-pyrophosphate synthetase activity leading to elevated levels of intracellular 5phosphoribosyl-1-pyrophosphate and overproduction of uric acid. These patients usually experience the onset of gouty arthritis in the second or third decade and have a high frequency of uric acid stones. Both diseases are inherited as an X-linked disorder, therefore affecting male subjects, with women as carriers. Some of these patients also have dysarthria, hyperreflexia, lack of coordination, and mental retardation. A severe form of the first disorder with almost a complete deficiency of this enzyme, referred to as the Lesch-Nyhan syndrome, is characterized by selfmutilation, choreoathetosis, and mental retardation.71 This disorder is classified under secondary hyperuricemia or gout because the neurologic disorder is predominant. Secondary gout is defined as gout or hyperuricemia occurring in patients with other disorders. Overproduction of uric acid results in hyperuricemia in patients with disorders associated with increased cell proliferation and turnover of nucleic acids. These disorders include myeloproliferative and lymphoproliferative diseases, multiple myeloma, polycythemia, pernicious anemia, hemoglobinopathies, and some carcinomas. The hereditary 1659

disorder glucose 6-phosphatase deficiency (von Gierke’s glycogen storage disease) is also manifested by overproduction of uric acid. Secondary hyperuricemia can also result from renal failure or the effects of drugs or toxins on renal clearance of uric acid. Diuretic agents, low doses of aspirin (less than 2 g per day), alcohol, ethambutol, cyclosporine, and lead are some of the agents that decrease the clearance of uric acid and thereby raise the serum urate level.

Pathophysiology of Acute Gouty Arthritis Acute gouty arthritis results from the inflammatory reaction to urate crystals that form in the joint space or are released into the joint from synovium or articular cartilage. Plasma becomes supersaturated with urate at concentrations of approximately 6.8 mg/dL.67 Factors in addition to supersaturation of plasma urate are necessary for crystal precipitation because most patients with hyperuricemia do not develop gout. The lower temperatures found in peripheral joints or tissues might contribute to urate precipitation at these sites. Urate is less soluble at 32° C, which is the temperature observed in a normal knee, compared with the core body temperature of 37° C.72 Another mechanism for urate precipitation might be the faster reabsorption of extracellular fluid than urate from the joint space, resulting in a transient increased urate concentration and crystal formation.73 Trauma or impact loading of a joint that breaks crystals loose from the joint surface is yet another possible mechanism and might explain the high frequency of gout at the base of the great toe, which is a joint subjected to great stress. Urate crystals induce inflammation by several mechanisms.68 Urate crystals activate Hageman’s factor in joint fluid, leading to the formation of kinins that induce vasodilatation and increased vascular permeability. Urate crystals activate the complement system with the generation of leukocyte chemotactic factors and also stimulate the formation of leukotrienes from arachidonic acid. Furthermore, urate crystals can activate platelets, which secrete several inflammatory mediators including prostaglandins. Urate crystals can also stimulate synovial lining cells and macrophages that secrete prostaglandins and collagenase. The key to urate-induced inflammation is the polymorphonuclear white 1660

cell. Urate crystals activate toll-like receptors on the surface of cells that lead to the activation of the inflammasome inside the cell which in turn leads to the release of inflammatory mediators such as IL-1.74 Crystals also bind immunoglobulin G (IgG), leading to their attachment to and phagocytosis by polymorphonuclear white cells.68 This process mediates the production of superoxide anions, which damage tissue. In addition, ingestion of crystals results in the release of chemotactic factors from the polymorphonuclear white cells, thus attracting more polymorphonuclear white cells. On ingestion by polymorphonuclear white cells, crystals are incorporated into phagosomes, which fuse with lysosomes. The rupture of phagolysosomes inside polymorphonuclear white cells damages these cells. Lysosomal and cytoplasmic enzymes are released into the joint space, resulting in tissue inflammation and injury. Gouty arthritis often develops with fluctuation of serum urate levels. A rapid increase in serum uric acid results in precipitation of crystals in tissue or fluid. A rapid decrease in serum urate brings about release of urate from the joint surface into the joint space. Drinking of alcohol is also associated with the precipitation of gouty attacks. Metabolism of ethanol results in an increased concentration of blood lactate, which blocks the renal excretion of uric acid by inhibiting tubular secretion and raising the serum urate level. Alcohol consumption also leads to accelerated degradation of adenosine triphosphate to adenosine monophosphate with accumulation of adenine nucleotides that are degraded to uric acid and other purine metabolites.75 Beers and ales in particular increase the risk of gout due to the amount of purines these contain. The drinking of moonshine whiskey is associated with gouty arthritis and is referred to as saturnine gout.76 Moonshine whiskey is often distilled in automobile radiators containing a lead core. Lead reduces the excretion of urate and decreases its solubility. In addition, lead may affect renal mechanisms for handling urate, leading to elevated levels. Gout follows periods of fasting. During fasting, the increased plasma level of acetoacetate and hydroxybutyrate interferes with renal excretion of urate.72 Overindulgence of food and wine has often been associated with gout. When a large protein- and purine-rich diet is ingested along with copious amounts of wine or other liquor, the uric acid serum concentration 1661

rises because of increased formation and decreased excretion of sodium urate. Acute gouty arthritis attacks occur when drugs increase or lower the serum uric acid level. Attacks are precipitated by allopurinol, which lowers the uric acid concentrations, and thiazides or low doses of aspirin, which raise the level. Cyclosporine interferes with the renal excretion of uric acid and induces hyperuricemia and gout.73 An increased frequency of gout is seen in transplant recipients receiving cyclosporine and may affect atypical joints such as the hips, sacroiliac joints, or shoulders.

Signs and Symptoms Gouty arthritis occurs mainly in middle-aged and older men and after menopause in women. Approximately one-fourth of the patients have a family history of gout. Nephrolithiasis precedes the first attack of arthritis in approximately 10% of patients. The first attack occurs most often in the MTP joint of the great toe (podagra) or ankles. Subsequent attacks might be separated by several months or even years. The involved joint usually returns to normal between attacks. In untreated cases, the attacks become more frequent and involve other joints, such as wrists, elbows, olecranon bursae, and the small joints of the hand. Gouty arthritis can occur in DIP joints already involved with OA and Heberden’s nodes77 (Figs. 34.10 and 34.11). Gout can be overlooked in these joints because acute inflammation can also occur with Heberden’s nodes. Gouty arthritis of intervertebral joints, sacroiliac joints, and shoulders and hips is uncommon.

FIGURE 34.10 Tophaceous gout affecting the distal interphalangeal joint.

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FIGURE 34.11 X-ray of same patient with tophaceous gout. Note erosions in the middle phalanx of the index finger caused by gout.

The typical attack of gout comes on acutely, often during the early hours of morning. Attacks also occur after surgery. Pain and swelling reach a peak within 24 hours. The joint is exquisitely tender, and overlying soft tissue is swollen and erythematous even to the degree that it could be mistaken for cellulitis. Pain is intense and throbbing. Patients are unable to tolerate even a light sheet touching the involved great toe. Jarring of the bed can make the patient wince with pain. The patient might even dread the landing of a fly on the involved toe. Both a low-grade fever and leukocytosis can accompany the attack, especially in polyarticular gout. An untreated attack of gout usually lasts for several days to 2 weeks. Chronic tophaceous gout develops in patients if hyperuricemia is not corrected. Before the effective control of hyperuricemia, approximately one-half of the patients with episodes of gouty arthritis eventually developed deposits of monosodium urate dihydrate in and around joints as well as in other tissues. These deposits, referred to as tophi, usually become apparent at least 10 years after the onset of gouty arthritis. They develop in the olecranon, infrapatellar and prepatellar bursae, Achilles tendons, synovium, subchondral bone, and, infrequently, cartilage of the ear. Tophi can ulcerate and drain material that contains microscopic needle-shaped crystals of monosodium urate. Patients with tophaceous gout have frequent episodes of acute gouty arthritis or may have 1663

continuous joint inflammation. Joint deformity and destruction leading disability can be quite severe in the untreated patient. There is recent data that suggests patients with hyperuricemia and chronic kidney disease may accelerate loss of kidney function more rapidly than those whose hyperuricemia is controlled.78 Likewise, patients with coronary artery disease and hyperuricemia have an increased allcause mortality compared to those without hyperuricemia. Treatment of patients with underlying myeloproliferative or lymphoproliferative disorder results in extremely high levels of serum urate that can precipitate in the renal tubules, producing obstruction and oliguria. Patients should be treated with allopurinol and colchicine before treatment of the blood dyscrasia. Renal calculi develop in approximately 20% of patients with gout. Hypertension, diabetes mellitus, and hypertriglyceridemia occur more frequently in patients with gout.

Laboratory Findings Radiography of the affected joint in acute gouty arthritis is usually normal. When the first MTP joint is involved, radiography might show underlying changes of OA. The typical erosion caused by urate deposition is sharply defined and has a thin shell-like overhanging edge at the margins of the erosion. The diagnosis of gout is established by demonstration of the characteristic crystal of monosodium urate monohydrate in the synovial fluid or from tissue deposits. Crystals are found both in the polymorphonuclear white cells and free in fluid. The crystals in joint fluid are usually rod-shaped and 7 to 10 µm in length. They are identified by use of polarized microscopy. With use of a first-order red compensator, crystals have a sign of strongly negative birefringence.79

Treatment Treatment of a patient with gout has two components: treatment of the acute gouty arthritis and treatment of hyperuricemia.80,81 Each is treated independently. Even though they are closely interrelated, the drugs used for each are different. In fact, the indiscriminate use of a drug to lower the uric acid can exacerbate or prolong an attack of gouty arthritis. 1664

Anti-inflammatory Drugs For the acute attack of gouty arthritis, the patient is given indomethacin 50 mg three times a day for 7 days, or naproxen 500 mg twice a day for 7 days has also been successful. NSAIDs for the treatment of acute gout should be avoided or used with caution in patients with symptomatic heart failure, renal failure, oliguria, or peptic ulcer disease.69 Glucocorticoids are also quite effective in treatment of acute gout. Prednisone is given over a 7-day period with an initial dose of 40 mg as a single dose and then gradually tapered over a 7-day period or 35 mg daily for 5 to 7 days has also shown to be effective. Intra-articular corticosteroids can also be used to treat gout in a large joint such as the knee. Colchicine can be used if started within 24 hours of the initial symptoms with 1.2 mg given the first hour and 0.6 mg the second hour. Anakinra 100 mg subcutaneously for 1 to 3 days has also been shown to be very effective in patients who cannot tolerate these other therapies, but it is not yet approved for gout by the U.S. Food and Drug Administration.82 In patients who experience frequent attacks of acute gouty arthritis, colchicine, 0.6 mg once or twice a day, is effective in preventing attacks. Colchicine is also used to prevent flares of gout when hypouricemic therapy is initiated. Myopathy and polyneuropathy may occur on maintenance doses of colchicine in patients who have renal insufficiency.83 Myositis manifests as proximal muscle weakness, and serum creatine kinase becomes elevated. These abnormalities return to normal 3 to 4 weeks after stopping the drug. Polyneuropathy also disappears on discontinuing colchicine. In addition, agranulocytosis or aplastic anemia can occur in patients with renal insufficiency who are on regular doses of colchicine because the plasma drug levels in these patients greatly increase. Hypouricemic Medications Treatment of hyperuricemia in patients with gout is directed at lowering uric acid levels with a target serum level of 5 to 6 mg/dL in patients without tophi and 4 to 5 mg/dL in patients with tophi.82 Lowering serum uric acid levels will prevent the formation of tophaceous deposits and eventually resolve existing tophi. 1665

The uric acid concentration can be lowered by probenecid, which is a uricosuric agent.84 In patients with normal renal function and no renal stones, probenecid is an effective agent. The dose of probenecid is 1 to 3 g per day given twice a day. It is given generally at mealtime to coincide with fluid intake and relative alkaline urine. Dumping uric acid in the urine when there is low urine flow and acidic urine will foster the development of renal stones. Serum uric acid level is effectively reduced by allopurinol, which is a potent inhibitor of xanthine oxidase.81 This drug blocks the conversion of hypoxanthine to xanthine and xanthine to uric acid. This leads to the accumulation of other oxypurines in the blood. The daily dose of allopurinol is 100 to 800 mg per day, which is regulated to reduce uric acid to a concentration below 6 mg/dL as noted. It is suggested that allopurinol be started at a low dose (i.e., 100 mg or even less in patients with chronic kidney disease) and slowly increased until serum uric acid levels are reached.81 Allopurinol administration can precipitate an acute attack of gout, presumably because of fluctuation of sodium urate between tissue and blood. Colchicine, 0.6 mg once or twice a day, is given along with the allopurinol to prevent an acute attack. In general, current guidelines suggest the use of allopurinol over probenecid for ease of use and compliance. Transient leukopenia and abnormalities of liver function are observed in some patients. In patients treated for many years, xanthine stones may occur. These tend to occur in patients who are overproducers and hyperexcretors of uric acid. A serious side effect of allopurinol is a rash that occasionally progresses to a severe life-threatening Stevens-Johnson syndrome/toxic epidermal necrolysis. This is particularly true in Asian patients who are HLA-B5801–positive. This allele is found in Han Chinese, Koreans, and Thai patients but low in Europeans and Japanese. These patients are also at risk for the most serious complication of allopurinol use which is the allopurinol hypersensitivity syndrome. This occurs in patients with chronic kidney disease and those on thiazide diuretics. The hallmarks of this hypersensitivity syndrome include fever, a serious rash, eosinophilia, hepatic abnormalities, and acute renal failure. The allopurinol hypersensitivity syndrome has a high mortality. It is 1666

thought to be avoided by starting with low doses of allopurinol and slowing increasing over time. Allopurinol potentiates the action of 6mercaptopurine and azathioprine. The dose of the cytotoxic agent is usually reduced by at least one-third in patients on allopurinol. There is another xanthine oxidase inhibitor available for use called febuxostat dosed 40 to 80 mg a day, and the advantage is that it is cleared by the liver and less so by the kidney. It can be used in patients with allopurinol associated rashes, but the use of febuxostat with 6mercaptopurine or azathioprine still requires dose reduction of these agents as noted earlier. Finally, a pegylated uricase inhibitor called pegloticase is available in intravenous (IV) form to treat patients with a significant tophaceous burden. Uricase metabolizes uric acid to the more soluble allantoin and will drop serum uric acid levels precipitously. It has a high immunogenicity but can be effective in selected patients.

INFECTIOUS ARTHRITIS Nongonococcal Bacterial Arthritis Acute bacterial or septic arthritis is a serious problem that requires prompt treatment to avoid joint damage.84,85 Bacteria usually reach the joint by hematogenous spread from a primary infection elsewhere. Often, however, no primary source of infection is found. An infection in the adjacent bone or soft tissue can extend directly into the joint. Acute bacterial arthritis is most often caused by Staphylococcus aureus, Streptococcus pneumoniae, Staphylococcus pyogenes, or Haemophilus influenzae, with Staphylococcus spp. being the most common causative organisms. Gramnegative organisms include Escherichia coli, Salmonella, and Pseudomonas and are usually seen in patients who are immunosuppressed or use IV drugs. In the past, Neisseria gonorrhoeae was at the head of this list, but its importance has waned over time. Patients with diabetes mellitus or blood dyscrasias or those receiving glucocorticoids or immunosuppressive drugs are more susceptible to joint infection. Septic arthritis is more likely to occur in joints previously damaged by trauma or inflammatory arthritis. Patients with rheumatoid arthritis in particular have an increased risk of septic arthritis and an 1667

increased mortality rate.48 Pathophysiology The synovium is edematous and infiltrated by neutrophils. As the disease progresses, small abscesses are present in the synovium and subchondral bone. Proteolytic enzymes from neutrophils damage the cartilage, bone, and joint capsule. Healing is manifested by proliferation of fibroblasts, which can lead to ankylosis. Symptoms and Signs The onset of bacterial arthritis is usually abrupt and associated with severe pain and fever. A shaking chill occasionally accompanies the onset. Any motion of the joint causes excruciating pain. The overlying skin is usually erythematous. In elderly patients and those who are on glucocorticoids, the symptoms can be less severe. The joint affected most frequently by septic arthritis is the knee, which is involved in at least one-half of the cases. Other commonly involved joints are hips, shoulders, wrists, ankles, elbows, and sternoclavicular and sacroiliac joints. Involvement of the latter two joints has been noted in IV drug users. The small joints of the hands and feet are rarely infected. In the spine, the intervertebral disk space and adjacent vertebral bodies are infected. Infection in the hip is more difficult to recognize because swelling is less evident. Patients with hip infection might hold the thigh in adduction, flexion, and internal rotation. Pain is felt in the groin or thigh and is also referred to the anterior surface of the knee. An overlying infected bursa or cellulitis can be mistaken for septic arthritis. It is important in aspirating a joint not to insert the needle through an infected bursa or cellulitis and possibly infect a normal joint. Laboratory Findings Joint fluid usually shows increased numbers of neutrophils ranging from 10,000 to greater than 100,000 per cubic millimeter. The white cell count in infected bursa fluid is not as high as observed in the joint. Data from a study taking place in the emergency room suggests that a white count in the synovial fluid over 25,000 per cubic millimeter has a likelihood ration over one and should raise suspicion for an infected joint.86 A peripheral 1668

blood leukocytosis might also be present. Gram stain performed on synovial fluid often shows bacteria except in gonococcal infections. Culture results of synovial fluid as well as blood are positive in over 90% of cases and are important to send if infection is suspected. Radiography of the joint initially shows swelling as manifested by distension of the joint capsule, followed later by juxta-articular osteoporosis. As the process continues, destruction of articular cartilage leads to joint space narrowing followed by bony erosions. Juxta-articular bone destruction might indicate osteomyelitis. In the spine, the initial change consists of narrowing of the disk space and proliferation of bone at vertebral margins. Osteolytic lesions in adjacent vertebrae are seen later. MRI can be helpful in identifying infection in certain joints such as the hip, shoulder, spine, and sacroiliac joints. Treatment An infected joint requires immediate aspiration and rapid initiation of parenteral antibiotic therapy. It has been reported that joint outcome is best when patients are seen within 7 days of initial symptoms. Joint fluid should be immediately cultured and a Gram stain performed. Vancomycin is the current suggested antibiotic for gram-positive infections (especially where methicillin-resistant S. aureus [MRSA] infection is common) and generally a third-generation cephalosporin for gram-negative organisms. (The details of antibiotic therapy are beyond the scope of this text.) Antibiotics should be given intravenously for 2 to 4 weeks depending on the organism. Antibiotics do not need to be infused into the joint. The joint should be adequately drained to prevent damage. Usually, drainage can be accomplished with a large-gauge needle. Drainage reduces intra-articular pressure and removes white cells, which is a source of proteolytic enzymes. Repeated aspirations are only necessary during the first 5 days of treatment. Surgical drainage is required when the joint cannot be adequately aspirated and irrigated by needle or when the cell count in the synovial fluid does not decline in spite of what appears to be adequate drainage. Surgical drainage via arthroscopy should also be considered in patients with underlying arthritis and those with prolonged symptoms (i.e., longer than 7 days).48 During the first few days of treatment, splinting of the involved joint in extension makes the patient more comfortable and 1669

reduces the possibility of a flexion contracture. Daily physical therapy, once the acute process has resolved, improves the range of motion. In a severely damaged joint, bony fusion might be required.

Gonococcal Arthritis Gonococcal arthritis was once considered the most frequent of bacterial arthritis in young adults. Women are more susceptible to gonococcal arthritis during menses and pregnancy. Persons who have a homozygous deficiency of complement component C5, C6, C7, or C8 are also susceptible to disseminated neisserial infections.87 Patients with low complement levels caused by consumption of complement might also be more susceptible to disseminated neisserial infections. Symptoms and Signs Patients typically present with fever and migratory arthritis or arthralgias that evolve in several days into monoarticular arthritis. Patients also directly present with monoarticular arthritis. Wrists and knees are common sites of involvement, but any joint can be affected. Arthritis is manifested by swelling, erythema, and severe pain as in other bacterial arthritides. Skin lesions can accompany gonococcal arthritis. These lesions can be pustular, vesicular, or hemorrhagic and can ulcerate. Laboratory Findings Joint fluid shows increased numbers of polymorphonuclear white cells, but the white cell count might not be as high as in other bacterial infections. The joint fluid glucose is also not decreased to the low levels found in other bacterial joint infections. Diagnosis Gonococcal arthritis is suspected in a patient presenting with fever, typical skin lesions, and polyarthralgia or arthritis that evolves into monoarticular arthritis. Diagnosis is confirmed by positive culture results from synovial fluid or from blood, but culture results from these sites are positive in fewer than 50% of cases. Cultures from skin lesions are also usually negative. Gram stain or culture results from cervix, urethra, or rectum might be positive when joint, skin, and blood culture results are negative. 1670

Polymerase chain reaction (PCR) may be useful if patients with suspected gonococcal arthritis where the organism cannot be demonstrated by direct culture of the synovial fluid. Treatment The patient should be admitted to the hospital and receive parenteral antibiotics. Currently, the recommendation is to start a third-generation cephalosporin such as ceftriaxone because penicillin-resistant strains are now widespread. The dose of ceftriaxone is 1 g IV every 24 hours for daily for 2 to 4 days.85 Most patients can be converted to oral antibiotic therapy in 48 hours. The patient is placed at bed rest for the first 2 days. Splinting of the affected joint provides pain relief. The infected joint should be immediately aspirated. The frequency of aspirations depends on the degree of inflammation. In most patients, residual joint damage does not occur.

POLYMYALGIA RHEUMATICA Polymyalgia rheumatica (PMR) is an inflammatory disease affecting people over the age to 50 years and typically those of Northern European ethnic background. Patients can generally remember the day or the week the symptoms began and the symptoms include marked stiffness of the shoulders and hip girdle regions, fatigue, and low-grade fever.88 A clue to PMR is a senior patient with bilateral “rotator cuff tendonitis.” Patients may have rotator cuff signs and symptoms, but it is unusual to have bilateral rotator cuff tendonitis. PMR is a synovitis, and the tenosynovitis around the shoulder may lead to rotator cuff symptoms and signs. The general stiffness is often profound, and a patient will describe significant difficulty getting out of bed. Patients will relate that they had to roll out of bed in order to get up. A related illness, giant cell arteritis (GCA), can present with manifestations of PMR but also includes headache and may include visual changes, jaw pain with chewing, and more pronounced systemic symptoms. It is important to recognize the difference between isolated PMR versus PMR plus GCA. If GCA is untreated, it may lead to permanent visual loss in up to 50% or stroke in up to 10% of patients. More recently, modern imaging techniques have identified subclinical vascular inflammation in up to one-third of patients with isolated PMR.89 1671

Additional information will be necessary to determine if these patients are treated more aggressively than those with isolated PMR. The laboratory hallmark of PMR is a markedly elevated ESR or CRP, with the CRP being more sensitive than the ESR in PMR.88 A few patients though (10% to 15%) may have normal levels and still have PMR so that the history is the key as well and the response to prednisone. Patients can also have mild anemia typical of other inflammatory diseases. Treatment is prednisone and has been for almost 50 years. If suspected, an initial of dose of 15 to 20 mg is sufficient in most patients with PMR especially if a small portion is given in the evening. The initial dose is maintained for 4 to 6 weeks and then slowly tapered. One taper regimen is to reduce the prednisone by 1 mg a week to 10 mg, 1 mg every 2 weeks to 5 mg, and then 1 mg every month until completely tapered off, but there are may be many small ups and downs on the prednisone dose. It must be recognized that the average length of disease duration is 24 months. If GCA is suspected, start the patients on high-dose prednisone (40 to 60 mg per day) and refer to a rheumatologist. The patient will need to have temporal artery biopsy scheduled as soon as possible and may need additional therapy. Methotrexate may offer steroid sparing therapy in patients who cannot reduce prednisone. References 1. Bone and Joint Initiative. The big picture: burden of musculoskeletal disease (BMUS). Available at: http://www.boneandjointburden.org/2014-report/i0/big-picture. Accessed January 2, 2018. 2. Simkin PS, Gardner GC. Musculoskeletal system and joint physiology. In: Hochberg MC, Silman AJ, Smolen JS, et al, eds. Textbook of Rheumatology. Philadelphia: Mosby; 2003. 3. Brodal A. Neurological Anatomy in Relation to Clinical Medicine. 3rd ed. New York: Oxford University Press; 1981. 4. Zhang Y, Jordan JM. Epidemiology of osteoarthritis. Clin Geriatr Med 2010;26:335–369. 5. Johnson VL, Hunter DJ. The epidemiology of osteoarthritis. Best Pract Res Clin Rheumatol 2014;28:5–15. 6. Acheson RM, Collart AB. New Haven survey of joint diseases. Ann Rheum Dis 1975;34:379– 387. 7. Stecher RM. Heberden’s nodes. Heredity in hypertrophic arthritis of the finger joints. Am J Med Sci 1941;201:801–809. 8. Knowlton RG, Katzenstein PL, Moskowitz RW, et al. Genetic linkage of a polymorphism in the type II procollagen gene (COL2A1) to primary osteoarthritis associated with mild chondrodysplasia. N Engl J Med 1990;322:526–530. 9. Eyre DR, Weis MA, Moskowitz RW. Cartilage expression of a type II collagen mutation in an inherited form of osteoarthritis associated with a mild chondrodysplasia. J Clin Invest

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1991;87:357–361. Carman WJ, Sowers M, Hawthorne VM, et al. Obesity as a risk factor for osteoarthritis of the hand and wrist: a prospective study. Am J Epidemiol 1994;139:119–129. Simkin PA. Bone pain and pressure in osteoarthritic joints. Novartis Found Symp 2004;260:179–186. Lane NE. Osteoarthritis of the hip. N Eng J Med 2007;3587:1413–1421. Wang X, Hunter D, Xu J, et al. Metabolic triggered inflammation in osteoarthritis. Osteoarthritis Cartilage 2015;23:22–30. Sharma L, Pai YC. Impaired proprioception and osteoarthritis. Curr Opin Rheumatol 1997;9:253–258. Bruckner FE, Howell A. Neuropathic joints. Semin Arthritis Rheum 1972;2:47–49. Beighton P. Articular manifestations of the Ehlers-Danlos syndrome. Semin Arthritis Rheum 1972;1:246–261. Askari AD, Muir WA, Rosner IA, et al. Arthritis of hemochromatosis. Clinical spectrum, relation to histocompatibility antigens, and effectiveness of early phlebotomy. Am J Med 1983;75:957–965. Faraawi R, Harth M, Kertesz A, et al. Arthritis in haemochromatosis. J Rheumatol 1993;20:448. Schumacher HR, Holdsworth DE. Ochronotic arthropathy. I. Clinicopathologic studies. Semin Arthritis Rheum 1977;6:207–246. Bluestone R, Bywaters EG, Hartog M, et al. Acromegalic arthropathy. Ann Rheum Dis 1971;30:243–258. Messier SP, Loeser RF, Miller GD, et al. Exercise and dietary weight loss in overweight and obese older adults with knee osteoarthritis: the Arthritis, Diet, and Activity Promotion Trial. Arthritis Rheum 2004;50:1501–1510. Brouwer RW, van Raaij TM, Verhaar JA, et al. Brace treatment for osteoarthritis of the knee: a prospective randomized multi-centre trial. Osteoarthritis Cartilage 2006;14(8):777–783. Reginster JY, Deroisy R, Rovati LC, et al. Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial. Lancet 2001;357(9252):251–256. Clegg DO, Reda DJ, Harris CL, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med 2006;354:795–808. Vasiliadis HS, Tsikopoulos K. Glucosamine and chondroitin for the treatment of osteoarthritis. World J Orthop 2017;8:1–11. Hochberg MC, Altman RD, April KT, et al. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res 2012;64:465–474. Raynauld JP, Buckland-Wright C, Ward R, et al. Safety and efficacy of long-term intraarticular steroid injections in osteoarthritis of the knee: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2003;48(2):370–377. Lo GH, LaValley M, McAlindon T, et al. Intra-articular hyaluronic acid in treatment of knee osteoarthritis. JAMA 2003;290:3115–3121. Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet 2016;388:1–16. Kourilovitch M, Galarza-Maldonado C, Ortiz-Prado E. Diagnosis and classification of rheumatoid arthritis. J Autoimmun 2014;48–49:26–30. Ferucci ED. Rheumatoid arthritis in American Indians and Alaska Natives: a review of the literature. Semin Arthritis Rheum 2005;34:662–667. van Venrooij WJ, van Beers JJ, Pruijn GJ. Anti-CCP antibody, a marker for early detection of rheumatoid arthritis. Ann NY Acad Sci 2008;1143:268–285.

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33. Rothschild BM, Woods RJ, Rothschild C, et al. Geographic distribution of rheumatoid arthritis in ancient North America: implications for pathogenesis. Semin Arthritis Rheum 1992;22:181–187. 34. Klareskog L, Malmstron V, Lunfberg K, et al. Smoking, citrullination, and genetic variability in the immunopathogenesis of rheumatoid arthritis. Semin Immunol 2011;23:92–98. 35. Avouac J, Gossec L, Dougados M. Diagnostic and predictive value of anti-citrullinated protein antibodies in rheumatoid arthritis: a systematic literature review. Ann Rheum Dis 2006;65;845–851. 36. Scott DL, Symmons DP, Coulton BL, et al. Long-term outcome of treating rheumatoid arthritis: results after 20 years. Lancet 1987;1:1108–1111. 37. Wilske KR, Healey LA. Remodeling the pyramid—a concept whose time has come. J Rheumatol 1989;16:565–567. 38. Fuchs HA, Kaye JJ, Callahan LF, et al. Evidence of significant radiographic damage in rheumatoid arthritis within the first 2 years of disease. J Rheumatol 1989;16:585–591. 39. Stoffer MA, Schoels MM, Smolen JS, et al. Evidence for treating rheumatoid arthritis to target: results of a systematic literature search update. Ann Rheum Dis 2015;75:16–22. 40. Zampeli E, Vlachoyiannopoulos PG, Tzioufas AG. Treatment of rheumatoid arthritis: unravelling the conundrum. J Autoimm 2015;65:1–18. 41. Singh JA, Saag KG, Bridges SL Jr, et al. 2015 American College of Rheumatology guidelines for the treatment of rheumatoid arthritis. 2016;68:1–26. 42. Cronstein BN. Low-dose methotrexate: a mainstay in the treatment of rheumatoid arthritis. Pharmacol Rev 2005;57:163–172. 43. van der Heijde D, Klareskog L, Landewé R, et al. Disease remission and sustained halting of radiographic progression with combination etanercept and methotrexate in patients with rheumatoid arthritis. Arthritis Rheum 2007;56:3928–3939. 44. Rhen T, Cidlowski JA. Anti-inflammatory actions of glucocorticoids: new mechanism for old drugs. N Eng J Med 2005;353:1711–1723. 45. Bakker MF, Jacobs JW, Welsing PM, et al. Low-dose prednisone inclusion in a methotrexatebased, tight control strategy for early rheumatoid arthritis. Ann Int Med 2012;156;329–339. 46. Turesson C, Matteson EL. Vasculitis in rheumatoid arthritis. Curr Opin Rheumatol 2009;21:35–40. 47. Puechal X, Gottenberg JE, Berthelot JM, et al. Investigators of the AutoImmunity Rituximab Registry. Rituximab therapy for systemic vasculitis associated with rheumatoid arthritis: results from the AutoImmunity and Rituximab Registry. Arthritis Care Res (Hoboken) 2012;64:331–339. 48. Gardner GC, Weisman MH. Pyarthrosis in patients with rheumatoid arthritis: a report of 13 cases and a review of the literature from the past 40 years. Am J Med 1990;88:503–511. 49. Brewerton DA, Hart FD, Nicholls A, et al. Ankylosing spondylitis and HLA27. Lancet 1973;1:904–907. 50. Benjamin M, McGonagle D. The anatomical basis for disease localisation in seronegative spondyloarthropathy at entheses and related sites. J Anat 2001;199:503–526. 51. Haroon N, Kim T, Inman RD. NSAIDs and radiographic progression in ankylosing spondylitis Bagging big game with small arms? Ann Rheum Dis 2012;71:1593–1595. 52. Dougados M, van der Linden S, Leirisalo-Repo M, et al. Sulfasalazine in the treatment of spondyloarthropathy. Arthritis Rheum 1995;5:618–627. 53. Calin A, Dijkmans BA, Emery P, et al. Outcomes of a multicentre randomized clinical trial of etanercept to treat ankylosing spondylitis. Ann Rheum Dis 2004;63:1594–1600. 54. Marzo-Ortega H, McGonagle D, O’Connor P, et al. Efficacy of etanercept in the treatment of the entheseal pathology in resistant spondyloarthropathy: a clinical and magnetic resonance

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55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80.

imaging study. Arthritis Rheum 2001;44:2112–2117. Mitchell MJ, Sartoris DJ, Moody D, et al. Cauda equina syndrome complicating ankylosing spondylitis. Radiology 1990;175:521–525. Hunter T. The spinal complications of ankylosing spondylitis. Semin Arthritis Rheum 1989;19:172–182. Brewerton DA, Caffrey M, Nicholls A, et al. Reiter’s disease and HLA 27. Lancet 1973;2:996–998. Calin A, Fries JF. An “experimental” epidemic of Reiter’s syndrome, revisited: follow-up evidence on genetic and environmental factors. Ann Intern Med 1976;84:564–566. Hannu T. Reactive arthritis. Best Pract Res Clin Rheumatol 2011;25:347–357. Carter JD, Espinoza LR, Inman RD, et al. Combination antibiotics as a treatment for chronic Chlamydia induced reactive arthritis. Arthritis Rheum 2010;62:1298–1307. Ritchlin C. Psoriatic disease—from skin to bone. Nat Clin Pract Rheumatol 2007;3:698–706. Ritchlin CT, Colbert RA, Gladman DD. Psoriatic arthritis. N Eng J Med 2017;376:957–970. Voulgari PV. Rheumatological manifestations of inflammatory bowel disease. Ann Gastroenterol 2011;24:173–180. Rosenthal AK, Ryan LM. Calcium pyrophosphate deposition disease. N Eng J Med 2016;374:2575–2584. Hamilton EBD. Diseases associated with CPPD deposition disease. Arthritis Rheum 1976;19:353–357. Russell RG. Metabolism of inorganic pyrophosphate (PPi). Arthritis Rheum 1976;19:465– 478. McGonagle D, Tan AL, Madden J, et al. Successful treatment of resistant pseudogout with anakinra. Arthritis Rheum 2008;58:631–633. Choi HK, Mount DB, Reginato AM. Pathogenesis of gout. Ann Intern Med 2005;143:499– 516. Neogi T. Gout. N Eng J Med 2011;364:443–452. Healey LA, Bayani-Sioson PS. A defect in the renal excretion of uric acid in Filipinos. Arthritis Rheum 1971;14:721–726. Lesch M, Nyhan WL. A familial disorder of uric acid metabolism and central nervous system function. Am J Med 1964;36:561–570. Maclachlan MJ, Rodnan GP. Effects of food, fast, and alcohol on serum uric acid and acute attacks of gout. Am J Med 1967;42:38–57. Lin HY, Rocher LL, McQuillan MA, et al. Cyclosporine-induced hyperuricemia and gout. N Engl J Med 1989;321:287–292. Chruch LD. Primer: inflammasomes and interleukin 1 beta in inflammatory disorders. Nat Clin Pract Rheumatol 2008;4:34–42. Faller J, Fox IH. Ethanol-induced hyperuricemia: evidence for increased urate production by activation of adenine nucleotide turnover. N Engl J Med 1982;307:1598–1602. Halla JT, Ball GV. Saturnine gout: a review of 42 patients. Semin Arthritis Rheum 1982;11:307–314. Simkin PA, Campbell PM, Larson EB. Gout in Heberden’s nodes. Arthritis Rheum 1983;26:94–97. Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascular risk. N Eng J Med 2008;359:1811–1821. Gatter RA. The compensated polarized light microscope in clinical rheumatology [editorial]. Arthritis Rheum 1974;17:253–255. Khanna D, Fitzgerald JD, Khanna P, et al. 2012 American College of Rheumatology guidelines for the management of gout part 2: therapy and antiinflammatory prophylaxis for

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acute gouty arthritis. Arthritis Care Res 2012;64:1447–1461. Khanna D, Fitzgerald JD, Khanna P, et al. 2012 American College of Rheumatology guidelines for the management of gout part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res 2012;64:1431– 1446. Ghosh P, Cho M, Rawat G, et al. Treatment of acute gouty arthritis in complex hospitalized patients with anakinra. Arthritis Care Res (Hoboken) 2013;65(8):1381–1384. Kuncl RW, Duncan G, Watson D, et al. Colchicine myopathy and neuropathy. N Engl J Med 1987;316:1562–1568. Tarkowski A. Infectious arthritis. Best Pract Res Clin Rheumatol 2006;20:1029–1044. Horowitz DL, Katzap E, Horowitz S, et al. Approach to septic arthritis. Am Fam Physician 2011;84:653–660. Carpenter CR, Schur JD, Everett WW, et al. Evidenced-based diagnostics: adult septic arthritis. Acad Emerg Med 2011;18(8):781–796. Petersen BH, Lee TJ, Snyderman R, et al. Neisseria meningitidis and Neisseria gonorrhoea bacteremia associated with C6, C7, or C8 deficiency. Ann Intern Med 1979;90:917–920. Salvarani C, Pipitone N, Versari A, et al. Clinical features of polymyalgia rheumatica and giant cell arteritis. Nat Rev Rheumatol 2012;8:509–521. Dejaco C, Duftner C, Buttgereit F, et al. The spectrum of giant cell arteritis and polymyalgia rheumatica: revisiting the concept of disease. Rheumatology (Oxford) 2017;56(4):506–515.

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CHAPTER 35 Myofascial Pain Syndrome JAN DOMMERHOLT and JAY P. SHAH Muscle pain is a common manifestation of many chronic pain conditions and is described as a diffuse, difficult to pinpoint, aching pain that may refer to deep somatic structures.1 Muscle pain is common in all age groups, but chronic muscle pain is more frequent in the elderly than in younger populations.2 Muscle-referred pain involves nociceptive-specific neurons in the spinal cord and in the brainstem. Wall and Woolf3 have shown that muscle nociceptive afferents are especially effective in inducing neuroplastic changes in the spinal dorsal horn. Muscle pain activates specific cortical structures, such as the anterior cingulate gyrus, which is also involved in the emotional, affective component of pain.4,5 Muscle pain is inhibited strongly by descending pain-modulating pathways, and under normal circumstances, there is a dynamic balance between the degree of activation of dorsal horn neurons and the descending inhibitory systems. Prolonged input from muscle nociceptors can be misinterpreted in the central nervous system and eventually can lead to allodynia, hyperalgesia, and an expansion of receptive fields.6 Although muscle pain is very common,7 there is considerable controversy regarding its nature, existence, and relevance. Some clinicians consider muscle pain only secondary to other diagnoses, such as tendonitis, muscle strain, inflammation, degeneration, or injuries to joints and nerves.8 Others view persistent muscle pain primarily as a manifestation of a presumed somatoform disorder.9 Yet, others deny the existence of muscle pain all together as, in their view, all pain is produced by the brain, and focusing on peripheral tissues would be counterproductive.10 With the development of orthopedic and manual medicine, many physicians, chiropractors, and physical therapists directed their attention mostly to articular dysfunction, although early manual 1677

medicine pioneers did include muscle dysfunction in their thinking.11,12 In this context, it is noteworthy that although skeletal muscle comprises nearly half of the body’s weight, it is the only organ in the human body that is not linked to a particular medical specialty. This led Simons13 to suggest that muscle is an orphan organ, further evidenced by the fact that muscle research and the development of a knowledge base of musclespecific ailments, pathophysiology, and diagnostic and treatment options have not evolved until fairly recently. The literature on myofascial pain is scattered among the literature of many different disciplines. One could wonder why persistent muscle pain and dysfunction have largely been ignored by the medical professions, but such contemplations are outside the scope of this chapter.

Brief Historical Overview Muscle pain has been described by many different terms, including fibrositis, interstitial myofibrositis, myogeloses, nonarticular rheumatism, myofascial pain, idiopathic myalgia, myofasciitis, perineuritis, myodysneuria, and fibromyalgia.14 Publications by Kellgren describing referred pain patterns from muscles and other soft tissues strongly influenced physicians James Cyriax in England and Janet Travell in the United States. At the time of Kellgren’s first publications, Travell was a cardiologist and researcher. Initially, she was interested in the applicability of Kellgren’s findings to cardiac pain, but soon, she became interested in musculoskeletal medicine.15 In 1942, she coauthored the first of many articles about the diagnosis and treatment of muscle pain.16 In 1952, Travell and Rinzler17 published an article of observed pain referral patterns of 32 muscles (Fig. 35.1).

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FIGURE 35.1 Examples of trigger point referred pain patterns. A: Referred pain patterns of the multifidi muscles. B: Referred pain patterns of the hamstrings muscles. C: Referred pain pattern of the pectoralis major muscle.

At that time, there was virtually no research on muscle pain, and many of Travell’s writings were based on her empirical observations and ability to establish clinical correlations. For example, Travell and Rinzler17 observed that the fascia generated similar referred pain patterns as the contractile elements of the muscle; she subsequently modified her 1679

terminology to myofascial pain to encompass both the fibrous and contractile aspects. The similarities between referred pain patterns of fascia and muscle and the mechanical relationships between fascia and muscle were not further investigated until much later.18 Travell’s work culminated in the publication of a two-volume textbook on myofascial pain, which she coauthored with Simons.19,20 These books became known as the Trigger Point Manuals, and they have been translated in multiple languages. The term trigger point was introduced by Steindler in 1940 in a paper on muscle pain.21 Travell and Rinzler17 introduced the terms myofascial trigger point and myofascial pain syndrome, which are now intricately linked to a particular theoretical model, referred to as the “integrated trigger point hypothesis.”22 Although muscle pain and myofascial pain are sometimes used interchangeably, muscle pain is really a descriptive term, whereas myofascial pain, as introduced by Travell, is a more specific entity.23 In 1981, Simons and Travell24 developed the “energy crisis hypothesis,” which postulated that direct trauma and subsequent damage to the sarcoplasmic reticulum or the muscle cell membrane leads to an increase in intracellular calcium (Ca2+) concentration, increased activation of actin and myosin, a relative shortage of adenosine triphosphate (ATP), and an impaired calcium pump, which in turn would increase the intracellular calcium concentration even more, perpetuating the cycle. Under normal physiologic conditions, the calcium pump is responsible for returning intracellular Ca2+ to the sarcoplasmic reticulum against a concentration gradient, which requires a functional energy supply. Eventually, the energy crisis hypothesis developed into the integrated trigger point hypothesis and more recently developed hypotheses, which incorporate newer electrodiagnostic, histopathologic, and pain science research.25–27 It is now acknowledged that actual tissue damage is not required for the development of trigger points. This chapter provides an updated review of the etiology, mechanisms, pathophysiology, and clinical implications of myofascial trigger points.

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Over time, research in the etiology, epidemiology, pathophysiology, diagnosis, and clinical management of myofascial pain has grown exponentially. Although the integrated trigger point hypothesis is not a perfect theoretical concept, it quickly became the most comprehensive evidence-informed model to explain the role of muscle tissue in acute and persistent pain conditions. Researchers around the world are conducting basic trigger point research, prevalence studies, and clinical outcome studies. Their findings show that trigger points are associated with virtually all painful musculoskeletal problems, including migraines, tension-type headaches, craniomandibular dysfunction, epicondylalgia, low back pain, postlaminectomy syndrome, neck pain, disk pathology, carpal tunnel syndrome, osteoarthritis, radiculopathies, whiplashassociated disorders, fibromyalgia, postherpetic neuralgia, and complex regional pain syndrome, among others.28 Trigger points have also been associated with visceral dysfunction, including endometriosis, interstitial cystitis, irritable bowel syndrome, urinary/renal and gallbladder calculosis, dysmenorrhea, and prostadynia.29–33 Although trigger points are reportedly the most common diagnosis responsible for chronic pain and disability, they are frequently overlooked in the clinic.34 Trigger points have been reported in all age groups except infants.35–39 A trigger point is defined as “a hyperirritable spot in skeletal muscle that is associated with a hypersensitive palpable nodule in a taut band”.19 Palpating for trigger points begins with identifying this taut band by palpating perpendicular to the fiber direction (Fig. 35.2). Taut bands are stiffer than relaxed muscle fibers, and the degree of stiffness can be assessed by phase-contrast analysis of vibration-induced cyclic shear waves.40–46

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FIGURE 35.2 Palpation of trigger points. As the palpating finger of the examiner moves from normal areas of muscle (A) and encounters a painful trigger point (B), a local twitch response often occurs within the muscle surrounding the trigger point. (Redrawn after Simons DG, Travell JG, Simons LS. Upper Half of the Body. 2nd ed. Baltimore, MD: Lippincott Williams & Wilkins; 1999. Travell & Simons’ Myofascial Pain and Dysfunction: The Trigger Point Manual; vol 1.)

An active trigger point can spontaneously produce local tenderness and pain, referral of pain or other paresthesia to a distant site, and peripheral and central sensitization. A latent trigger point is only painful when stimulated. Motor phenomena associated with trigger points include disturbed motor function, muscle weakness as a result of motor inhibition, muscle stiffness, and restricted range of motion. Nociceptive input can perpetuate altered motor control strategies and lead to muscle overload or disuse.47–49 Subjects with latent trigger points in several shoulder muscles featured altered shoulder abduction patterns when compared to healthy subjects.50–52 Autonomic aspects may include, among others, vasoconstriction, vasodilatation, lacrimation, and piloerection.53 To discuss the current research and the clinical implications of myofascial trigger points and contemporary trigger point hypotheses, a brief review of muscle physiology, the role of the motor endplate, muscle pain, dorsal horn, and central sensitization is provided in the context of 1682

myofascial trigger points. The motor phenomena of trigger points are best explained by understanding the functions and structure of the motor endplate and the sarcomere assembly.

Muscle Physiology Skeletal muscles consist of groups of fascicles, which are made of muscle fibers and myofibrils, accountable for contraction and relaxation of the fiber. The myofibril is approximately 1 to 2 µm in diameter and is separated from surrounding myofibrils by the mitochondria, the sarcoplasmic reticulum, and the transverse tubular systems or T-tubules. The T-tubules lie perpendicular to the long axis of the muscle fiber with two zones of transverse tubules to each sarcomere. T-tubules conduct impulses from the exterior to the interior of the muscle fiber and activate voltage-dependent L-type calcium channels in the transverse tubular membrane, including type 1 sarcoplasmic reticulum calcium release ryanodine receptors and surface membrane calcium channel dihydropyridine receptors. Activation of these channels and receptors results in the release of Ca2+into the myoplasm.54 The sarcoplasmic reticulum is a store for the release and uptake of Ca2+. Muscle contractions occur after actin and troponin are activated by Ca2+. Calcium allows tropomyosin to shift its position and expose myosin-binding sites on actin, thus regulating the cross-bridge interactions between actin and myosin.55 ATP-dependent processes are responsible for muscle force generation, which implies that both calcium and ATP are critical for the maintenance of the actin-myosin cross-bridges.56 The organization of thin actin and thicker myosin filaments are responsible for the striated patterning observed when viewed under longitudinal electron micrograph scanning. In addition to actin and myosin, there are several other important proteins, such as titin, nebulin, desmin, tropomyosin, troponin, and tropomodulin, among others, which together maintain the architecture and stability of the sarcomere (Fig. 35.3).

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FIGURE 35.3 Sarcomere.

Titin is the largest known vertebrate protein. It connects the Z-line with myosin filaments and cross-links with titin molecules of adjacent sarcomeres. Titin positions the myosin filaments at the center of the sarcomere as a spring.57,58 One particular section of titin, referred to as the PEVK segment, is able to interact with actin filaments in close proximity to the Z-line, which may limit the degree of sarcomere contraction as the tip of the myosin filament may literally bounce back against a “viscous bumper” of the actin-titin interaction, comparable to a dragnet.59,60 Titin filaments are responsible for passive tension generation when sarcomeres are stretched and provide muscle stiffness by virtue of their spring mechanism in the I-band. During sarcomere contractions, titin filaments are folded into a sticky gel-like structure at the Z-line,57,58,61,62 which is an important contributor to the force generated by a contracting muscle.63 It is conceivable that myofascial trigger points have a damaged sarcomere assembly; myosin filaments may have broken the actin–titin barrier and gotten stuck in the sticky titin substance at the Z-line. Single molecules of nebulin span the full length of the actin filaments, and nebulin dictates the architecture of actin with direct involvement of titin and the Z-line protein myopalladin.64 Titin and nebulin interact at many levels, especially during myofibrillogenesis.65 Nebulin connects to the proteins myopalladin and desmin in the Z-line. Myopalladin binds to α-actinin, which in turn connects to actin and to titin.66 Desmin filaments link adjacent Z-lines and interconnect the myofibrils with the sarcolemma, the nuclei, the T-tubules, the mitochondria, and possibly the 1684

microtubules.55,67 Nebulin acts as a stabilizing structure through its specific binding sites at different places on actin, tropomyosin, troponin, and tropomodulin.55,65,68–71 It regulates muscle contractions by inhibiting the cross-bridge formation until actin is activated by Ca2+.65 Troponin is a Ca2+-receptive protein that sensitizes actomyosin to Ca2+ in association with tropomyosin, among other functions.72 Of interest is that tropomyosin and tropomodulin can influence molecular processes related to synaptic signaling and modulate neuronal morphology.73 A key feature of the integrated trigger point hypothesis is the presence of excessive acetylcholine (ACh) at the neuromuscular junction, which stimulates voltage-gated sodium (Na+) channels of the sarcoplasmic reticulum and ultimately results in a continuous increase of intracellular Ca2+ levels. This results in ongoing activation of nebulin, troponin, and tropomyosin and causes persistent muscle contractures consistent with taut bands and myofascial trigger points. The role of the motor endplate is reviewed in the next section.

The Motor Endplate The terms neuromuscular junction and motor endplate are used interchangeably, although technically, the neuromuscular junction refers to function, whereas the motor endplate refers to structure. A motor endplate is the synapse between the terminal ends of motor neurons and skeletal muscle. The terminal branches of a single motor neuron terminate in multiple presynaptic boutons containing many ACh vesicles.74 When nerve impulses from a α-motor neuron reach the motor nerve terminal, voltage-gated Na+ channels are opened, which trigger a Na+ influx that depolarizes the terminal membrane. Voltage-gated Ca2+ channels are opened, which causes an influx of Ca2+ and a quantal release of ACh and other molecules, such as ATP, from the nerve terminal into the synaptic cleft (Fig. 35.4). When two ACh molecules bind to a nicotinic ACh receptor (nAChR) across the synaptic cleft, the nAChR opens a cation-specific pore, which facilitates a Na+ influx and a potassium (K+) efflux across the muscle cell membrane. Each single quantum of ACh will depolarize the postsynaptic cell and trigger a miniature endplate potential 1685

(MEPP). A sufficient number of MEPPs will produce a depolarization and an action potential, which travels along the T-tubules, triggers the ryanodine receptor in the sarcoplasmic reticulum, and causes a release of Ca2+ from the sarcoplasmic reticulum.

FIGURE 35.4 The motor endplate.

As stated, the release of Ca2+ triggers tropomyosin to shift its position and nebulin to allow cross-bridges to form between the actin and myosin filaments, resulting in a muscle contraction. The K+ efflux restores the resting membrane potential. During the brief period before the actual muscle contraction, ACh is hydrolyzed by the enzyme acetylcholinesterase (AChE) into acetate and choline. Choline is reabsorbed into the nerve terminal, where it is synthesized into ACh by acetyltransferase by combining choline and acetyl coenzyme A from the mitochondria. ACh release is not only activated by motor nerve stimulation, but it is also modulated by the concentration of AChE. Inhibition of AChE will cause an accumulation of ACh in the synaptic cleft, which may stimulate motor 1686

nerve endings and tonically activate nAChRs. A 1993 publication illustrating spontaneous electrical activity in myofascial trigger points initiated a new line of research into the role of motor endplates.75 Initially, the electrical activity was assumed to be the result of dysfunctional muscle spindles, but soon, multiple human, rabbit, and even equine studies confirmed that the activity was in fact abnormal endplate noise related to an excess of ACh at the motor endplate.22,76–83 It is conceivable that in myofascial trigger points, the contractures resulting from excessive ACh may cause myosin filaments to get stuck in sticky titin gel at the Z-line, thereby damaging the sarcomere assembly. The persistent contractures compromise local blood vessels, reducing the local oxygen supply, resulting in hypoxia, a lowered pH, and hypoperfusion, which all contribute to muscle pain, tenderness, dysfunction, and peripheral nociceptor sensitization.84 The reduced oxygen levels in myofascial trigger points and an increased metabolic demand result in a local energy shortage and a local shortage of ATP.25 Under normal physiologic circumstances, presynaptic ATP inhibits the release of ACh. Inversely, a decrease in ATP leads to an increased ACh release. Insufficient postsynaptic ATP results in a failure of the calcium pump, increased levels of Ca2+, and a Ca2+-induced Ca2+ release. An increase in the Ca2+ concentration will reinforce muscle contractures. The local energy crisis is likely related to the finding of abnormal mitochondria in the nerve terminal and ragged red fibers, which are an indication of structural damage to the cell membrane and the mitochondria.85 The presence of excessive ACh can be the result of AChE insufficiency, an acidic pH, hypoxia, a lack of ATP, certain genetic mutations, drugs and particular chemicals, such as calcitonin gene-related peptide (CGRP), diisopropyl fluorophosphate, or organophosphate pesticides, and increased sensitivity of the nAChRs.26,86,87 Myofascial tension or muscle hypertonicity, as seen in trigger points, may also enhance the excessive release of ACh.88,89 There are many possible vicious cycles capable of maintaining the resulting contractures and trigger points. For example, hypoxia leads to an acidic milieu, muscle damage, and an excessive local release of multiple nociceptive substances, including CGRP, bradykinin 1687

(BK), and substance P (SP).90 Hypoxia may even trigger an immediate increased ACh release at the motor endplate.87 CGRP stimulates the release of ACh from the motor endplate, decreases the effectiveness of AChE, and upregulates the nAChR. An acidic pH enhances the release of CGRP, downregulates AChE, and causes hyperalgesia.26,91,92 There are many similarities between the mechanisms and consequences of myofascial trigger points and eccentric loading or eccentric exercise. Eccentric training or exposure is frequently characterized by a certain degree of cytoskeletal muscle damage. Even very short bouts of eccentric exercise can result in a disorganization of the A-band, streaming of the Zline, and a disruption of several cytoskeletal proteins, including titin, nebulin, vimentin, fibronectin, and desmin.93–98 By comparison, postmortem histologic studies of myofascial trigger points show pathologic alterations of the mitochondria as well as an increased width of A-bands and decreased width of I-bands in muscle sarcomeres of trigger points.99,100 A biopsy study of trigger points in a dog gracilis muscle revealed a similar pattern of severely shortened sarcomeres in the center and lengthened sarcomeres outside the immediate trigger point region.101 The diagnosis of trigger points in animals is comparable to that in human subjects. Although an animal cannot verbalize recognition of pain, skilled palpation combined with an analysis of dysfunctional movement patterns will direct the investigator or clinician to clinically relevant trigger points.102,103 In addition to these similarities, eccentric loading and myofascial trigger points also involve local hypoxia, impaired local circulation, and local and referred pain.104 Eccentric contractions in unconditioned muscle or unaccustomed eccentric contractions are likely sources of myofascial trigger point development.26 Itoh and colleagues105 confirmed that eccentric exercise triggers the formation of taut bands and myofascial trigger points in exercised muscle. There are other possible causes of trigger points. Patients commonly report an onset of pain associated with trigger points following either acute, repetitive, prolonged, or chronic muscle overload. Piano students developed significantly decreased pressure thresholds over latent trigger points after only 20 minutes of continuous piano playing.106 Computer 1688

operators developed trigger points after as little as 30 to 60 minutes of continuous typing.107,108 In other words, low-level muscle contractions can contribute to the development of trigger points, which is best explained by the so-called Cinderella hypothesis.109 According to the Cinderella hypothesis, low-level muscle contractions follow stereotypical patterns, where smaller motor units are recruited before and derecruited after larger motor units, which means that smaller type 1 fibers may be continuously activated during prolonged low-level contractions.110,111 Low-level contractions have been shown to lead to muscle fiber degeneration, an increase in Ca2+ release, energy depletion, and the release of various cytokines, which all have been associated with the formation of trigger points.112–115 During low-level contractions, the intramuscular pressure increases considerably especially near the muscle insertions, which may impair the local circulation, cause hypoxia, and eventually lead to trigger point formation.28,116 As noted, motor phenomena associated with trigger points include disturbed motor function, muscle weakness as a result of motor inhibition, muscle stiffness, and restricted range of motion.

Sensitization and Activation of Muscle Nociceptors To better understand the sensory aspects of myofascial trigger points, including local and referred tenderness, pain, and other paresthesia, as well as peripheral and central sensitization, a brief review of the current understanding of muscle nociceptors, spinal cord mechanisms, and sensitization is necessary. Muscle nociceptors are dynamic structures that can be activated mechanically by deforming the axonal membrane of the nerve ending, as for example, following a blow to a muscle. Many receptors are susceptible to chemical activation by nociceptive substances released from the surrounding tissues and immune cells.117 Matched receptors at the nociceptor exist for a variety of substances including BK, prostaglandins (PGs), serotonin (5-HT), protons (H+), ATP, glutamate, and others, including the so-called purinergic and vanilloid receptors. Purinergic receptors bind ATP and stimulate nociceptors accordingly. Vanilloid receptors are especially sensitive under conditions of lowered tissue pH 1689

and muscle ischemia. Pain during tension-type headaches, tooth clenching, and bruxism is partially mediated by the vanilloid receptor molecule.117 BK, 5-HT, and PG interact at many levels at the vanilloid receptors, potentially synergistically producing local muscle pain.118 When injected together into the temporalis muscle of normal volunteers, BK and 5-HT produced more pain than when each stimulant was injected alone.119 The mechanism of chemical activation is of clinical interest, especially in evaluating chronic pain states where often there is little gross swelling evident. Endogenous substances such as BK, PG, and 5-HT not only are very effective at sensitizing or activating muscle nociceptors but also cause local vasodilation. Therefore, the release of these substances can lead to mechanoreceptor activation by distorting the normal tissue relationships. A sensitized muscle nociceptor has a lowered stimulation threshold into the innocuous range, such that it will respond to harmless stimuli like gentle pressure and muscle movement.120 The nociceptor terminals contain neuropeptides, such as SP and CGRP. When these substances are released, they stimulate local vasodilation, plasma extravasation, and liberation of sensitizing substances from the surrounding tissue. Upon activation by a noxious stimulus, the nociceptor releases the stored neuropeptides, which directly influence the local microcirculation by stimulating vasodilation and increasing the permeability of the microvasculature.121,122 More importantly, the secretion of the neuropeptides in sufficient quantity leads to a cascade of events, including the release of histamine from mast cells, BK from kallidin, 5-HT from platelets, and PGs from endothelial cells.123 The cumulative effect is the increased production and release of sensitized substances in a localized region of edema in the muscle tissue. Therefore, the muscle nociceptor is not merely a passive structure designed to record potentially noxious stimuli. Rather, muscle nociceptors play an active role in the maintenance of normal tissue homeostasis by sensing the peripheral biochemical milieu and mediating the vascular supply to peripheral tissue. With tissue injury, the secretion of SP and CGRP increases, leading to the response outlined earlier that can alter the responsiveness of the nociceptor. Muscle tenderness is mainly due to the sensitization of muscle nociceptors by BK, PG, and 5-HT, which may account for the exquisite 1690

tenderness found when firm pressure is applied over an active trigger point.124,125 As noted before, the activation of a nociceptive terminal is not primarily due to a nonspecific damage of the nerve ending by a strong stimulus but rather the binding of specific substances, including BK, PG, and 5-HT, to their paired receptors on muscle nociceptors. Receptor responsiveness is dynamic. For example, inflammation alters the population of BK G protein-coupled metabotropic receptors at the nociceptive terminal. In normal muscle tissue, the B2 receptor is more prevalent. With tissue inflammation, an additional BK receptor (B1) is synthesized in the cell body of the ending in the dorsal root ganglion and inserted into the nociceptor terminal membrane. Unlike the B2 receptor, which is constitutively expressed, the B1 receptor is inducible and is involved in sensitization of the peripheral nociceptor. The B2 and B1 receptors are mediators of several physiologic and pathologic responses via the kallikrein–kinin system.126 Induction and binding of the B1 receptor can also lead to the production of pro-inflammatory mediators, including tumor necrosis factor-α (TNF-α) and interleukin-1 β (IL-1β). Stimulation of B2 receptors leads to only transient increases in the intracellular calcium concentration, making nociceptor sensitization unlikely; however, the B1 and B2 receptors do influence each other on many levels.127 Stimulation of the B1 receptor results in prolonged elevation of intracellular Ca2+ concentration, which can lead to sustained peripheral sensitization.128 If the conformational change of the BK receptor persists after the inflammation subsides, this maladaptive change may herald the transition from acute to chronic pain. Therefore, the degree to which muscle nociceptors in a trigger point become sensitized or activated will vary according to the balance of sensitizing substances in the muscle tissue and the threshold of their respective receptors. There may be a spectrum of nociceptor irritability based on this balance that distinguishes a normal muscle from a muscle with a latent or active trigger point.

Central Sensitization In addition to sensitization of the peripheral nociceptors, pain and 1691

dysfunction induced by trigger points may also be related to alterations in the responsiveness of the dorsal horn.129,130 A chronic active trigger point may contribute to inflammatory exacerbation of the fascia and be a source of ongoing noxious input that sensitizes dorsal horn neurons and generates increased or referred pain to other spinal cord segments via central sensitization.131 Conversely, a sensitized central nervous system may lead to a lowering of the activation threshold of the peripheral nociceptors in a trigger point, inducing the transition from latent to active. The latter may occur when trigger points develop secondary to referred pain from viscera or joints or as a result of psychological stress.104,130 Giamberardino et al.132 have established that visceral referred pain with hyperalgesia is usually associated with cutaneous hyperalgesia and trigger points.132 Vecchiet et al.133 measured significantly lower pain thresholds with electrical stimulation over active trigger points in the muscles and the overlying cutaneous and subcutaneous tissues. With latent trigger points, the sensory changes did not involve the cutaneous and subcutaneous tissues.133,134 Sensitization in the central nervous system can occur both segmentally and multisegmentally at the spinal level and also involve changes in activity of higher brain centers. Clinical characteristics of central sensitization include spontaneous pain, allodynia and hyperalgesia, and widespread pain.129,130 Spontaneous pain is often related to increased background activity in nociceptive neurons in the spinal cord and higher brain centers. When background activity is great enough to elicit an action potential, pain may be sensed without specific visceral or peripheral nociception. The central mechanisms for allodynia, hyperalgesia, and widespread pain are discussed in more detail in the following text. The primary peripheral sensing apparatus in muscle involves group III (thinly myelinated, low-threshold fibers) and group IV (unmyelinated, high-threshold fibers) afferent nerve fibers. These fibers cause aching, cramping pain when stimulated with microneural techniques. The central projections of these fibers share several important characteristics especially when compared to cutaneous nociception. First, a reduced spatial resolution, because of a lower innervation density of muscle tissue, makes it harder to localize muscle pain. Second, convergence of sensory 1692

input from skin, muscle, periosteum, bone, and viscera into lamina IV and V of the dorsal horn onto wide dynamic range neurons can blur the identification of the origin of the pain. Third, divergence of sensory input into the dorsal horn–sustained noxious stimulation as demonstrated, for example, in group IV fibers in animal models can open previously ineffective synaptic connections in the dorsal horn such that these fibers begin to respond to lower levels of stimulation, leading to mechanical allodynia, hyperalgesia, and secondary hyperalgesia. Compared to normal muscle and muscle with latent trigger points, a muscle with active trigger points is more tender and mechanically sensitive, suggesting that peripheral nociceptors are already sensitized.135 Once sensitized, the group IV afferent nerve fibers fire at lower thresholds, even though they are normally high-threshold nociceptors. For example, in animal models, injection of BK into muscle causes the group IV afferents to respond to much lower levels of stimulation, suggesting they have become sensitized.136 Because muscle tenderness is mainly due to the sensitization of muscle nociceptors by BK, PGs, and 5-HT, peripheral sensitization by these substances presumably contributes to the tenderness seen in active trigger points and may contribute to the pain that individuals with active trigger points describe. Studies on the biochemical milieu of trigger points in the upper trapezius muscle have shown that active trigger points are associated with elevated levels of inflammatory mediators, neuropeptides, pro-inflammatory cytokines, and catecholamines.137,138 These chemicals can act to sensitize and activate local nociceptors. It is important to note that active trigger points are associated with elevated levels of these biochemicals compared to both normal muscle tissue and that with latent trigger points, which suggests that the presence of these biochemicals is related to the pain experience. Central sensitization is more readily induced as the activation threshold is lowered for peripheral muscle nociceptors. In animal models of pain, a nociceptive input from skeletal muscle is much more effective at inducing neuroplastic changes in the spinal cord than cutaneous input.3 Experimentally induced myositis in animal models causes a marked expansion of the response of second-order neurons beyond the muscle’s target area of the dorsal horn. Hoheisel et al.139 found that after a localized 1693

inflammatory reaction was created, noxious input from the gastrocsoleus muscle (L5 segment) also activated second-order neurons in the L3 segment. This segment would not ordinarily be activated by noxious stimulation of the gastrocsoleus in noninflamed muscle. This study demonstrated an expansion of the receptive field in the dorsal horn as a result of a central sensitization. The L3 dorsal horn neurons became hyperexcitable after continuous nociceptive input from the inflamed L5 muscle. The sensitized surrounding segments caused the L3 segment to respond to previously ineffective afferent input. This model of referred pain combines peripheral input and central processing and is known as the central hyperexcitability theory.140 Several supraspinal mechanisms contribute to referred pain or secondary hyperalgesia.4,5,141 Pain from myofascial trigger points is associated with increased activity in the somatosensory and limbic regions and suppressed hippocampal activity. The limbic regions of the brain are responsible for the emotional/affective component of pain, whereas the hippocampus modulates stress.5 Increased cortical and subcortical activity spurred by disinhibition can disrupt function in descending pain-modulating pathways, which may lower pain thresholds peripherally.142–144 Trigger points and myofascial pain are also associated with widespread microstructural changes concentrated in limbic system gray matter that may indicate damage.145 A recent study showed that disinhibition of the motor cortex, consisting of either decreased intracortical inhibition or increased intracortical facilitation, is a marker of myofascial pain.146 Until recently, pain has been considered primarily related to neuronal activity; however, recent work has uncovered the contribution of microglia to the pain experience.147–149 Microglia are not static cells; rather, they are capable of releasing a number of neuroexcitatory substances that modulate local neuronal activity.150 Studies by Chacur and colleagues have helped characterize the role of microglia in spinal sensitization.151 After experimentally induced myofascial inflammation, microglial cells evince morphologic changes both ipsilaterally and contralaterally to the inflamed tissue without activating the contralateral microglia cells to the point of inducing measurable effects of central sensitization. Inhibition of microglia through application of minocycline is sometimes effective at 1694

attenuating hypersensitivity in animals with muscle pain, which supports the role of microglia in mediating the pain experience.152 Expansion of the receptive field in the spinal cord with myositis-induced excitation is clinically relevant, helping to explain the unusual referral patterns seen in myofascial pain. For example, trigger points in the suboccipital muscles may refer to the frontal region of the head, and trigger points in the piriformis may cause pseudosciatica. Expansion of the receptive field may also explain the symptomatic hyperalgesia reported by many patients, as many of these neurons become hyperexcitable. It is likely that these myositis-induced changes in the spinal cord occur due to a rewiring of dorsal horn neurons in response to sustained peripheral drive from an irritable, sensitized muscle nociceptor, such as that found in an active trigger point.153 Visceral dysfunction can also manifest through central sensitization as trigger point development. For example, trigger points in the abdominal wall can be used for diagnostic purposes. Jarrell154 found that the presence or absence of a trigger point in the abdominal wall helps to determine whether there is evidence of current or previously treated visceral disease. The presence of an abdominal wall trigger point predicted evidence of visceral disease in 90% of subjects. However, the absence of a trigger point was associated with no visceral disease in 64% of the subjects.154,155 A cohort study of men with chronic pelvic pain syndrome found that abdominal pain or tenderness was present in 51% of patients, compared to only 7% of healthy controls.156 Trigger points may also be associated with joint dysfunction. Trigger points in the upper trapezius were found to correlate with cervical spine dysfunction at the C3 and C4 segmental levels, although a causal relationship was not established.157 A single spinal manipulation induced changes in pressure pain sensitivity in latent trigger points in the upper trapezius muscle.158 It is important to add that referred pain is not unique to muscle tissue or myofascial trigger points. All tissues, including fascia, intervertebral disks, internal organs, ligaments, and zygapophyseal joints are capable of referring pain.132,159–162 Referred pain patterns from cervical zygapophyseal joints are very similar to those of trigger points in cervical muscles.163 Clinically, referred pain phenomena can be rather 1695

confusing as patients frequently complain of pain in an area of the body where the pain did not originate.164,165 For instance, pain in the elbow region, often considered a local problem due to epicondylitis, may in fact be referred pain from shoulder muscles.166 Hsieh et al.167 demonstrated that inactivating trigger points in the infraspinatus muscle using dry needling inactivated trigger points in the anterior deltoid muscle. Similarly, pain in the region of the masseter muscle can be resolved by treating trigger points in the trapezius muscle.168 Headley169 suggested that trigger points in a particular muscle can inhibit other muscles especially in the area of referred pain. For example, trigger points in the infraspinatus muscles may weaken the extensor carpi radialis muscles.167,169 In other cases, muscle pain and trigger points may be secondary to other, nonmuscular disorders, such as internal organ, joint, or disk pathology. This finding underscores the necessity of an excellent and comprehensive differential diagnostic process to uncover the nuances of referred pain.170 Patients with osteoarthritis of the hip or knee joint were found to have significantly higher numbers of trigger points in muscles crossing these joints than healthy controls.171 The correlations between pathologic conditions and an increased number of trigger points may partially explain why localized painful conditions can become more widespread.23 There are several hypotheses of the causal relation between trigger points and central sensitization.130 Hoheisel and colleagues studied central sensitization in the dorsal horn through histologic, electrophysiologic, and behavioral studies.172 Experimentally induced fascial inflammation in animal models leads to an increase in input from the fascia to the dorsal horn, which may be due to the activation of ineffective or silent synapses. Increased input to the dorsal horn increases afferent bombardment and background activity leading to spinal sensitization. The synaptic changes observed at the dorsal horn after induced fascial inflammation make a clear connection between fascial dysfunction and central nervous system structure and function. The integrated trigger point hypothesis is a popular model, but it is not without flaws.27 Notably, it fails to account for trigger points observed with nonmusculoskeletal pathologies. The neurogenic hypothesis attempts 1696

to address the observation of trigger points in regions without local injury by suggesting a neurogenic incitement of trigger point formation after primary pathology, local or remote, within the common neurometric field.173 According to Srbely, trigger points do not simply perpetuate central sensitization but are its neurogenic manifestations.173 Central sensitization, spurred by the primary pathology, results in neurogenic inflammation and sensitization of peripheral nociceptors.174 These in turn may lead to the formation of the characteristic discrete tender nodule or trigger point.173 Hocking175,176 maintained that an upregulation of L- or Ntype voltage-dependent calcium channels and α1-adrenergic receptors combined with a downregulation of calcium-activated K+ channels would lead to an increase in the motor terminal cytosolic Ca2+ concentration. According to Hocking,175,176 sympathetic activity would facilitate these phenomena because α1-adrenergic receptors are linked to L-type voltagedependent calcium channels. Furthermore, the integrated trigger point hypothesis does not include other pertinent mechanisms, such as the role of reactive oxygen species (ROS).27,154,173,174 Recently, Jafri27 expanded the integrated trigger hypothesis by incorporating mechano-activation of ROS signaling to destabilized calcium signaling. Striated muscle generates ROS, especially superoxide that usually is produced by mitochondria. Under stressful or pathologic conditions, the enzyme xanthine oxidase and phospholipase A2-dependent processes have been shown to also produce ROS.177,178 During repetitive contractions, nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2), located within the sarcoplasmic reticulum, the sarcolemma, and the transverse tubules,179–181 is the major source of superoxide ROS.182 In patients with Duchenne muscular dystrophy, the mechano-activation of NOX2-dependent ROS production plays a significant role in the pathogenic calcium and ROS signaling. Jafri27 hypothesized that mechanical stress can trigger an excessive release of calcium in muscles through X-ROS signaling. According to Jafri,27 mechanical deformation of the microtubule network can activate NOX2, which would produce ROS. The ROS oxidizes ryanodine receptors leading to increases in Ca2+ release from the sarcoplasmic reticulum. The Ca2+ mobilization resulting from mechanical stretch through this pathway is 1697

referred to as X-ROS signaling. In skeletal muscles, X-ROS sensitizes Ca2+-permeable sarcolemmal transient receptor potential or TRP channels, which may be a source of nociceptive input and inflammatory pain.27,183 Activating the transient receptor potential vanilloid 1 (TRPV1) leads to a quick increase in intracellular Ca2+ concentrations.184,185 Jafri27 suggested that myofascial pain is likely due to a combined activation of several ligand-gated ion channels, including the TRPV1 receptor, other acidsensing ion channels (ASIC3), BK, and purinergic receptors, among others.

The Biochemical Milieu of Myofascial Trigger Points Until recently, myofascial pain was characterized primarily by a physical finding and symptom cluster without demonstrable pathology. Research in the upper trapezius muscle has characterized the unique biochemical milieu of myofascial trigger points and has even identified quantitative differences between active and latent trigger points.138,186 The presence and possible effects of these biochemicals are discussed in the following sections. It has not yet been determined whether the unique biochemical environment develops before and perhaps causes trigger points or is somehow a result of trigger point formation. Further study of the biochemical milieu of trigger points may not only lead to an improved biochemical characterization of trigger points but may also identify those who are at risk for developing persistent symptoms. Discovering if and which measurable substances are predictive of pain could lead to focused therapies in the future.

pH and Muscle Pain A previous study demonstrated a positive correlation between pain and local acidity.187 Sluka et al.91 demonstrated that an acidic milieu without muscle damage is sufficient to cause profound changes in the properties of the pain matrix such that alterations in pH would be sufficient to modify the threshold sensitivity of the nociceptor. An acidic pH stimulates the 1698

production of BK during local ischemia and inflammation; therefore, a local acidic milieu may explain some of the pain associated with an active trigger point. Mechanical hyperalgesia is a hallmark of a trigger point; however, ongoing nociceptive activity is not necessary to cause mechanical hyperalgesia. In a rat model, repeated injections of acidic saline boluses into one gastrocnemius muscle produced bilateral, longlasting mechanical hyperalgesia of the paws.91 Furthermore, the study showed that the persistent hyperalgesia does not require muscle tissue damage nor continued nociceptive input from the injection site, demonstrating that secondary mechanical hyperalgesia may be maintained by neuroplastic changes in the central nervous system, such as dorsal horn and thalamic neurons.91 Specific ASICs on muscle nociceptors can be sensitized and activated by acidic pH. For example, ASIC3 knockout mice do not develop hyperalgesia following repeated bolus injections of acidic saline.92 Hong et al.188,189 suggest that an integrative mechanism at the spinal cord level in response to sensitized nociceptors plays a role in the development of active trigger points and should be considered in any pathogenetic hypothesis. In an expansion of Simons’s integrated hypothesis, Gerwin et al.26 proposed that the acidic pH may also modulate the motor endplate by inhibiting AChE. This would result in increased concentration of ACh at the synaptic cleft, promoting sarcomere contraction and formation of the taut band characteristic of trigger points.26

Neuropeptides, Inflammatory Mediators, and Tissue Injury and Pain Significantly elevated levels of SP and CGRP are found in the vicinity of active trigger points. The orthodromic and antidromic release of these substances is greatly increased in response to nociceptor activation, for example, by protons and BK binding to their matched receptors.190 This may lead to neuroplastic changes in the dorsal horn and profound changes in neuronal activity and the perception of pain. In the studies by Shah et al.,137,138 SP and CGRP were the only two analytes at active trigger points with concentrations significantly below their original baselines in the 1699

recovery period following a local twitch response. These biochemical changes correspond with the commonly observed decrease in pain and local tenderness after the inactivation of a trigger point by dry needling (Fig. 35.5).191

FIGURE 35.5 Concentrations of calcitonin gene-related peptide and substance P across time. A local twitch response was elicited at 5 minutes.

SP causes mast cell degranulation with the subsequent release of histamine, 5-HT, and upregulation of both pro-inflammatory cytokines, including TNF-α and IL-6, and anti-inflammatory cytokines, including IL4 and IL-10. TNF-α is the only cytokine restored in the mast cell and is released immediately following mast cell degranulation.192,193 The finding of elevated levels of 5-HT, BK, norepinephrine, and pro-inflammatory cytokines in active trigger points is consistent with biochemical pathways involved in tissue injury and inflammation.137,138

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Catecholamines and the Autonomic Nervous System Significantly elevated levels of 5-HT and norepinephrine are found in the vicinity of active trigger points, supporting the effect of the elevated TNFα. The increased levels of norepinephrine may be associated with increased sympathetic activity in the motor endplate region of trigger points. In one study, sympathetic activity was recorded from rabbit myofascial trigger spots. Intra-arterial injection of phentolamine, an αadrenergic antagonist, decreased the spontaneous electrical activity from a locus of a myofascial trigger spot in rabbit skeletal muscle.79 Conversely, the nAChR antagonist curare had no effect on the spontaneous electrical activity. Elevated levels of norepinephrine in the local milieu of active trigger points suggest that the autonomic nervous system is involved in the pathogenesis of spontaneously painful trigger points. A study by Ge et al.53 provides evidence of sympathetic facilitation of mechanical sensitization of trigger points. The presence of α- and β-adrenergic receptors at the endplate may provide a possible mechanism for autonomic interaction,26,84 for example, stimulation of the α- and β-adrenergic receptors stimulated the release of ACh in the phrenic nerve of rodents.194

Cytokines and Pain A unique cascade of cytokines is released following tissue injury and inflammation. For example, BK stimulates the release of TNF-α, which leads to the release of IL-1β and IL-6. These two cytokines stimulate the cyclooxygenase (COX) nociceptive pathway, which leads to the production of PGs.195,196 TNF-α also stimulates a separate nociceptive pathway via the release of IL-8, which mediates sympathetic pain by stimulating the liberation of sympathetic amines.197 TNF-α, IL-1β, IL-6, and IL-8 have been found at elevated levels at active trigger points in the upper trapezius.138,186 TNF-α produces a timeand dose-dependent muscle hyperalgesia within several hours after injection into the gastrocnemius or biceps brachii of a rat. The hyperalgesia is completely reversed by systemic treatment with the nonopioid analgesic metamizol.198 Furthermore, TNF-α does not cause

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histopathologic tissue damage or motor dysfunction. One day after injection of TNF-α, elevated levels of CGRP, nerve growth factor, and prostaglandin E2 are found in the muscle. According to Schafers et al.,198 TNF-α and other pro-inflammatory cytokines such as IL-1β may play a role in the development of muscle hyperalgesia, and the targeting of proinflammatory cytokines might be beneficial for the treatment of muscle pain syndromes. In rat model studies, Loram et al.199 measured the tissue and plasma levels of cytokines following injection of carrageenan into the hind paw compared with intramuscular injection into the gastrocnemius muscle. They demonstrated, for the first time, that the initiation of primary muscle hyperalgesia is not associated with elevated levels in local muscle of TNFα, IL-1β, or IL-6.199 Loram et al.199–201 also showed that IL-1β and IL-6 are elevated at a time interval when there is no hyperalgesia. One possible explanation, they suggest, is that elevated intramuscular levels of IL-1β and IL-6 induce central sensitization but do not contribute to the initiation of hyperalgesia.199 Cytokines that lead to PG release via the COX pathway have been targeted for pharmacologic intervention because of their roles in the inflammatory response.195,196 IL-1β is the major cytokine stimulus for central COX-2 expression during inflammation. Loram et al.199 found that IL-1β was the only cytokine that reached a higher concentration in the muscle compared to the hind paw after carrageenan injection in the rat. Furthermore, IL-1β was significantly elevated 24 hours after inducing muscle inflammation at a time when secondary hyperalgesia was induced.199 IL-1β also stimulates IL-6 production during muscle injury. Together, both cytokines are necessary for repair and regeneration of muscle.202–204 In light of the importance of cytokines to muscle regeneration, Loram et al.199 suggest that pharmacologic interventions preferentially target action of IL-1β and not IL-6 in order to reduce secondary muscle hyperalgesia and still conserve the cytokines’ regenerative qualities. Moreover, which cytokines and when to target them may depend on the time course of the muscle injury and inflammatory response. Whereas some groups have found that TNF-α produces a time- and dose-dependent 1702

muscle hyperalgesia within several hours after injection into rat muscle, others have found that injection of TNF-α into a rat’s gastrocnemius muscle does not excite but rather has a short-term desensitizing action on group IV muscle afferents.205 The data suggest that TNF-α has a dual action when released intramuscularly. Initially, it suppresses neuronal excitability, but in a later stage, it contributes to neuronal hyperexcitability.205 Therefore, the elevated levels of TNF-α, IL-1β, and IL-6 found in active trigger points may mediate secondary hyperalgesia and central sensitization via the COX pathway. A second distinct nociceptive pathway moderates the inflammatory hyper-nociception following tissue injury. Rat cytokine-induced neutrophil chemo-attractant 1 (CINC-1) and its homolog in humans, IL-8, coordinate the sympathetic components of hyper-nociception. Loram et al.199 demonstrated that of the four cytokines—TNF-α, IL-1β, IL-6, and CINC-1 —measured in muscle after carrageenan injection, only levels of CINC-1 were elevated at the time of primary hyperalgesia.199 Moreover, CINC-1 and IL-8 induce a dose- and time-dependent mechanical hypernociception. Therefore, the elevated levels of IL-8 found in active myofascial trigger points may mediate inflammatory hyper-nociception, muscle tenderness, and pain via this pathway. Furthermore, this pathway is inhibited by β-adrenergic receptor antagonists, although not COX antagonists.196

Clinical Management TRIGGER POINT DIAGNOSIS The literature on the clinical management of patients with myofascial pain is scattered over multiple specialties and disciplines, including algology, physiatry, dentistry, otolaryngology, urology, neurology, osteopathy, orthopedics, gynecology, physical therapy, chiropractic, acupuncture, and massage therapy, among others. No medical specialty has claimed muscle as its organ of focus; therefore, the term myofascial pain may have different meanings among different disciplines, making understanding across disciplines challenging. In dentistry, for example, “myofascial pain dysfunction syndrome” is commonly used for nonspecific muscle pain 1703

with or without limited mouth opening.206,207 The finding of trigger points should not preclude other aspects of the differential diagnosis, including neurologic examinations, biomechanical assessments of posture and movement patterns, and assessments of other possible contributing factors. Trigger points may elicit symptoms similar to those of other conditions. Some trigger point–referred patterns are very similar to radicular pain patterns. For example, referred pain patterns of trigger points in the teres minor muscle or gluteus minimus muscle resemble a C8 or L5 radiculopathy, respectively.208,209 However, the presence of myofascial trigger points does not rule out a radiculopathy and vice versa. Trigger points may also be associated with lumbar disk lesions or contribute to symptoms of thoracic outlet syndrome.210–212 Even in fibromyalgia, which is considered a central sensitization disorder, myofascial trigger points play an important role in the perception of pain and sensitization.213–215 As part of the diagnostic process, clinicians should consider other diagnoses, which may feature widespread pain, including but not limited to hypothyroidism; systemic lupus erythematosus; Lyme disease; babesiosis; ehrlichiosis; Candida albicans infections; myoadenylate deaminase deficiency; herpes zoster; complex regional pain syndrome; hypoglycemia; parasitic diseases such as fascioliasis, amoebiasis, and giardia; systemic side effects of medications including any of the statin drugs or even glucosamine sulfate; and metabolic or nutritional deficiencies or insufficiencies of vitamin B12, vitamin D, and ferritin.216 Having patients complete standardized pain questionnaires at the time of the initial examination allows for objective outcome measurements. Because individual clinicians may not be familiar with discipline-specific differential diagnoses outside their own specialty, a multidisciplinary approach to assessment and treatment is preferred especially for more complex patients.217 However, the underlying mechanisms and principles of muscle dysfunction, described earlier in this chapter, apply to all disciplines. A significant problem in the myofascial pain literature is the inconsistent use of criteria to identify trigger points.218 Palpation is the criterion standard for identifying myofascial trigger points in spite of the lack of research-validated definitional criteria. Simons et al.19 defined 1704

empirically derived criteria, which have been applied to a number of interrater and intrarater reliability studies.219–231 A recent Delphi study of 60 experts from 12 countries revealed that more than 70% of the experts considered only two palpatory findings and one symptom as essential criteria for the diagnosis of myofascial pain, namely, a taut band, a hypersensitive spot, and referred pain.232 The presence of a taut band and spot tenderness has been shown to be a reliable indicator of myofascial trigger points in one comprehensive study, although in a more recent study, referred pain and a jump sign were the most reliable indicators.219,221 The local twitch response is more difficult to elicit manually and has not been shown to be a reliable feature of trigger points. A systematic review in 2017 found that the overall interrater reliability of palpation for myofascial trigger points was moderate.233 Experienced and inexperienced clinicians reached different levels of agreement when identifying trigger points.234,235 Occasionally, the concept of myofascial pain is challenged because acceptable interrater reliability is only achieved with experienced and well-trained clinicians.234,236 However, the fact that trigger point palpation has to be learned is no different than most other clinical skills and procedures. Palpation and, more specifically, trigger point palpation is not taught in the vast majority of medical, physical therapy, and chiropractic schools, and it should come as no surprise that clinicians do not necessarily master trigger point palpation without specific training.237 It is encouraging that several recent studies indicate that there has been much progress in the quality of myofascial pain studies, but there is always a need for better and higher quality research.238,239

PHYSICAL EXAMINATION AND DIAGNOSIS The physical examination of myofascial trigger points is performed with either a flat or pincer palpation technique. With the flat palpation technique, the taut band and trigger point are compressed in between a finger or thumb against the underlying tissue or bone (Fig. 35.6). With the pincer palpation technique, the taut band and trigger point are held in between the clinician’s fingers and thumb (Fig. 35.7). The initial palpation focuses on the presence of taut bands as, by definition, trigger points are 1705

always located within a band of contracted muscle fibers. Palpation for trigger points is performed perpendicular to the fiber direction, which requires good anatomical knowledge of muscles and their fiber directions. Whether a muscle should be shortened, lengthened, or kept in a resting position depends entirely on the individual muscle, the tension in connective tissues and fascia, and available range of motion. The muscle needs to be placed in a position where the taut band can optimally be palpated. For patients with very tight and restricted muscles, the muscle may need to be placed in a relaxed position, whereas in hypermobile patients, the muscle may need to be prestretched to facilitate identification of taut bands.28

FIGURE 35.6 Flat palpation technique.

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FIGURE 35.7 Pincer palpation technique.

Familiarity with referred pain patterns of trigger points is essential in guiding clinicians to clinically relevant muscles and trigger points. Recent studies have established new and confirmed previously suggested referred pain patterns, especially in the head and neck region.166,240–246 Prolonged pressure on trigger points for as long as 10 to 15 seconds may elicit referred pain patterns, and the patient’s familiar pain complaint. Local twitch responses may be elicited by strumming the taut band, but this has little utility as part of the diagnostic process. The minimum criteria for identification of an active trigger point are the presence of a taut band with exquisite spot tenderness and patient-recognized pain. The physical examination for myofascial trigger points should be a standard component of the diagnostic process but does not preclude any other part of the standard examination process. In addition to trigger points, there are many other possible sources of nociception and pain. A detailed history is critical. There are also several predisposing or perpetuating factors that need to be assessed in addition to possible medical diagnoses.170 Mechanical perpetuating factors are relatively easy to identify by clinicians across disciplines and include forward head posture, which frequently contributes to migraines or tension-type headaches, neck pain, and upper thoracic pain,247–249 decreased spinal mobility, structural misalignments, such as leg length discrepancies or pelvic torsions, or systemic or local hypermobility.158,250–252 The combination of static and 1707

awkward postures, excessive force, and repetitive tasks predisposes a patient to the development of trigger points.107,108 Ergonomic measures often play a vital role in correction and prevention of myofascial pain problems.253 Psychological arousal has a direct impact on the electrical activity of myofascial trigger points, although autogenic relaxation reduces the electrical activity.254–256 Whether specific regions of the brain, such as the anterior cingulate gyrus and periaqueductal gray, which have been linked to nociceptive input from muscles and to depression, anxiety, and anger, can explain at least part of the association of psychological factors and trigger points remains to be seen.4,257 In 2013, Gerber et al.170 found that patients with cervical pain secondary to active myofascial trigger points had significantly poorer health status and quality of life compared to individuals with latent or no trigger points. Their poor health status was characterized by higher rates of depression, fatigue, tension, confusion, mood disturbances, and sleep disruption as well as greater disability. Adequate treatment of myofascial pain involves consideration not only of the physiologic cause of pain but also of the psychosocial deficiencies patients may experience. Depending on the severity of these symptoms, it may be prudent to include psychologists or social workers in a patient’s long-term treatment plan. Any nutritional or metabolic condition that interferes with the energy supply of muscle tissue can contribute to the development of myofascial trigger points.216 Laboratory levels can be within the “normal” range yet be insufficient for a given individual. The connection between the insufficiency and an individual’s pain may be difficult to appreciate, but it is no less important than in individuals with “abnormal” results. Empirically, common nutritional and metabolic deficiencies or insufficiencies include vitamins B1, B6, B12, and D; iron, magnesium, and zinc insufficiency states; and thyroid deficiency states, among others. The importance of metabolic and nutritional perpetuating factors is illustrated for vitamin D. Vitamin D deficiency is commonly observed with chronic, nonspecific musculoskeletal pain.258 Nearly 90% of 150 subjects with musculoskeletal pain had vitamin D levels less than 20 ng/mL and 28% had less than 8 1708

ng/mL, where levels above 30 ng/mL are considered optimal. Vitamin D deficiency in adults is defined as serum 25(OH)D levels below 20 ng/mL and vitamin D insufficiency as 25(OH)D levels between 20 and 30 ng/mL.259,260 Vitamin D deficiencies are endemic in Northern Europe and America and are associated with muscle weakness, myofibrillar protein degradation, reduced muscle mass, osteoporosis, and decreased functional ability.261–264 Low levels of magnesium and 25(OH)D have been linked not only to myofascial pain but also to cancer, adenomatous colon polyps, and tendon ruptures.265 Although palpation is truly the gold standard for trigger point identification, meaningful palpation takes time to learn and perfect.237 This has driven researchers to seek ways to identify and characterize trigger points using more objective and quantitative techniques. Magnetic resonance and ultrasound elastography are increasingly used in research but are not yet common in clinical practice.40,41,266 Piezoelectric and electrohydraulic shockwave emitters are common in Germany for the identification and treatment of trigger points and their specific referred pain patterns.267,268 Both types of shockwave emitters are able to reproduce patients’ familiar referred pain patterns. Although endplate noise was found to be characteristic of trigger points, in clinical practice, there is no advantage to using electromyography for the identification of trigger points.269 Recent advances in ultrasound technology have made it an especially appealing tool to try to bring into the clinical assessment of myofascial pain secondary to trigger points. Studies have focused on three modes of ultrasound imaging: two-dimensional (2D) grayscale (B-mode), Doppler, and vibration sonoelastography.135,266,270–272 Under 2D grayscale ultrasound, healthy muscle appears uniform in fiber orientation and echotexture. Active and latent trigger points both appear as hypoechoic ellipses or bands, although no significant differences have been noted between them in terms of echogenicity or echotexture.266,273 The underlying reason for the hypoechoic appearance is not known at this time. Color Doppler imaging of blood vessels in the vicinity of trigger points shows that although both active and latent trigger points have similar unique waveforms indicative of retrograde diastolic flow relative to 1709

normal muscle, more active than latent trigger points show abnormality (69% of active vs. 16.7% of latent).45,273 Spectral Doppler imaging illustrates that both kinds of trigger points also have high pulsatile flow more frequently than normal muscle, further indicating that trigger points are associated with blood flow abnormality.44,45,273 Under vibration sonoelastography, trigger points appear as regions of increased tissue stiffness corresponding to the localized hypoechoic regions in the 2D grayscale imaging. Although these results are promising, ultrasound is not a substitute for a comprehensive physical examination including palpation; however, it has the potential to be a useful supplemental clinical tool for the assessment of the heterogeneity and soft tissue properties of muscle and determination of treatment outcomes.45

TREATMENT OPTIONS One of the first decisions to make after the initial examination is whether the patient’s pain complaints have a significant myofascial component. Patients with chronic pain problems may present with a combination of possible contributing factors. If metabolic or nutritional insufficiencies are found, it is unlikely that therapy will be successful until such insufficiencies are adequately addressed. The choice of treatment modalities is partially based on a clinician’s bias, preferences, experience, and skills. A dentist treating a patient with facial pain and trigger points in the masseter muscle may decide to improve the patient’s occlusion assuming that the muscle pain is secondary to the malocclusion. An orthopedic surgeon may manage a patient’s complaint of radiating pain down the leg with epidural injections to reduce radicular pain, whereas a physician familiar with referred pain patterns of myofascial trigger points may decide to treat trigger points in the gluteus medius muscle with trigger point injections or myofascial release techniques. Many patients with chronic myofascial pain may benefit from a comprehensive pharmacologic management strategy, which may include nonsteroidal antiinflammatories, opiates, antidepressants, and anticonvulsants, although these are not specific for myofascial pain.274

Patient Education 1710

Following the initial examination, patients need to be educated about the nature and complexity of their pain. Studies have shown that patients with chronic pain gain understanding and insight when the clinician explains the principles of peripheral and central sensitization rather than focuses on anatomical concepts such as spinal mechanics.275–277 Excellent patient education can reduce disability and assist patients in making appropriate choices, overcoming counterproductive beliefs, and modifying dysfunctional behaviors by increasing physical activity and selfefficacy.278,279 If the patient’s pain complaint could easily be provoked by pressure on certain trigger points, it is likely that trigger point therapy will make significant improvements. However, clinicians should be cautious in promising complete relief, especially for chronic pain conditions with multiple interacting aspects.

Physical Therapy The role of physical therapy in pain management centers is often limited to instructing patients in proper stretching and strengthening exercises, stabilization programs, and posture corrections as well as providing limited manual therapy interventions. Relatively few physical therapists receive adequate training in pain management, and physical therapists are poorly represented in professional pain management associations.280 Few physical therapy schools have adopted a specific pain science curriculum,281,282 which may explain why as many as 96% of orthopedic physical therapists preferred not to work with patients with chronic pain.283 Patients need to learn self-pacing and setting appropriate and achievable goals, including physical, psychological, functional, and social goals.284 An important variable is the degree of a patient’s belief in their self-efficacy, which is defined as “the belief in one’s capabilities to organize and execute the sources of action required to manage prospective situations.”278,285,286 Patients with a weak belief in their self-efficacy tend to avoid difficult tasks, have low aspirations, maintain a self-diagnostic focus, and emphasize personal deficiencies and adverse outcomes. They are more prone to depression and stress and give up quickly. Patients with a strong belief in their self-efficacy are more likely to set challenging goals, consider difficult tasks as challenges rather than as threats, and 1711

maintain a task-diagnostic focus. They usually are not depressed and increase their effort when faced with difficulties.

Needling Therapies Invasive trigger point therapy usually involves either trigger point injections or dry needling. As Steinbrocker287 already suggested in 1944, the mechanical stimulation of trigger points is an important mechanism to explain the effects of needling therapies. Trigger point injections are usually performed by medical doctors and their professional support staff. A growing number of physical therapists and physicians around the world utilize trigger point dry needling.191 The first comprehensive paper about dry needling was published in 1979 and reported that dry needling of various structures, including trigger points, ligaments, and fascia, caused immediate analgesia in almost 87% of the needle sites.288 Lewit288 referred to the immediate reduction of pain as “the needle effect.” In 1980, a prospective dry needling study of injured workers with low back pain showed that dry needling was an effective treatment for low back pain.289 A Cochrane review supported the use of dry needling as an adjunct for the treatment of patients with chronic low back pain.290 Trigger point dry needling consists of superficial and deep dry needling based on the depth of needling.191 The technique used with deep dry needling is similar to the technique of trigger point injections and usually aims to elicit local twitch responses (Fig. 35.8).

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FIGURE 35.8 Trigger point dry needling of the trapezius muscle.

The mechanisms and effectiveness of deep dry needling are comparable to trigger point injections.191,291–294 Earlier studies suggested that dry needling would cause more post-needling soreness, but there are no differences between injections and dry needling using solid filament needles. Post-needling soreness occurs in most patients and can vary in duration from just a few minutes to several 2 days.295 Applying a cold application, using manual compression techniques, applying transcutaneous electrical stimulation, or performing low load exercises following needling procedures does reduce the post-needling soreness in the short term.296–299 Psychological factors do impact the degree of postneedling soreness.295,300 Vasovagal reactions can occur with any needling procedure, but they are relatively rare. To avoid unnecessary complications from possible vasovagal reactions, patients are needled preferably while lying down on a treatment table. A local twitch response is an involuntary spinal cord reflex contraction of muscle fibers within a taut band, which can be elicited by manually strumming or needling of a taut band. Local twitch responses can be observed visually, recorded electromyographically, or visualized with diagnostic ultrasound.301 When a trigger point is needled with a monopolar Teflon-coated electromyography needle, local twitch responses appear as high-amplitude polyphasic discharges.302 Eliciting local twitch responses is helpful when using deep dry needling in clinical practice not only to accomplish optimal treatment results but also to confirm that the needle is placed into a taut band, which is critically important when needling close to peripheral nerves or internal organs, such as the lungs.188,291,303,304 In a study of dry needling for low back pain, Koppenhaver et al.305 noted that subjects who experienced a local twitch response reported a greater improvement in the function of the lumbar multifidus muscle compared to those who did not experience a twitch response; however, the difference was of short duration. Eliciting a local twitch response had no effect on levels of disability, nociceptive activity, or pain intensity.305 Nevertheless, eliciting local twitch responses does normalize the chemical environment of active trigger points.138,186,304 In clinical practice, patients commonly 1713

report never having experienced local twitch responses when they were treated with trigger point injections previously. With superficial dry needling, a solid filament needle is placed into the tissues overlying active trigger points at a depth of approximately 5 to 10 mm for 30 seconds. If there is residual pain, the needle is inserted for another 2 or 3 minutes.306,307 Local twitch responses are usually absent with superficial dry needling. The degree of available endogenous opioid peptide antagonists may determine how intensely a patient responds to the therapy. So-called weak responders may have excessive amounts of endogenous opioid peptide antagonists. A rodent model has shown that mice with deficient opioid peptide receptors did not respond well to needle-evoked nerve stimulation.308 The efficacy of dry needling may be monitored visually with ultrasound imaging. A 2015 study sought to characterize changes in ultrasound images taken before and after treatment while also recording changes in trigger point status from active to latent and resolution of pain symptoms.45 Participants with at least one active trigger point received a 3-week course of dry needling at their most active trigger point. Grayscale 2D B-mode and color Doppler ultrasound images were taken at the trigger point and palpably normal muscle tissue at baseline and posttreatment. A significant reduction in the heterogeneity of muscle stiffness was observed at those trigger points that responded to treatment.45 However, although ultrasound is a promising tool to objectively evaluate trigger points before and after treatment, further research is needed to improve reproducibility and standardize imaging methods and quantitative measures before it can be used reliably for diagnosis. Trigger point injections are administered with a variety of injectables, including procaine and lidocaine, steroids, and vitamin B12 (Fig. 35.9). Travell preferred procaine hydrochloride, which is no longer available everywhere.16,309 The current recommendation is to use 0.25% lidocaine, which was found to be more effective than stronger concentrations.310,311 Other anesthetics used with trigger point injections include ropivacaine, levobupivacaine, and mepivacaine, among others.312,313 Trigger point injections with the 5-HT antagonist tropisetron were found to be more effective than injections with lidocaine solution, but injectable 5-HT 1714

antagonists are not available in all countries.314,315 Although widely used, there is no scientific evidence for injections with steroids, vitamin B12, nonsteroidal anti-inflammatories, or bee venom. Bee venom has some potential based on its anti-nociceptive and anti-inflammatory effects through activation of brainstem catecholaminergic neurons and activation of the α2 adrenergic and serotonergic pathways of the descending inhibitory system.316–318 Melitin, an active ingredient of bee venom, can suppress lipopolysaccharide-induced nitric oxide and the transcription of COX-2 genes and pro-inflammatory cytokines, including TNF-α and IL-1β in microglia.319,320 Injections of bee venom into specific acupuncture points in several animal and human studies of knee arthritis have been shown to be beneficial and reduced pain levels significantly, but there are no studies that demonstrate the effectiveness of trigger point injections with bee venom.317,321,322

FIGURE 35.9 Trigger point injection to the frontalis muscle.

There is a growing body of literature supporting the use of botulinum toxin in the treatment of myofascial trigger points, although this remains a controversial issue. Many botulinum toxin studies fail to demonstrate superiority of botulinum toxin over placebo.323 However, clinicians familiar with myofascial trigger points support its use based on the demonstrated mechanisms of botulinum toxin and empirical 1715

evidence.324,325 Indeed, several studies have shown significant benefit of botulinum toxin injections in the treatment of myofascial trigger points and various pain states including migraine, tension-type headache, low back pain, and phantom pain.326–335 Potential problems with these studies relate to the use of different dosages, varying injection sites, and the degree of familiarity with myofascial trigger points.336 Botulinum toxin prevents the release of ACh from the presynpatic nerve terminal.337 ACh is released in response to evoked stimulation of the nerve or spontaneously without axonal nerve activation.87,338,339 Botulinum toxin also has an antinociceptive effect, which in part may be due to its ability to also block the release of CGRP from the nerve terminal.340–342 Extensive training is required to gain the necessary palpation skills and kinesthetic awareness, without which trigger point needling would become a random process. Anatomical knowledge is required prior to developing the sensory motor skills needed to visualize the tip of the needle and the pathway the needle follows inside patients’ bodies.191 Clinicians should be able to visualize a three-dimensional image of the exact location and depth of the trigger point and accurately elicit local twitch responses. The needle should not be used as a search tool except in muscles that cannot be palpated directly, such as the subscapularis or lateral pterygoid muscles.343,344 Trained clinicians can almost always identify clinically relevant trigger points, except in obese patients where certain muscles may not be accessible to palpation.191 Myofascial trigger point injections were the second most common procedure after epidural injections in a study of Canadian pain anesthesiologists, although the art of trigger point injections and trigger point palpation is not usually covered in medical schools, and there are no formal postgraduate training programs in Canada.345 Dry needling and injections can eliminate or reduce trigger point pain often in just a few sessions with a skilled clinician, allowing the patient to be more successful in the conditioning phase of the rehabilitation program.51,131,346 There are many clinical outcome studies confirming that needling therapies are effective in inactivating trigger points, reducing pain levels, and improving function.212,239,293,347–358 In spite of a rapidly increasing number of clinical outcome studies, the exact mechanisms of trigger point injections and dry needling are still not 1716

known.191 Deep dry needling and trigger point injections may destroy motor endplates and cause distal axon denervations,359 which may trigger changes in the endplate cholinesterase and ACh receptors as part of the normal muscle regeneration process.360,361 In a rodent study, dry needling caused a significant decrease of spontaneous electrical activity and ACh and AChR levels and a significant increase of AChE.362 It is likely that trigger point needling involves central pain mechanisms, including the limbic system, the subcortical gray structures, and the descending inhibitory system. Most deep needling procedures are painful, possibly stretch fibroblasts in connective tissues, and activate the enkephalinergic, serotonergic, and noradrenergic inhibitory systems associated with Aδ fibers through segmental inhibition.363–365 Superficial dry needling is often explained in a similar fashion but is a painless procedure that would not activate Aδ fibers unless the needle is rotated after insertion.191,306 Aδ nerve fibers are only activated by nociceptive mechanical stimulation for type I high-threshold Aδ fibers or by cold stimuli for type II Aδ fibers. It is conceivable that the light stimulus of superficial dry needling activates mechanoreceptors coupled to slowconducting unmyelinated C-fiber afferents, stimulating the anterior cingulate cortex with emotional and hormonal reactions representing a sense of progress, reduction of pain, and well-being.366–368

NONINVASIVE TREATMENT OPTIONS Rickards369 and Fernández-de-las-Peñas et al.370 published comprehensive systematic reviews of noninvasive treatment options for myofascial pain. A wide variety of manual therapies are being used in the treatment of myofascial trigger points, such as spray and stretch, trigger point compression, muscle energy techniques, and massage.371–375 There is some evidence of the short-term effectiveness of manual therapies, but no conclusions can be made in relation to the medium- and long-term effectiveness.370 Fernández-de-las-Peñas et al.376 demonstrated that trigger point compression and transverse friction massage were equally effective in treating trigger points with a significant reduction in visual analogue scores and significant increase in the pressure pain threshold. Hou et al.377 showed that trigger point compression reduced pain levels within minutes. 1717

Several modalities have been applied to trigger points, such as laser, ultrasound, and electrotherapy. Laser proved to be an effective modality in most trials.378–381 Therapeutic ultrasound has mixed reviews. Srbely and Dickey382 demonstrated a short-term decrease of the sensitivity of trigger points following ultrasound. Another study of high-power static ultrasound was more beneficial than more traditionally applied ultrasound, whereas two other papers did not show any benefit of ultrasound.383–386 Transcutaneous electrical stimulation is the most studied electrotherapy modality, but it remains difficult to draw any conclusions beyond shortterm effects.299,387–389 A prospective, randomized study of extracorporeal shockwave therapy in the treatment of athletes with acute or chronic shoulder pain showed significantly improved isokinetic force production, a reduction in pain, and overall performance.390

Summary Myofascial trigger points are a very common cause of clinically observed local muscle pain, tenderness, and referred pain in patients with acute and chronic pain. However, they are also a common physical finding in asymptomatic individuals. This dichotomy challenges and behooves pain management practitioners to learn how to palpate the soft tissue and distinguish active from latent myofascial trigger points. Making this distinction is critical in order to adequately identify and treat a myofascial component of pain. Several independent and emerging lines of scientific inquiry, including histologic, neurophysiologic, biochemical, and somatosensory research into the nature of myofascial trigger points have revealed objective abnormalities. These findings suggest that myofascial pain consists of both motor and sensory abnormalities involving the peripheral and central nervous systems. Accordingly, active myofascial trigger points may be viewed as part of a complex series of changes in the peripheral tissue and central nervous system that occur with central sensitization, characteristic of a form of neuromuscular dysfunction. From this perspective, future clinical research studies should focus on identifying the mechanisms responsible for the pathogenesis, amplification, and perpetuation of myofascial pain syndrome. Successful 1718

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for myofascial pain syndrome management. Methods Find Exp Clin Pharmacol 2007;29(5):353–357. Ettlin T. Trigger point injection treatment with the 5-HT3 receptor antagonist tropisetron in patients with late whiplash-associated disorder. First results of a multiple case study. Scand J Rheumatol Suppl 2004;(119):49–50. Müller W, Stratz T. Local treatment of tendinopathies and myofascial pain syndromes with the 5-HT3 receptor antagonist tropisetron. Scand J Rheumatol Suppl 2004;119:44–48. Kim HW, Kwon YB, Han HJ, et al. Antinociceptive mechanisms associated with diluted bee venom acupuncture (apipuncture) in the rat formalin test: involvement of descending adrenergic and serotonergic pathways. Pharmacol Res 2005;51(2):183–188. Kwon YB, Kim JH, Yoon JH, et al. The analgesic efficacy of bee venom acupuncture for knee osteoarthritis: a comparative study with needle acupuncture. Am J Chin Med 2001;29(2):187– 199. Kwon YB, Lee JD, Lee HJ, et al. Bee venom injection into an acupuncture point reduces arthritis associated edema and nociceptive responses. Pain 2001;90(3):271–280. Son DJ, Kang J, Kim TJ, et al. Melittin, a major bioactive component of bee venom toxin, inhibits PDGF receptor beta-tyrosine phosphorylation and downstream intracellular signal transduction in rat aortic vascular smooth muscle cells. J Toxicol Environ Health A 2007;70(15–16):1350–1355. Han S, Lee K, Yeo J, et al. Effect of honey bee venom on microglial cells nitric oxide and tumor necrosis factor-alpha production stimulated by LPS. J Ethnopharmacol 2007;111(1):176–181. Lee JD, Park HJ, Chae Y, et al. An overview of bee venom acupuncture in the treatment of arthritis. Evid Based Complement Alternat Med 2005;2(1):79–84. Son DJ, Lee JW, Lee YH, et al. Therapeutic application of anti-arthritis, pain-releasing, and anti-cancer effects of bee venom and its constituent compounds. Pharmacol Ther 2007;115(2):246–270. Ho KY, Tan KH. Botulinum toxin A for myofascial trigger point injection: a qualitative systematic review. Eur J Pain 2007;11(5):519–527. Silberstein N. More than a cosmetic fix. Combined with physical therapy, botulinum toxin type A can help provide relief for chronic muscle pain. Rehab Manag 2007;20(1):44, 46. Ranoux D, Gury C, Fondarai J, et al. Respective potencies of Botox and Dysport: a double blind, randomised, crossover study in cervical dystonia. J Neurol Neurosurg Psychiatry 2002;72(4):459–462. Dodick DW, Mauskop A, Elkind AH, et al. Botulinum toxin type A for the prophylaxis of chronic daily headache: subgroup analysis of patients not receiving other prophylactic medications: a randomized double-blind, placebo-controlled study. Headache 2005;45(4):315–324. Benecke R, Heinze A, Reichel G, et al. Botulinum type A toxin complex for the relief of upper back myofascial pain syndrome: how do fixed-location injections compare with trigger point-focused injections? Pain Med 2011;12(11):1607–1614. Göbel H. Botulinum toxin in migraine prophylaxis. J Neurol 2004;251(suppl 1):I8–I11. Göbel H, Heinze A, Heinze-Kuhn K, et al. Evidence-based medicine: botulinum toxin A in migraine and tension-type headache. J Neurol 2001;248(suppl 1):34–38. Göbel H, Heinze A, Reichel G, et al. Efficacy and safety of a single botulinum type A toxin complex treatment (Dysport) for the relief of upper back myofascial pain syndrome: results from a randomized double-blind placebo-controlled multicentre study. Pain 2006;125(1– 2):82–88. Silberstein SD, Göbel H, Jensen R, et al. Botulinum toxin type A in the prophylactic treatment

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of chronic tension-type headache: a multicentre, double-blind, randomized, placebocontrolled, parallel-group study. Cephalalgia 2006;26(7):790–800. Kern KU, Martin C, Scheicher S, et al. Auslosung von Phantomschmerzen und—sensationen durch muskulare Stumpftriggerpunkte nach Beinamputationen. Schmerz 2006;20(4):300–306. Kern U, Martin C, Scheicher S, et al. Botulinum toxin type A influences stump pain after limb amputations. J Pain Symptom Manage 2003;26(6):1069–1070. Halder GE, Scott L, Wyman A, et al. Botox combined with myofascial release physical therapy as a treatment for myofascial pelvic pain. Investig Clin Urol 2017;58(2):134–139. Ranoux D, Martiné G, Espagne-Dubreuilh G, et al. OnabotulinumtoxinA injections in chronic migraine, targeted to sites of pericranial myofascial pain: an observational, open label, reallife cohort study. J Headache Pain 2017;18(1):75. Gerwin R. Botulinum toxin treatment of myofascial pain: a critical review of the literature. Curr Pain Headache Rep 2012;16(5):413–422. Silberstein S. Botulinum neurotoxins: origins and basic mechanisms of action. Pain Pract 2004;4(suppl 1):S19–S26. Samigullin D, Bukharaeva EA, Vyskocil F, et al. Calcium dependence of uni-quantal release latencies and quantal content at mouse neuromuscular junction. Physiol Res 2005;54(1):129– 132. Wessler I. Acetylcholine release at motor endplates and autonomic neuroeffector junctions: a comparison. Pharmacol Res 1996;33(2):81–94. Aoki KR. Review of a proposed mechanism for the antinociceptive action of botulinum toxin type A. Neurotoxicology 2005;26(5):785–793. Bach-Rojecky L, Lackovic Z. Antinociceptive effect of botulinum toxin type a in rat model of carrageenan and capsaicin induced pain. Croat Med J 2005;46(2):201–208. Mense S. Neurobiological basis for the use of botulinum toxin in pain therapy. J Neurol 2004;251(suppl 1):I1–I7. Mesa-Jiménez JA, Sánchez-Gutiérrez J, de-la-Hoz-Aizpurua JL, et al. Cadaveric validation of dry needle placement in the lateral pterygoid muscle. J Manipulative Physiol Ther 2015;38(2):145–150. Gonzalez-Perez LM, Infante-Cossio P, Granados-Nunez M, et al. Deep dry needling of trigger points located in the lateral pterygoid muscle: efficacy and safety of treatment for management of myofascial pain and temporomandibular dysfunction. Med Oral Patol Oral Cir Bucal 2015;20(3):e326–e333. Peng PW, Castano ED. Survey of chronic pain practice by anesthesiologists in Canada. Can J Anaesth 2005;52(4):383–389. Dilorenzo L, Traballesi M, Morelli D, et al. Hemiparetic shoulder pain syndrome treated with deep dry needling during early rehabilitation: a prospective, open-label, randomized investigation. J Musculoskelet Pain 2004;12(2):25–34. Espí-López GV, Serra-Añó P, Vicent-Ferrando J, et al. Effectiveness of inclusion of dry needling in a multimodal therapy program for patellofemoral pain: a randomized parallelgroup trial. J Orthop Sports Phys Ther 2017;47(6):392–401. Ga H, Koh HJ, Choi JH, et al. Intramuscular and nerve root stimulation vs lidocaine injection to trigger points in myofascial pain syndrome. J Rehabil Med 2007;39(5):374–378. He C, Ma H. Effectiveness of trigger point dry needling for plantar heel pain: a meta-analysis of seven randomized controlled trials. J Pain Res 2017;10:1933–1942. Kietrys DM, Palombaro KM, Azzaretto E, et al. Effectiveness of dry needling for upperquarter myofascial pain: a systematic review and meta-analysis. J Orthop Sports Phys Ther 2013;43(9):620–634. Pérez-Palomares S, Oliván-Blázquez B, Pérez-Palomares A, et al. Contribution of dry

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needling to individualized physical therapy treatment of shoulder pain: a randomized clinical trial. J Orthop Sports Phys Ther 2017;47(1):11–20. Castro-Sanchez AM, Garcia-Lopez H, Mataran-Penarrocha GA, et al. Effects of dry needling on spinal mobility and trigger points in patients with fibromyalgia syndrome. Pain Physician 2017;20(2):37–52. Brennan KL, Allen BC, Maldonado YM. Dry needling versus cortisone injection in the treatment of greater trochanteric pain syndrome: a noninferiority randomized clinical trial. J Orthop Sports Phys Ther 2017;47(4):232–239. Tadros NN, Shah AB, Shoskes DA. Utility of trigger point injection as an adjunct to physical therapy in men with chronic prostatitis/chronic pelvic pain syndrome. Transl Androl Urol 2017;6(3):534–537. Shanmugam S, Mathias L. Immediate effects of paraspinal dry needling in patients with acute facet joint lock induced wry neck. J Clin Diagn Res 2017;11(6):YM01–YM03. Calvo S, Quintero I, Herrero P. Effects of dry needling (DNHS technique) on the contractile properties of spastic muscles in a patient with stroke: a case report. Int J Rehabil Res 2016;39(4):372–376. Arias-Buría JL, Fernández-de-Las-Peñas C, Palacios-Ceña M, et al. Exercises and dry needling for subacromial pain syndrome: a randomized parallel-group trial. J Pain 2017;18(1):11–18. Arias-Buría JL, Valero-Alcaide R, Cleland JA, et al. Inclusion of trigger point dry needling in a multimodal physical therapy program for postoperative shoulder pain: a randomized clinical trial. J Manipulative Physiol Ther 2015;38(3):179–187. Domingo A, Mayoral O, Monterde S, et al. Neuromuscular damage and repair after dry needling in mice. Evid Based Complement Alternat Med 2013;2013:260806. Gaspersic R, Koritnik B, Erzen I, et al. Muscle activity-resistant acetylcholine receptor accumulation is induced in places of former motor endplates in ectopically innervated regenerating rat muscles. Int J Dev Neurosci 2001;19(3):339–346. Sadeh M, Stern LZ, Czyzewski K. Changes in end-plate cholinesterase and axons during muscle degeneration and regeneration. J Anat 1985;140(pt 1):165–176. Liu QG, Liu L, Huang QM, et al. Decreased spontaneous electrical activity and acetylcholine at myofascial trigger spots after dry needling treatment: a pilot study. Evid Based Complement Alternat Med 2017;2017:3938191. Langevin HM, Bouffard NA, Badger GJ, et al. Subcutaneous tissue fibroblast cytoskeletal remodeling induced by acupuncture: evidence for a mechanotransduction-based mechanism. J Cell Physiol 2006;207(3):767–774. Langevin HM, Bouffard NA, Badger GJ, et al. Dynamic fibroblast cytoskeletal response to subcutaneous tissue stretch ex vivo and in vivo. Am J Physiol Cell Physiol 2005;288(3):C747–C756. Sandkühler J. The organization and function of endogenous antinociceptive systems. Prog Neurobiol 1996;50(1):49–81. Lund I, Lundeberg T. Are minimal, superficial or sham acupuncture procedures acceptable as inert placebo controls? Acupunct Med 2006;24(1):13–15. Mohr C, Binkofski F, Erdmann C, et al. The anterior cingulate cortex contains distinct areas dissociating external from self-administered painful stimulation: a parametric fMRI study. Pain 2005;114(3):347–357. Olausson H, Lamarre Y, Backlund H, et al. Unmyelinated tactile afferents signal touch and project to insular cortex. Nat Neurosci 2002;5(9):900–904. Rickards LD. Effectiveness of noninvasive treatments for active myofascial trigger point pain: a systematic review. In: Dommerholt J, Huijbregts PA, eds. Myofascial Trigger Points:

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Pathophysiology and Evidence-Informed Diagnosis and Management. Sudbury, MA: Jones & Bartlett; 2011:129–158. Fernández-de-las-Peñas C, Campo MS, Fernández-Carnero J. Manual therapies in myofascial trigger point treatment: a systematic review. J Bodyw Mov Ther 2005;9:27–34. Lee M, Kim M, Oh S, et al. A self-determination theory-based self-myofascial release program in older adults with myofascial trigger points in the neck and back: a pilot study. Physiother Theory Prac 2017;33(9):681–694. Morikawa Y, Takamoto K, Nishimaru H, et al. Compression at myofascial trigger point on chronic neck pain provides pain relief through the prefrontal cortex and autonomic nervous system: a pilot study. Front Neurosci 2017;11:186. Behrangrad S, Kamali F. Comparison of ischemic compression and lumbopelvic manipulation as trigger point therapy for patellofemoral pain syndrome in young adults: a double-blind randomized clinical trial. J Bodyw Mov Ther 2017;21(3):554–564. De Meulemeester KE, Castelein B, Coppieters I, et al. Comparing trigger point dry needling and manual pressure technique for the management of myofascial neck/shoulder pain: a randomized clinical trial. J Manipulative Physiol Ther 2017;40(1):11–20. Mohammadi Kojidi M, Okhovatian F, Rahimi A, et al. The influence of Positional Release Therapy on the myofascial trigger points of the upper trapezius muscle in computer users. J Bodyw Mov Ther 2016;20(4):767–773. Fernández-de-las-Peñas C, Alonso-Blanco C, Fernández-Carnero J, et al. The immediate effect of ischemic compression technique and transverse friction massage on tenderness of active and latent myofascial trigger points: a pilot study. J Bodyw Mov Ther 2006;10(1):3–9. Hou CR, Tsai LC, Cheng KF, et al. Immediate effects of various physical therapeutic modalities on cervical myofascial pain and trigger-point sensitivity. Arch Phys Med Rehabil 2002;83(10):1406–1414. Khalighi HR, Mortazavi H, Mojahedi SM, et al. Low level laser therapy versus pharmacotherapy in improving myofascial pain disorder syndrome. J Lasers Med Sci 2016;7(1):45–50. De Carli BM, Magro AK, Souza-Silva BN, et al. The effect of laser and botulinum toxin in the treatment of myofascial pain and mouth opening: a randomized clinical trial. J Photochem Photobiol B 2016;159:120–123. Altan L, Bingol U, Aykac M, et al. Investigation of the effect of GaAs laser therapy on cervical myofascial pain syndrome. Rheumatol Int 2005;25(1):23–27. Gur A, Sarac AJ, Cevik R, et al. Efficacy of 904 nm gallium arsenide low level laser therapy in the management of chronic myofascial pain in the neck: a double-blind and randomizecontrolled trial. Lasers Surg Med 2004;35(3):229–235. Srbely JZ, Dickey JP. Randomized controlled study of the antinociceptive effect of ultrasound on trigger point sensitivity: novel applications in myofascial therapy? Clin Rehabil 2007;21(5):411–417. Gam AN, Warming S, Larsen LH, et al. Treatment of myofascial trigger-points with ultrasound combined with massage and exercise—a randomised controlled trial. Pain 1998;77(1):73–79. Lee JC, Lin DT, Hong CZ. The effectiveness of simultaneous thermotherapy with ultrasound and electrotherapy with combined AC and DC current on the immediate pain relief of myofascial trigger points. J Musculoskelet Pain 1997;5(1):81–90. Majlesi J, Unalan H. High-power pain threshold ultrasound technique in the treatment of active myofascial trigger points: a randomized, double-blind, case-control study. Arch Phys Med Rehabil 2004;85(5):833–836. Unalan H, Majlesi J, Aydin FY, et al. Comparison of high-power pain threshold ultrasound

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therapy with local injection in the treatment of active myofascial trigger points of the upper trapezius muscle. Arch Phys Med Rehabil 2011;92(4):657–662. Ardiç F, Sarhus M, Topuz O. Comparison of two different techniques of electrotherapy on myofascial pain. J Back Musculoskeletal Rehabil 2002;16:11–16. Graff-Radford SB, Reeves JL, Baker RL, et al. Effects of transcutaneous electrical nerve stimulation on myofascial pain and trigger point sensitivity. Pain 1989;37(1):1–5. Hsueh TC, Cheng PT, Kuan TS, et al.The immediate effectiveness of electrical nerve stimulation and electrical muscle stimulation on myofascial trigger points. Am J Phys Med Rehabil 1997;76(6):471–476. Müller-Ehrenberg H, Thorwesten L. Improvement of sports-related shoulder pain after treatment of trigger points using focused extracorporeal shock wave therapy regarding static and dynamic force development, pain relief, and sensomotoric performance. J Musculoskelet Pain 2007;15(suppl 13):33.

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CHAPTER 36 Fibromyalgia: A Discrete Disease or the End of the Continuum DANIEL J. CLAUW and CHAD BRUMMETT Clinical practitioners commonly see patients with pain and other somatic symptoms that they cannot adequately explain based on the degree of damage or inflammation noted in peripheral tissues. In fact, this may be among the most common predicament for which patients seek medical attention.1 Typically, an evaluation is performed looking for a “cause” for the pain. If none is found, these individuals are often given a diagnostic label that merely connotes that the patient has chronic pain in a region of the body, without an underlying mechanistic cause (e.g., chronic low back pain, headache, temporomandibular disorder [TMD]). In other cases, the label given alludes to an underlying mechanism that may or may not be responsible for the individual’s pain (e.g., “knee osteoarthritis”). Fibromyalgia is merely the current term for individuals with chronic widespread musculoskeletal pain, for which no alternative cause can be identified. Gastroenterologists often see the exact same patients and focus on their gastroenterologic complaints and often use the terms functional gastrointestinal disorder, irritable bowel syndrome (IBS), nonulcer dyspepsia, noncardiac chest pain, or esophageal dysmotility to explain the patient’s symptoms.2 Neurologists see these patients for their headaches and/or unexplained facial pain; urologists for pelvic pain and urinary symptoms (and use labels such as interstitial cystitis, chronic prostatitis, vulvodynia, and vulvar vestibulitis); dentists for TMD, and so on.3 Until recently, these unexplained pain syndromes perplexed researchers, clinicians, and patients. However, it is now clear that • Individuals will sometimes only have one of these “idiopathic” pain syndromes over the course of their lifetime. But more often, individuals with one of these entities, and their family members, are likely to have several of these conditions.4,5 Many terms have been 1739

•

•

•

•

used to describe these coaggregating syndromes and symptoms, including functional somatic syndromes, somatization disorders, allied spectrum conditions, sensory sensitivity syndromes, chronic multisymptom illnesses, and medically unexplained symptoms. The most recent term coined by the National Institutes of Health in the United States is probably the best accepted at present: “chronic overlapping pain conditions” (COPCs).6,7 Women are more likely to have these disorders than men, but the sex difference is much more apparent in clinical cohorts (especially tertiary care) when compared to population-based samples.8,9 Groups of individuals with these conditions (e.g., fibromyalgia, IBS, headache, TMD) typically display diffuse hyperalgesia (increased pain to normally painful stimuli) and/or allodynia (pain to normally nonpainful stimuli) that is identifiable both via quantitative sensory testing and functional neuroimaging.10–12 In addition, a number of other central nervous system (CNS) mechanisms are reproducibly seen in these conditions. This suggests that these individuals have a fundamental problem with augmented pain and/or sensory processing rather than simply a nociceptive focus confined to the region of the body where the person is currently experiencing pain. Similar types of therapies are efficacious for all of these conditions, including both pharmacologic (e.g., tricyclic compounds, serotonin norepinephrine reuptake inhibitors [SNRIs] and gabapentinoids) and nonpharmacologic treatments (e.g., education, exercise, cognitivebehavioral therapy). Conversely, individuals with these conditions typically do not respond to therapies that are typically more effective when pain is due to damage or inflammation of tissues (e.g., nonsteroidal anti-inflammatory drugs [NSAIDs], opioids, injections, surgical procedures). Subsets of individuals with any chronic pain condition (e.g., low back pain, osteoarthritis, autoimmune disorders, sickle cell disease) also have the same phenotypic features and underlying mechanisms as those seen in fibromyalgia.3,13 These individuals with subthreshold fibromyalgia display the same pathologic features and differential responsiveness to peripherally directed versus centrally directed 1740

therapies. Thus, it is critical that clinicians seeing patients with chronic pain evaluate individuals for the presence of this phenotype as it can dramatically affect which treatments will work, or not work, for a given individual with chronic pain. Until perhaps a decade ago, these conditions were all on somewhat equal (and tenuous) scientific ground. But within a relatively short period of time, research methods such as experimental pain testing, functional imaging, and genetics have led to tremendous advances in the understanding of several of these conditions, most notably fibromyalgia, IBS, and TMD. Many in the pain field now feel that much chronic pain itself is a neural disease and that many of the underlying mechanisms operative in these heretofore considered “idiopathic” or “functional” pain syndromes may be similar no matter whether that pain is present throughout the body (e.g., in fibromyalgia) or localized to the low back, the bowel, or the bladder. Because of this, the more contemporary terms used to describe conditions such as fibromyalgia, IBS, TMD, vulvodynia, and many other entities include “centralized pain” or “central sensitization” to imply that the CNS is playing a prominent role in amplifying or causing the pain in most individuals with these syndromes.3,14 This review of fibromyalgia in the following discussion focuses on our current understanding of this disorder as the prototypical “centralized pain syndromes.”

Historical Perspective Although the term fibromyalgia is relatively new, this condition has been described in the medical literature since the early 1900s. Sir William Gowers coined the term “fibrositis” in 1904. During the next half century, fibrositis (as it was then called) was considered by some to be a common cause of muscular pain, by others to be a manifestation of “tension” or “psychogenic rheumatism,” and by the rheumatology community in general to be a nonentity. The current concept of fibromyalgia was established by Smythe and Moldofsky15 in the mid-1970s. The name change reflected the fact that there was increasing evidence that there was no -itis (inflammation) in the 1741

connective tissues of individuals with this condition but instead -algia (pain). These authors characterized the most common tender points (regions of extreme tenderness in these individuals) and reported that patients with fibromyalgia had disturbances in deep and restorative sleep and that selective stage 4 interruptions induced the symptoms of fibromyalgia.16 Yunus and colleagues17 then reported on the major clinical manifestations of patients with fibromyalgia seen in rheumatology clinics. The next advance in fibromyalgia was the development of the American College of Rheumatology (ACR) criteria for fibromyalgia, which were published in 1990.18 These classification criteria required that an individual have both a history of chronic widespread pain (CWP) and the finding of ≥11 of a possible 18 tender points on examination. These ACR classification criteria were intended for research use to standardize definitions of fibromyalgia. In this regard, the criteria have been extremely valuable. Unfortunately, many practitioners use these criteria in routine clinical practice to diagnose individual patients, and this unintended use led to many of the current misconceptions regarding fibromyalgia that are discussed in the following text. New criteria that eliminate the need for the tender point exam were developed in 2010 and refined in 2011 and in 2016.19–21 These criteria focus on identifying the cardinal symptoms seen in this condition including widespread pain, fatigue, sleep, memory, and mood disturbances. Once structural damage to tissues or inflammation had been excluded as pathogenic factors in fibromyalgia, many groups of investigators began to explore neural mechanisms to explain the underlying pathogenesis of these disorders.22,23 Fortuitously, newer neuroscience research techniques such as functional, chemical, and structural brain imaging were all becoming available tools to examine the CNS, in both healthy individuals and those with chronic pain. Thus, the conditions we now mechanistically understand best within this spectrum include conditions where these central factors were first studied, including fibromyalgia, IBS (previously termed spastic colitis until the recognition that there was little -itis and that motility changes were not the major pathologic feature), and TMD (previously termed temporomandibular joint syndrome until it was recognized the problem 1742

was not largely within the joint24–27) and urinary chronic pelvic pain syndromes (where again, the condition previously called interstitial cystitis is now called bladder pain syndrome28–31). This is not to say peripheral factors, or low-grade inflammation that is not identifiable clinically, do not play some role in these entities. But it is relevant that clinicians who care for individuals with these conditions, and who are quite adept at identifying (with blood tests, imaging, or endoscopy) peripheral damage or inflammation, have generally concluded that these are not inflammatory or peripheral-based disorders.

Epidemiology CHRONIC WIDESPREAD PAIN Epidemiologic studies of the historical component of the ACR criteria for fibromyalgia, CWP, have been extremely instructive. CWP is typically operationalized as pain above and below the waist, involving the left and right sides of the body and also involving the axial skeleton. Populationbased studies of CWP suggest that roughly 6% to 12% of the population has these features at any given point in time.32,33 Chronic regional pain is found in 20% to 25% of the population. Both chronic widespread and regional pain occur about 1.5 times as commonly in women than men. These findings are very similar in different countries, ethnicities, and cultures, dispelling an early notion that this problem was somewhat unique to more developed countries.

FIBROMYALGIA The original 1990 ACR criteria for fibromyalgia required that an individual has both a history of CWP and the finding of 11 or greater of 18 possible tender points on examination. Tender points represent nine paired predefined regions of the body, often over musculotendinous insertions.18 If an individual reports pain when a region is palpated with 4 kg of pressure, this is considered a positive tender point. Between 25% and 50% of individuals who have CWP will also have 11 or greater tender points and thus meet the 1990 criteria for fibromyalgia.34 Just as with CWP, the prevalence of fibromyalgia is just as high in rural or nonindustrialized 1743

societies as it is in countries such as the United States.35

SIGNIFICANCE OF TENDER POINTS When the 1990 ACR criteria were published, it was thought that there may be some unique significance to the locations of tender points. In fact, a term “control points” was coined to describe areas of the body that should not be tender in fibromyalgia, and individuals were assumed to have a psychological cause for their pain is they were tender in these regions. Since then, we have learned that the tenderness in fibromyalgia extends throughout the entire body. Thus, relative to the pain threshold that a normal nonfibromyalgia patient would experience at the same points, “control” regions of the body such as the thumbnail and forehead are just as tender as in fibromyalgia tender points.36 The tender point requirement in the ACR criteria not only misrepresents the nature of the tenderness in this condition (i.e., local rather than widespread) but also strongly influences the demographic and psychological characteristics of fibromyalgia. Women are only 1.5 times more likely than men to experience CWP but are 11 times more likely than men to have 11 or more tender points.37 Because of this, women are approximately 10 times as likely to meet the 1990 ACR criteria for fibromyalgia than men. Yet, most of the men in the population who have CWP but are not tender enough to meet criteria for fibromyalgia likely have the same fundamental underlying pathophysiologic problems as the women who meet the ACR criteria for fibromyalgia. Another unintended consequence of requiring both CWP and at least 11 tender points to be diagnosed with fibromyalgia is that many individuals with fibromyalgia will have high levels of distress. Wolfe38 has described tender points as a “sedimentation rate for distress” because of populationbased studies showing that tender points are more common in distressed individuals. Until recently, many assumed that because tender points were associated with distress, that tenderness (an individual’s sensitivity to mechanical pressure) was associated with distress. However, recent evidence suggests that this latter association is probably due to the standard tender point technique, which consists of applying steadily increasing pressure until reaching 4 kg. In this situation, individuals who 1744

are anxious or “expectant” have a tendency to “bail out” and report tenderness. Recently, more sophisticated measures of tenderness have been developed which give stimuli in a random, unpredictable fashion, and the results of these tests are independent of psychological status.39,40 Because tender points are associated with high levels of distress, requiring 11 or greater tender points in order to diagnose someone with CWP with fibromyalgia dramatically increases the likelihood that these individuals will be female and/or and distressed, compared to individuals with CWP and 30 minutes), ratio of sleep time to time spent in bed 4 weeks. A history of cancer increases the likelihood of having sleep disturbance.177 Insomnia is 2042

a prominent problem for patients with cancer and 25% to 60% of patients may be affected178–180 and a prevalence rate almost twice that of the general population.181 The prevalence of sleep disturbance varies depending on the cancer type, cancer stage, treatment received, and time since completion of treatment. Compared with other types of cancer, breast cancer is associated with an exceptionally high rate of reduced sleep quality.182,183 Insomnia in patients with lung cancer undergoing chemotherapy may be as high as 52%.184 Sleep disturbance is one of the five most common symptoms reported as moderate to severe by primary brain tumor patients and occurs anywhere between 17% and 54% of patients.185 Despite its prevalence and importance, insomnia is often unrecognized and poorly managed. Insomnia refers to difficulty falling or staying asleep, whereas sleep impairment refers to sleepiness, tiredness, and perceived functional impairments during wakefulness associated with sleep problems or impaired alertness. Insomnia typically occurs as a transient inability to initiate or maintain sleep or as hyperarousal, often in response to a situation or event. Daytime consequences of fatigue and insomnia are similar and include dysphoric states, such as irritability, impaired cognition (poor concentration and memory), and interference with usual activities. Identification of sleep disturbance typically involves screening for the problem followed by a comprehensive assessment for those who screen positive. The National Institutes of Health recommends that screening may include asking two questions: (1) Do you have problems with your sleep or sleep disturbance on average for three or more nights a week? If yes, (2) does the problem with your sleep negatively affect your daytime functioning? If the answer is yes to both questions, a more focused assessment of sleep disturbance is indicated.186 Use of the Insomnia Severity Index (7-item, self-report questionnaire) was also recommended to screen for cases of insomnia in cancer patients and for assessing the effects of treatment (Table 42.5).187 Once identified, the Pittsburgh Sleep Quality Index (PSQI) can be administered for a more detailed assessment. The PSQI is a 19-item questionnaire evaluating sleep quality and disturbances over the past month.188 The first 4 items are open questions, whereas items 5 to 19 are rated on a 4-point Likert scale. Individual items 2043

scores yield 7 components (subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction). A total score (global PSQI), ranging from 0 to 21, is obtained by adding the 7 component scores. A score >5 suggests poor sleep quality. TABLE 42.5 Insomnia Severity Index For each question, please CIRCLE the number that best describes your answer. Please rate the CURRENT (i.e., LAST 2 WEEKS) SEVERITY of your insomnia problem(s). Insomnia Problem None Mild Moderate Severe Very Severe 1. Difficulty falling asleep 0 1 2 3 4 2. Difficulty staying asleep 0 1 2 3 4 3. Problem waking up too early 0 1 2 3 4 4. How SATISFIED/DISSATISFIED are you with your CURRENT sleep pattern? Very Moderately Very Satisfied Satisfied Satisfied Dissatisfied Dissatisfied 0 1 2 3 4 5. How NOTICEABLE to others do you think your sleep problem is in terms of impairing the quality of your life? Not at all Very Much Noticeable A Little Somewhat Much Noticeable 0 1 2 3 4 6. How WORRIED/DISTRESSED are you about your current sleep problem? Not at all Very Much Worried A Little Somewhat Much Worried 0 1 2 3 4 7. To what extent do you consider your sleep problem to INTERFERE with your daily functioning (e.g., daytime fatigue, mood, ability to function at work/daily chores, concentration, memory, mood, etc.) CURRENTLY? Not at all Very Much Interfering A Little Somewhat Much Interfering 0 1 2 3 4 Guidelines for Scoring/Interpretation: Add the scores for all seven items (questions 1 + 2 + 3 + 4 + 5 + 6 + 7) = ________ your total score Total score categories: 0–7 = No clinically significant insomnia 8–14 = Subthreshold insomnia 15–21 = Clinical insomnia (moderate severity) 22–28 = Clinical insomnia (severe) From Charles M. Morin, PhD, Université Laval.

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Treatment of insomnia favors the use of pharmacologic aids. The common hypnotics including barbiturates, benzodiazepines, the “Z” drugs (eszopiclone, zaleplon, zolpidem, zopiclone), and other benzodiazepinereceptor agonists bind to γ-aminobutyric acid (GABA) receptors. However, a European study demonstrated that publication bias exists for insomnia trials and that the positive trials are two times more likely to be published than the negative ones.189 There is little controlled evidence that long-term uses of hypnotics produce benefits of any sort.190 A study of almost 2,000 cancer patients found that 22.6% were taking hypnotic medication for sleep problems, and half of those were taking medication every night for periods longer than 6 months.191 Use of hypnotic drugs is associated with a greatly increased risk of all-cause mortality. Some of this mortality has been documented as deaths caused by hypnotics by medical examiners, attributed to respiratory arrests resulting from “overdose.” However, it is likely that many deaths from respiratory depression occur among patients never seen by coroners, especially when the death is caused by a combination of hypnotics with other contributing factors, so that the lethal hypnotic dosage may by itself have been within customary dosage ranges.192 In addition to respiratory depression, hypnotics appear to be causally related to serious illnesses and premature deaths from cancer, serious infections, mood disorders, accidental injuries, suicides, and homicides.193 Cognitive-behavior therapy for insomnia (CBT-I) includes components of sleep restriction (limiting time in bed), stimulus control (conditioning the bed for sleep by restricting behaviors incompatible with sleep in the bedroom), and cognitive restructuring (addressing maladaptive thoughts and beliefs about sleep) to reestablish a regular sleep pattern. CBT-I was superior to zopiclone both in short- and long-term management of insomnia in older adults.194

Sources of Pain in the Cancer Patient Pain in the oncology patient can arise from different sources (Table 42.6): • Direct or indirect tumor involvement • Cancer-directed therapy • Mechanisms unrelated to cancer or its treatment 2045

• A combination of the above TABLE 42.6 Causes of Pain in Patients with Cancer Cause

Example

As a direct consequence of tumor

Involvement of bones Obstruction of hollow organs Compression of nerves By infections By metabolic imbalances By venous/lymphatic occlusion By paraneoplastic syndromes Following surgical intervention Following chemotherapy Following radiation therapy Migraine Diabetic neuropathy Myofascial pain problems Metastatic lung cancer to bone with hypertrophic osteoarthropathy affecting tubular bones in a patient with painful peripheral diabetic neuropathy and chemotherapy-induced peripheral neuropathy

As an indirect consequence of tumors

As a consequence of tumor therapy

Without relation to cancer

A combination of the above

Patients may present with complex patterns of pain that result from combinations of these categories, thus complicating the diagnosis. Factors influencing the pain complaint include the primary tumor type, stage of disease, tumor site, and mood factors (anxiety and depression). Although estimates vary, the prevalence of pain in cancer survivors has been reported to be as high as 40%195–198 with variable durations of painful symptoms199 and with disparities in race and sex.200 The prevalence of pain in patients with cancer varies with tumor type, treatment phase, and stage of disease. Van den Beuken-van Everdingen et al.196 estimated the pain prevalence rates were 39.3% after curative treatment; 55% during anticancer treatment; and 66.4% in advanced, metastatic, or terminal disease with 50.7% in all cancer stages. Moderate to severe intensity pain (numerical rating scale score ≥5) was reported by 38.0% of all patients. Of note, lower pain prevalence rates occurred in prostate cancer patient compared to head and neck, lung, and breast cancer patients. In 2007, the authors previously reported prevalence rates of 33% after curative treatment; 59% during treatment; 64% in advanced, metastatic, or terminal disease; and 64% in all cancer stages with approximately 33% grading 2046

pain intensity as moderate to severe and the highest prevalence in head/neck cancer patients.201 High prevalence of pain has also been documented in hematologic tumor patients initially at diagnosis, during treatment, and in the last month of life.202,203 Many patients with advanced disease frequently have multiple pain complaints at different sites and were more common in patients with breast, lung, and prostate cancer compared with gastrointestinal cancers.204 In a prospective study of 2,266 cancer patients, Grond et al.61 assessed localization, etiology, and pathophysiologic mechanisms of pain syndromes associated with cancer. Thirty percent of the patients presented with one, 39% with two, and 31% with three or more distinct pain syndromes. The majority of patients had pain caused by cancer (85%) or antineoplastic treatment (17%); 9% had pain related to cancer disease and 9% due to etiologies unrelated to cancer. These investigations classified pain as originating from nociceptors in bone (35%), soft tissue (45%) or visceral structures (33%), or of neuropathic origin (34%). Patients had localized pain syndromes in the lower back (36%), abdominal region (27%), thoracic region (23%), lower limbs (21%), head (17%), and pelvic region (15%). Regions and systems affected by the main pain syndrome varied widely depending on the site of cancer origin, whereas the cancer site did not markedly influence the pain’s temporal characteristics, intensity, or etiology. Many metastatic bone lesions cause few or no symptoms and are diagnosed incidentally during an initial staging workup or at follow-up restaging evaluations.205 Bone cancer pain is the most common pain in patients with advanced cancer, and approximately two-thirds of patients with metastatic bone disease experience severe pain.206 Many of the most common tumors (breast, prostate, thyroid, kidney, and lung) have a strong predilection for bone metastasis, and an estimated 70% of patients with breast and prostate cancers develop bone metastases compared with 20% to 30% of patients with lung or gastrointestinal cancers.207 Although pain is frequently associated with the presence of metastases, certain tumor types are exceptions, notably breast and prostate cancers. Neither the prevalence nor the severity of pain among breast cancer patients varied directly as a function of metastatic sites of disease.118,119 Palmer et al.208 2047

evaluated the sensitivity of pain as an indicator of bone metastases in patients with breast or prostate cancer. Pain was a common finding, whether or not metastatic disease was present, and it occurred in over half of the patients. Although most patients with bone metastases reported bone pain, some (21% of breast and 22% of prostate patients) were asymptomatic. The majority of neoplasms are responsible for symptoms caused by mass effects to surrounding tissues and/or through the development of metastases. Paraneoplastic syndromes arise from tumor secretion of hormones, peptides, or cytokines or from immune cross-reactivity between malignant and normal tissues and may affect different organ systems, most notably the endocrine, neurologic, dermatologic, rheumatologic, and hematologic systems. The most commonly associated malignancies include small-cell lung cancer (SCLC), breast, gynecologic, and hematologic malignancies. Hypertrophic pulmonary osteoarthropathy (HPO) is characterized by periostosis and subperiosteal new bone formation along the shaft of long bones and the phalanges (“digital clubbing”), joint swelling, and pain and may be present in 1% to 10% of patients with lung tumors209,210 and may also been seen in patients with mesothelioma and lymphoma. Classically, HPO is diagnosed based on clinical symptoms (severe pain, edema, and erythema in the extremities) and radiologic findings. Periostitis is the hallmark of HPO, and imaging shows periosteal membrane thickening and periosteal new bone formation particularly in the distal long bones (especially the tibia). Bone scan is also useful for the detection of HPO. Peripheral nerves are a common target in paraneoplastic syndromes.211 Antibodies directed against neural antigens expressed by the tumor (onconeural antibodies) may occur in most of those affected by classical paraneoplastic syndromes, suggesting that an autoimmune process underlies these disorders. Subacute sensory neuronopathy (SSN) is a classical paraneoplastic syndrome.212 The neuropathy generally develops subacutely accompanied by pain and rapidly progressive paresthesia. Involvement of the upper extremities may occur with asymmetric sensory deficit or multifocal with facial, thoracic, and abdominal involvement. Many patients with SSN also have signs and symptoms suggestive of multifocal involvement including areas of the 2048

CNS. Paraneoplastic vasculitis of the peripheral nervous system usually precedes the tumor diagnosis and presents as multineuritis or asymmetric distal sensory-motor neuropathy with pain as a commonly reported symptom. This form is generally associated with lymphoma or cancer at various sites (lung, prostate, uterus, kidney, or gastric).213 Cancer-directed therapy pain syndromes may result from chemotherapy, radiation therapy, or surgery. Chemotherapy-induced peripheral neuropathy (CIPN) is well described with a variety of agents.214 Sensory symptoms tend to be greater than motor or autonomic, and the majority of signs and symptoms due to CIPN arise from damage to dorsal root ganglion neurons or their axons, leading to acral pain, sensory loss, and sometimes sensory ataxia. With platinum compounds, as many as 30% of patients experience worsening of neuropathy for a few months following completion of therapy, and a sizable cohort report persistent symptoms lasting years. Paclitaxel-associated CIPN usually improves in the months following treatment cessation but still has been associated with long-term persistence of some degree of neuropathy in up to 80% of patients, with roughly a third of these patients reporting severe symptoms.215 Table 42.7 lists the National Cancer Institute Common Terminology Criteria for Adverse Events for neurotoxicity. TABLE 42.7 NCI CTCAE v4.0 Neurotoxicity: National Cancer Institute Common Terminology Criteria for Adverse Events Adverse Event

Grade 5

Grade 1

Grade 2

Grade 3

Grade 4

Asymptomatic, clinical or diagnostic observations only; intervention not indicated

Moderate symptoms; limiting instrumental ADLa

Severe symptoms; limiting self-care ADLa;

Life-threatening consequences; urgent intervention indicated

Death

Peripheral sensory neuropathy

Asymptomatic; loss of deep tendon reflexes or paresthesia

Moderate symptoms; limiting instrumental ADLa

assistive device indicated Severe symptoms; limiting self-care ADLa

Life-threatening consequences; urgent intervention indicated

Death

Paresthesia

Mild symptoms

Moderate

Severe

Peripheral motor neuropathy

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symptoms; limiting instrumental ADLa

symptoms; limiting self-care ADLa

aInstrumental

ADL include preparing meals, shopping, using the telephone, managing money. Selfcare ADLs include bathing, dressing, using the toilet, and taking medications. Paresthesia is characterized by functional disturbances of sensory neurons resulting in abnormal cutaneous sensations of tingling, numbness, pressure, cold, and warmth that are experienced in the absence of a stimulus. Peripheral motor neuropathy is characterized by inflammation or degeneration of the peripheral motor nerves. Peripheral sensory neuropathy is characterized by inflammation or degeneration of the peripheral sensory nerves. ADL, activities of daily living.

Chemotherapeutic toxicity may be attributable to steroids, which are coadministered in many chemotherapeutic protocols. In particular, avascular necrosis is a well-described complication of steroid use. Morbidity is related to progressive joint damage often leading to decreased range of motion, pain with movement, and arthritis. Weight-bearing joints are most commonly involved. The shoulder, elbow, wrist, hand, and vertebral bodies can also be involved. The total cumulative dose and daily dose of glucocorticoids, and likely the underlying condition, affect the risk of developing avascular necrosis.216 Short-term, low-dose protocols are occasionally associated with necrosis.217 It most commonly occurs in the femoral and humeral heads. Pain is usually the first symptom, but the clinical presentation is variable and depends on the site and size of the infarct. Persistent hip or shoulder pain, especially with joint movement, tenderness, or reduced range of motion, warrants magnetic resonance imaging (MRI) which can visualize aspects of the necrotic lesion (necrosis, reactive zone/granulation tissue, sclerotic changes, edema). Bone marrow signal abnormality, the double-line sign, and subchondral fracture are characteristic MRI findings of avascular necrosis.218 Combined medical and radiation therapies, both sequential and concurrent, are improving clinical outcomes for locoregional tumor control, with enhanced patient survival and delay of recurrence.219 During the course of external radiation therapy, treatment generally influences normal tissue function in tissues that have more rapid self-renewing proliferative index (e.g., mucosal surfaces such as skin, head/neck, and esophagus) and other surface tissues that have more limited potential for 2050

self-renewal (e.g., hair, nails, and surface glands). Injuries to these tissues are often self-limited and heal without specific intervention secondary to stem cell renewal. Acute effects from radiation therapy do not uniformly predict for late effects from treatment. Late effects generally affect tissues that have limited potential for self-renewal, and injury is often more permanent, requiring surgical débridement and possibly resulting in functional damage. Radiation-induced neural damage and pain may become apparent sometime after completion of radiation therapy confounding the diagnosis in some cases.220–222 Postsurgical pain syndromes come in many varieties, including postmastectomy, postamputation, postthoracotomy, and other chronic pain states. Treatments for head and neck cancer have the potential to cause persistent pain and discomfort. Radical surgery, such as resection of portions of the tongue, palate, and mandible, and radical neck dissection (RND) cause major structural changes. Radiation therapy, which frequently is the primary therapy, may cause mucositis, xerostomia, loss of taste, and decreased QOL. Subsequent late fibrosis of skin and soft tissues may lead to temporomandibular joint dysfunction and MPSs. Eating difficulties and persistent pain are frequent issues in head and neck cancer survivors.223,224 Cancer patients and, in particular, cancer survivors may experience chronic non–tumor-related pain. The challenge for the treating clinician is to distinguish between tumor-associated and non–tumor-associated pain. Many of the same interdisciplinary treatment paradigms apply to cancer survivors as apply to all chronic pain patients, but an appreciation for the disabilities associated with treatments of cancer is essential. Long-term management of pain associated with cancer and its treatment poses a substantial challenge for the clinician. Pain complaints frequently change over time, involve multiple sites, stem from several origins including chronic disabilities, involve several causes simultaneously, and may relate loosely or not at all to the tumor.

Classification of Cancer Pain by Feature Several schemata exist for classifying pain in the cancer patient and are 2051

potentially useful for diagnosis and management. One such scheme is presented in Table 42.8. TABLE 42.8 Methods Used for Classifying Pain in the Cancer Patient Chronicity Intensity/severity Pathophysiology/mechanism Individual type and stage of disease Pattern of pain Syndrome

CHRONICITY Acute pain is the normal, predicted physiologic response to a noxious stimulus and typically is associated with invasive procedures, trauma, and disease. Various anticancer therapies, particularly postoperative pain following surgical intervention and radiation therapy, can cause acute pain (Table 42.9). The course of acute pain is usually predictable and selflimiting, and the pain does not represent a difficult diagnostic problem. In contrast, assessment of patients with chronic pain tends to be much more difficult and complex. Chronic pain is best considered as persistent pain beyond the expected healing time. As healing times vary for different stimuli and trauma, conventional definitions of chronic pain based on arbitrary intervals between 3 months and 6 months are less useful. One exception to this is the development of postherpetic neuralgia (PHN) after the development of herpes zoster. Several cancers including oral, esophageal, stomach, colorectal, lung, breast, ovarian, prostate, kidney, bladder, and CNS cancers as well as lymphoma, myeloma, and leukemia were associated with an increased risk of zoster, particularly within the first 2 years after diagnosis and among younger individuals.225 Some have proposed that only clinically relevant pain be defined as PHN to avoid overestimation of the problem and as pain ≥3 on a 10-point scale persisting 120 days after rash healing.226–229

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TABLE 42.9 Acute Pain Associated with Cancer Management Procedure

Problem

Diagnostic procedures

Blood samples Lumbar puncture Biopsy Mucositis GI distress including typhlitis, colitis, pancreatitis Cardiomyopathy Extravasation of drug into tissues Skin burns Mucositis Pharyngitis Esophagitis Proctitis Itching Yttrium-90 radioembolization Chemoembolization Radiofrequency ablation Postoperative pain

Chemotherapy

Radiation treatment

Interventional radiology procedures Surgical therapy GI, gastrointestinal.

INTENSITY/SEVERITY Health care providers underestimate the severity of a patient’s pain, particularly when relying on their own observations.230–232 This tendency is problematic because pain is often undertreated when patients and physicians differ in their judgment of the pain’s severity.233 Patient selfreport is always the primary source of information for the measurement of symptoms, and subjective reporting of pain is considered a key component of pain assessment.234 Observer ratings of symptom severity correlate poorly with patient ratings and are generally inadequate substitutes for patient reporting. The discrepancies were most pronounced in those patients reporting severe pain.233 Although clinicians can monitor some objective signs to clarify the manifestations and impact of certain symptoms, these signs only complement subjective assessment and selfreporting. An assessment of pain intensity should include an evaluation of not only the present or average pain intensity but also pain at its least and worst over a defined time period. The three most commonly used instruments for assessing cancer pain 2053

intensity are the following:235 • Visual Analogue Scale (VAS): A slash mark corresponding to intensity of pain is placed on a 100 mm line ranging at one end from “No Pain,” to the other end, “Pain as bad as it could possibly be.” • Numeric Rating Scale (NRS): A number is assigned to the intensity of pain on a scale of 0 to 10; 0 reflecting “No Pain” and 10 reflecting the “Worst Pain Possible.” • Verbal Rating Scale (VRS): The patient chooses one of the following words that best describes pain: “No Pain,” “Mild Pain,” “Moderate Pain,” “Severe Pain,” “Worst Possible Pain.” All three measures correlate highly with one another. For pain assessment in clinical settings, the VAS, VRS, and NRS approach equivalency236 so that clarity, ease of administration, and simplicity of scoring become justifiable criteria in response scale selection. On the basis of relatively few studies in cancer, results or recommendations did not differ conclusively from those in other populations.235 In clinical scenarios, the NRS or VRS has proven more popular than the VAS and scales has high correlations, especially with less educated patients.237,238 Numerical scales as measures of QOL end points work well as cancer clinical trial instruments because they are easier to understand and easier to score.239 Several studies have shown that differences between categorical pain severity items are not linear.240,241 For instance, when pain severity is rated at the midpoint or higher on numeric rating scales, patients report disproportionately more interference with daily function.122 Many patients, both with and without cancer, function quite effectively with a background level of mild pain that does not seriously impair or distract them. As pain severity increases to moderate intensity, pain passes a threshold beyond which it is hard for the patient to ignore the pain. At this point, it disrupts many aspects of the patient’s life. When pain is severe, it becomes a primary focus of attention and prohibits most activities. Pain severity and the degree to which the patient’s function is impaired are highly associated. As a way of delineating different levels of cancer pain severity, Serlin et al.122 explored the relationship between numerical ratings of pain severity and ratings of pain’s interference with such functions as activity, 2054

mood, and sleep. Based on the degree of interference with function, ratings of 1 to 4 correspond to mild pain, 5 to 6 to moderate pain, and 7 to 10 to severe pain. In a follow-up study in categorizing the severity of cancer pain, Paul et al.123 confirmed a nonlinear relationship between cancer pain severity and interference with function and that the boundary between a mild and a moderate level of cancer pain was at 4. However, they failed to confirm the boundary between moderate and severe cancer pain and reported that a rating of 7 was in the moderate category and ratings >7 being in the severe category.

PATHOPHYSIOLOGY/MECHANISMS A general classification by pathophysiology distinguishes nociceptive (somatic and visceral) from neuropathic pain (see “Pain and the Cancer Patient” section). This distinction is fundamental in assessment because it may determine and guide therapy. In principle, pain results from stimulation of nociceptors or by lesions of afferent nerve fibers. Pain is nociceptive if the sustaining mechanisms are related to ongoing tissue pathology. Pain is neuropathic when there is evidence that the pain stems from injury to neural tissues and aberrant somatosensory processing in the periphery or in the CNS. Physical influences such as pressure, traction, compression, and tumor infiltration as well as metabolic or chemical disturbances produce pain. Obviously, classification by physiologic mechanism would be an improvement, but sufficient information to do this is not available.

Tumor Involvement of Encapsulated Organs Primary or secondary tumors of the liver are the most frequent examples of tumors of encapsulated organs. These can enlarge the organ to several times the normal size. Because the organ capsule of connective tissue grows less rapidly than the tumor, the intracapsular pressure rises as capsular distention develops. In addition, tumor infiltrates the capsule locally, producing dull, and rarely also stabbing, pains. The massive growth of the organ not only stimulates intracapsular nociceptors, but it also irritates larger nerves by pressure or traction on the tissue suspending the organ. Similar organ-enlarging processes in the spleen and kidneys do 2055

not lead to pain to the same extent as in the liver, perhaps because of the more stable suspension or embedding of these organs, which are farther away from the midline with its abundant nerve pathways. The initial presentation of renal tumors can include pain, weight loss, and hematuria but typically occurs in only 9% of patients and is often indicative of advanced disease with approximately 30% of patients with renal carcinoma present with metastatic disease, 25% with locally advanced renal carcinoma, and 45% with localized disease.242 The detection of kidney pain relies on input from sympathetic, parasympathetic, and sensory nerves. The sympathetic nerves supplying the kidneys originate in spinal cord segments T10–L1 and travel via white rami to the paravertebral ganglia. The sympathetic nerves travel via the lesser splanchnic nerves from the T10–T11 thoracic paravertebral ganglia to the synapse at the ipsilateral aorticorenal and celiac ganglia. From the 12th thoracic paravertebral ganglion, nerves travel via the least splanchnic nerve to the synapse either in the aorticorenal ganglion or in the renal plexus. The first lumbar splanchnic nerve and the postganglionic sympathetic nerves from the aorticorenal and celiac plexus synapse in the renal plexus. The parasympathetic innervation originates from the vagus nerve. These parasympathetic nerves traverse through the celiac plexus or pass directly to the renal plexus. Sensory renal nerves travel via the renal plexus, splanchnic nerves, thoracic sympathetic ganglia, T10–T12 spinal nerves, and spinal cord dorsal horn neurons. Patients may complain of abdominal, back, and flank pain in addition to the sensation of flank heaviness. Pain-sensitive structures in the head include extracranial structures such as the skin, muscles, and blood vessels in the head and neck; mucosa of the sinuses and dental structures; and intracranial structures including the regions of the large arteries near the circle of Willis, the great intracranial venous sinuses, parts of the dura and dural arteries, and cranial nerves (particularly glossopharyngeal, vagus, and trigeminal). The cranium (except the periosteum), brain parenchyma, ependymal lining of the ventricles, and choroid plexus are all pain insensitive. The brain is also an encapsulated organ. Its special feature is that the bony skull capsule prevents any enlargement. Pain arises here, not by destruction of 2056

parenchyma, but by the increase of intracranial pressure with stimulation of the meningeal nociceptors. Such an increase of intracranial pressure occurs in space-occupying tumor growth or in focal or generalized brain edema. Focally, edema can develop around isolated tumors. Generalized edema develops in diffuse metastatic invasion of the meninges due to disturbance of the circulation of CSF. Such a tumor invasion of the leptomeninges is frequent in malignant lymphomas. However, metastatic invasion of the leptomeninges occurs in patients with solid tumors (e.g., bronchial carcinoma and malignant melanoma), with the predominant symptom being headache. In such cases, tumor infiltration of cranial nerves may also occur.

Tumor Infiltration of Peripheral Nerves Because peripheral nerves can usually evade pressure from a tumor on one side, infiltration by tumor tissue is the quintessential tissue trauma stimulus. In addition, indirect damage of unknown pathogenesis might also occur to peripheral nerves in the context of tumor conditions such as occur with paraneoplastic syndromes. Paraneoplastic syndromes may affect diverse organ systems, most notably the endocrine, neurologic, dermatologic, rheumatologic, and hematologic systems. The best described paraneoplastic syndromes are attributed to tumor secretion of functional peptides and hormones (endocrine paraneoplastic syndromes) or immune cross-reactivity between tumor and normal host tissues (neurologic paraneoplastic syndromes) and may affect up to 8% of cancer patients.243 In paraneoplastic neurologic syndromes, tumor-directed onconeural antibodies are produced and may result in permanent damage to neural tissue. Tumor tissue often infiltrates the perineural cleft; however, this does not regularly cause pain. A massive and then painful entrapment of the nerve plexus or individual nerves sometimes occurs, especially in extensive breast carcinomas and their recurrences or in chest wall metastases of bronchial carcinomas. The perineural cleft widens tumor infiltration, and infiltration of the tumor into the nerve itself is common. Degenerative changes of the axis cylinders are sometimes visible with conventional screening methods. Primary tumors of the peripheral nerves themselves 2057

lead to painful destruction. Tumor compression regularly elicits pain when the affected nerve cannot give way (e.g., a spinal nerve).

Tumor Infiltration of Soft Tissues Tumor infiltration of soft tissues causes pain via the mechanisms described in the earlier discussion, as with massive infiltrations of the retroperitoneum. Infiltration and destruction of mobile structures (e.g., of the skeletal musculature) can lead to pain via disturbance of function. Here, the tumor spreads in the interstitium and destroys blood vessels, lymphatics, and nerves.

Tumor Infiltration of Bone The most frequent cause of pain in tumor patients is infiltration of bone. This applies to primary and secondary neoplasias originating from the bone marrow as well as to neoplasias of the bone itself. Such tumors always cause pain when they lead to an elevation of the intraosseous pressure, to loss of stability, or to a lesion of the periosteum resulting in periosteal elevation, or with the release of chemical mediators of nociception. The neural structures that generate nociception reside in the bone marrow, in the bone, and in the periosteum. In metastatic processes, the degree of bone destruction is often extensive. Vertebral spread of tumor may involve intervertebral foramina, where it can compress nerve roots. Further spread posteriorly leads to encroachment of the spinal cord and the spinal nerves. In the bone, metastases localized to the bone marrow result in osteolysis or osteosclerosis. Necroses and hemorrhages occur frequently in bone metastases and doubtless play a role in the etiology of pain. The hemorrhages probably result from microfractures. Metastatic bone disease is discussed in detail later.

Tumor Infiltration of Abdominal Hollow Organs Tumor involvement in abdominal hollow organs causes pain. This applies to all primary and secondary intestinal tumors. However, their paineliciting potency differs widely from individual to individual. The pain results from ulcerations, motility disorders, dilatations, and disorders of 2058

blood flow. In accordance with the extent of the lymphatic tissue, large tumors with extensive ulceration and hemorrhage occur in malignant lymphomas of the gastrointestinal tract. Perineural tumor infiltration, arteritis, or perineural inflammatory reactions are common in tumors of the abdominal and urogenital hollow organs. Tumor infiltration of the urinary bladder can vary from a sense of uneasiness felt in the suprapubic region or a severe, constant agonizing deep pelvic pain. The pain may also radiate and extend into the thighs. Intolerable cystitis may occur with tumor infiltration of the bladder wall.

Tumor Infiltration and Inflammation of Serous Mucosa The parietal pleura lines the inner chest wall, whereas the visceral pleura covers the lung surface including interlobar fissures. The peripheral part of the diaphragm and costal portion of the parietal pleura are innervated by somatic intercostal nerves with the central portion of the diaphragm innervated by the phrenic nerve. The visceral pleura are extensively innervated by pulmonary branches of the vagus nerve and the sympathetic trunk. Pleural carcinomatosis with infiltration of both parietal and visceral surfaces can be extremely painful and difficult to manage.244 Somatic nerves innervate the parietal peritoneum. These nerves also supply the muscles and skin of the overlying body wall. Afferent nerves that travel with the autonomic supply of the underlying viscera innervate the visceral peritoneum. Nociceptive information from diseases that affect the parietal or visceral peritoneum reflects these different patterns of innervation. Animals with peritoneal carcinomatosis exhibit hypersensitivity to mechanical stimulation and visceral pain-like behavior.245

TUMOR TYPE AND STAGE OF DISEASE Factors influencing the pain complaint include the primary tumor type, stage of disease, and tumor site. When metastatic disease appears, about one in three patients report significant pain. Vainio and Auvinen246 reported that moderate to severe pain was present in 51% of patients with advanced cancer with severe pain more commonly seen in patients with prostate, esophageal, gynecologic, colorectal, head/neck, breast, and lung cancers. At least half of lung and breast cancer patients had at least 2059

moderate intensity pain. Although pain tends to reflect the presence of metastases, this may not always be the case for certain tumor types, particularly for patients with breast or prostate cancers. Although many patients with bone metastases report bone pain, a significant fraction (21% of breast and 22% of prostate patients) was asymptomatic.208 Levren et al.247 examined the relationship between pain and bone metastases in patients with prostate or breast cancer referred for bone scintigraphy. In patients with prostate cancer, metastases were found in 47% of the patients with pain but only in 12% of the patients without pain (P = .01). In patients with breast cancer, metastases were more common in patients without pain (71%) than in patients with pain (34%; P = .02). Pain caused by tumor may occur at the onset of disease or at an advanced stage. Although rarely one of the early indicators of the onset of disease, pain is not a significant problem for the majority of patients in the early stages of disease, with 5% to 10% of patients with solid tumors reporting pain at a level that interferes with mood and activity. However, pain is obviously a major concern that often prompts the patient to seek medical consultation. Vuorinen248 found that 28% of newly diagnosed unselected cancer patients reported pain. Cleeland249 reported that the majority of patients with end-stage disease have pain of a severity that interferes with several aspects of the patient’s QOL. Daut and Cleeland118 found that pain was an early symptom of cancer in 40% to 50% of patients with cancer of the breast, ovary, prostate, colon, and rectum, and in about 20% of patients with cancer of the uterus and cervix. Knowing the natural history of the disease facilitates an understanding of the pain process and is important in determining the nature and timing of treatment. Examples of the more common disease processes follow.

Pancreatic Cancer Most pancreatic tumors are exocrine tumors, including ductal adenocarcinoma, acinar cell carcinoma, cystadenocarcinoma, adenosquamous carcinoma, signet ring cell carcinoma, hepatoid carcinoma, colloid carcinoma, undifferentiated carcinoma, pancreatoblastoma, and pancreatic mucinous cystic neoplasm. The most common form is ductal adenocarcinoma characterized by moderately to 2060

poorly differentiated glandular structures, comprising 80% to 90% of all pancreatic tumors. Endocrine pancreatic tumors are rare and account for only 1% to 2% of all pancreatic tumors. Pancreatic ductal adenocarcinoma is the fourth leading cause of cancer-related death in the United States.3 Surgical resection is the only potentially curative treatment, but because of the late presentation, only 15% to 20% of patients are candidates for surgical intervention. Even after complete resection, prognosis is poor with only 6% of patients (ranges from 2% to 9%) surviving 5 years after diagnosis.250,251 The highest incidence and mortality rates of pancreatic cancer are found in developed countries. Resectable cancers typically have no vascular or regional spread. Borderline cancers have regional spread into vessels (i.e., portal vein) or other organs (i.e., stomach), which would make surgery difficult, and locally invasive cancers have invasion into structures (e.g., celiac artery), which make curative surgery impossible. Up to 90% of patients with pancreatic cancer experience significant abdominal pain during the course of their illness.250 Incidence rates for pancreatic cancer in 2012 were highest in Northern America (7.4 per 100,000) and Western Europe (7.3 per 100,000), followed by other regions in Europe and Australia/New Zealand (equally about 6.5 per 100,000).251 In the United States, whites and blacks experienced opposite trends in pancreatic cancer death rates between 1975 and 2013 with white men death rates decreased by 0.7% per year from 1970 to 1995 and then increased by 0.4% per year through 2009. Among white women, rates increased slightly from 1970 to 1984, stabilized until the late 1990s, then increased by 0.5% per year through 2009. In contrast, the rates among blacks increased between 1970 and the late 1980s (women) or early 1990s (men) and then decreased thereafter.252 Pancreatic cancer is difficult to diagnose. The appearance of symptoms usually indicates an advanced stage and the most frequent presentations are progressive weight loss, anorexia, abdominal pain, and jaundice. These symptoms are nonspecific and varied in different regions of pancreas. Tumor in the head of the pancreas (75%) produces weight loss, painless jaundice, nausea, and vomiting. If cancer is located at the body/tail of the pancreas, patients usually present with abdominal pain that radiates to the sides or through to the back. Local tumor extension almost invariably 2061

involves the peripancreatic fat tissue through direct invasion of lymphatic channels and perineural spaces. Duodenum, stomach, gallbladder, and peritoneum are infiltrated by tumors located in the pancreatic head; body and tail tumors can invade liver, spleen, and left adrenal gland. Lymphatic spread to adjacent and distant lymph nodes seems to precede hematogenous spread, which affects, in descending order, liver, peritoneum, lungs, adrenals, kidneys, bones, and brain. At diagnosis, 30% to 40% of patients report abdominal pain, 80% develop pain with disease progression, and 44% of these describe the pain as severe. The presence of pain in newly diagnosed patients with potentially operable pancreatic cancer is an ominous predictor of resectability and of survival.253 A number of factors contribute to the generation and maintenance of pancreatic cancer pain. One of the most striking neural alterations in pancreatic cancer is neural invasion, which occurs in up to 100% of patients.254,255 Pancreatic cancer is characterized by invasion of nerves by cancer cells (neural invasion), pancreatic nerve damage, pancreatic neuroinflammation (neuritis), and noticeable hypertrophy with sprouting of intrapancreatic nerves.256 Cancer cells that invade nerves express a large set of neurotrophic factors such as NGF, artemin, neurturin that are similarly released by mast cells or other inflammatory cells and can strongly sensitize nociceptive nerve endings. Intrapancreatic nerves increase in size (neural hypertrophy) and number (increased neural density). The proportion of autonomic and sensory fibers (neural remodeling) is switched and is invaded by pancreatic cancer cells (neural invasion).257 These neuropathic alterations also correlate with neuropathic pain. Pain due to pancreatic cancer is usually abdominal, typically referred to the epigastric region or the upper abdominal quadrants, but it can also involve the lower quadrants or be diffuse.258 Back pain is associated with abdominal pain in 50% to 65% of cases, but only 5% to 10% of patients report it as their only complaint. In one series, 67% of patients could not describe their pain location better than as over the “diffuse abdomen.”259 Eating often aggravates the pain. Tumors of the head of the pancreas may cause epigastric pain with right flank radiation more often, whereas pain from tumors in the tail has left-sided radiation. Lying flat typically 2062

exacerbates it and sitting relieves it. This pain probably comes from retroperitoneal tumor involvement, and it may not respond to celiac plexus block. It often merges with similar syndromes caused by nodal or other soft-tissue tumor involvement in the retroperitoneal region (Table 42.10). The impact of pancreatic pain can be profound. It is commonly associated with depressed mood and contributes to the rapid decline in function that characterizes this disease.259,260 In addition, severe pain can influence survival.261–263 TABLE 42.10 Pancreatic Cancer Pain Syndromes Pain due to Tumor Involvement

Pain due to Cancer Therapies

Visceral pain: Pancreatic gland infiltration Gastric infiltration Duodenal infiltration Liver metastases: capsule distention, diaphragmatic irritation Biliary tree distention Bowel obstruction (duodenal, peritoneal carcinomatosis) Ischemic abdominal pain due to mesenteric vessel involvement

Postoperative pain syndromes: Delayed gastric emptying Wound dehiscence or non-healing

Somatic pain: Retroperitoneal involvement (direct, nodal) Parietal peritoneum and abdominal wall involvement Abdominal distention due to ascites Bone metastases

Biliary prosthesis complications

Neuropathic pain: Radiculopathy from retroperitoneal spread or bone metastatic involvement Lumbosacral plexopathy Epidural spinal cord compression

Post-chemotherapy pain syndromes: Liver chemoembolization Mucositis Post-radiation pain syndromes: Radiation enteritis

From Caraceni A, Portenoy RK. Pain management in patients with pancreatic carcinoma. Cancer 1996;78(3):639–653. Copyright © 1996 American Cancer Society. Reprinted by permission of John Wiley & Sons, Inc.

Ovarian Cancer Ovarian cancer may be subdivided into different histologic subtypes, which include epithelial cancer serous, endometrioid, clear-cell, and mucinous carcinomas. Of these types, high-grade serous carcinoma is the 2063

most commonly diagnosed. Histologically and clinically, low-grade endometrioid carcinoma and low-grade serous carcinoma are different compared with their high-grade counterparts. Other more rare pathology includes small-cell carcinoma (predominantly occurs in younger women) and carcinosarcoma. Nonepithelial ovarian cancers include germ cell tumors and sex cord stromal tumors, which account for approximately 10% of ovarian cancers. Estimated new cancer cases in the United States for 2017 were 22,440 with 14,080 deaths (fifth most common cause of death from cancer in women).3 Overall survival varies greatly based on stage at initial diagnosis with a 92% survival for stage I and 25% for stage IV.264 Epithelial ovarian cancer can spread by intraperitoneal, lymphogenous, and hematogenous mechanisms. The lifetime risk of ovarian cancer in women by the age 70 years is approximately 40% for BRCA1 and 18% for BRCA2.265 Most of these cancers are high-grade serous cancers. Other inherited disorders, such as Lynch syndrome, can increase the risk of ovarian cancer. Lynch syndrome is associated with colorectal, endometrial, and ovarian cancers but is also associated with cancers of the urinary tract, stomach, small intestine, and biliary tract. The symptoms of ovarian cancer are relatively nonspecific and often occur when the disease has spread throughout the abdominal cavity or with the presence of ascites. Abdominal discomfort or vague pain, abdominal fullness, bowel habit changes, early satiety, dyspepsia, and bloating are frequent presenting symptoms. Occasionally, patients may present with bowel obstruction due to intra-abdominal masses or shortness of breath due to pleural effusion. Early-stage disease is usually asymptomatic, and the diagnosis is often incidental, although such patients may occasionally present with dyspareunia or pelvic pain due to ovarian torsion. Serum CA-125 level has been widely used as a marker for a possible epithelial ovarian cancer in the primary assessment of a pelvic mass. Although CA-125 is the best known serum ovarian cancer biomarker, it is not the only one: Carcinoembryonic antigen (CEA) (mucinous), lactate dehydrogenase (LDH) (dysgerminoma, mixed germ cell tumors), β-human chorionic gonadotropin (β-hCG) (choriocarcinoma, mixed germ cell tumors), inhibin B (granulosa cell tumors), α-fetoprotein (yolk sac tumors, embryonal cell tumors), and HE4 are also available.266 2064

The prevalence of pain associated with ovarian cancer resembles the prevalence rates in populations with other solid tumors.267 Ovarian cancer spreads by intraperitoneal, lymphatic, and locally invasive pathways. Lymphatic pathways may extend from the abdominal retroperitoneum to the groin via the inguinal/femoral canals or across the diaphragm to the pleural space. Intraperitoneal spread of tumor begins with extension of tumor through the ovarian capsule, allowing implantation of tumor throughout the abdomen. Intraperitoneal metastases show a predilection for the omentum and diaphragm, but no organ is spared, and concomitant ascites is frequent. Portenoy et al.267 noted that pain, fatigue, and psychological distress were the most prevalent symptoms in patients with advanced (stage III or IV) ovarian cancer. Patients generally describe pain as occurring in the abdominopelvic or lower back region, as being frequent or almost constant and moderate to severe in intensity. Patients with advanced disease may experience pain in the lower extremities either from invasion of the lumbosacral plexus by tumor or by lymphedema secondary to iliac vessel occlusion.

Cervical Cancer Cervical cancer is the fourth most common malignancy diagnosed in women worldwide. Nearly all cases result from infection with the human papillomavirus (HPV), and prevention includes screening and vaccination. Rates have declined in the United States with an estimated 12,820 new cases in 2017 and 4,210 deaths.3 Disparities in incidence and mortality still occur, with black and Hispanic women continuing to have higher rates of cervical cancer than white women.268 There are several histologic subtypes of cervical carcinoma, but the majority of cases tend to be HPVassociated malignancies including adenocarcinoma, squamous cell carcinoma, or adenosquamous carcinoma. Neuroendocrine (small-cell or large-cell) carcinomas are not associated with HPV exposure and clear cell carcinoma and are rare. Computed tomography (CT) or MRI is often used to define lymph node status and to assess extent of local disease. Combined positron emission tomography (PET) and CT imaging may be useful for detecting smaller nodal disease.269 Cervical cancer usually spreads to regional lymph nodes, and parametrial invasion is common. The 2065

common sites of distant spread include the aortic (para-aortic, periaortic), lateral aortic and mediastinal nodes, lungs, and skeleton. Recurrent cervical cancer is almost always incurable.

Prostate Cancer Prostate cancer is one of the most prevalent cancers in men worldwide. Estimated new cancer cases in the United States for 2017 were 161,360 with 26,730 deaths.3 The majority of prostate cancer survivors (64%) tend to be older (aged 70 years or older) with less than 1% under the age of 50 years.8 Prostate cancer varies widely in its intrinsic development, ranging from indolent to aggressive. Once clinically significant disease is established, surgery, radiation, and androgen deprivation therapy (ADT), which all carry substantial morbidities, are considered standard treatment options for localized disease. It is often insidious and asymptomatic even when advanced and for detection, MRI is currently the best imaging modality.270 Prostate cancer is a heterogeneous group of malignant tumors and 95% are adenocarcinoma originating from the glands and ducts in the prostate. Most adenocarcinomas are of the acinar type, typically referred to as prostate carcinomas. More than 1% consist of other variants that often have a poor prognosis such as ductal carcinoma, mucinous carcinoma, signet ring cell carcinoma, and small cell carcinoma. Five percent of prostate cancer cases are of other types originating from transitional epithelial cells in the urethra or pars prostatic urethra (urothelial carcinoma), support tissue (sarcomas), or lymphoid tissue (lymphomas). Prostate adenocarcinoma may spread locally, by direct invasion of seminal vesicles, urinary bladder, or surrounding tissues or distantly. Distant metastases can derive from an initial lymphatic spread or from a direct hematogenous spreading, mainly to the bones. The Gleason system is the most widely used grading system for prostate cancer (adenocarcinoma only). Prostate cancers are stratified into five grades (1 to 5) on the basis of the glandular pattern and degree of differentiation. The Gleason score is derived from the sum of the most represented grade (primary grade) with the second most represented grade (secondary grade) (e.g., 3 + 4 = 7); this correlates better with prognosis than the single Gleason grade. The Gleason system can be applied to biopsy and surgical specimens, but not 2066

to fine needle biopsy (FNB), which lack architectural data. Most prostate cancers in the United States are diagnosed by prostate-specific antigen (PSA) testing, although many expert groups, including the American Cancer Society, have concluded that data on the efficacy of PSA screening are insufficient to recommend routine use of this test and recommend that for the average risk asymptomatic male over 50 years, a PSA with or without a digital rectal examination after receiving information about the benefits, risks, and uncertainties associated with prostate cancer screening is appropriate.271 Digital rectal examination is recommended along with PSA for men with hypogonadism because of reduced sensitivity of PSA. Men at higher risk, including African American men and men with a family member (father or brother) diagnosed with prostate cancer before age 65 years, should receive this information beginning at age 45 years. The clinical behavior of prostate cancer ranges from indolent, localized disease to aggressive, disseminated disease associated with significant morbidity and mortality. Although the majority of prostate cancer cases present while the disease is localized to the prostate, some patients have evidence of metastatic disease at diagnosis. Typically, metastases are found in the axial skeleton, pelvic lymph nodes, and the lungs. Because of the predilection of prostate cancer to spread to bony sites, a significant proportion of patients with metastatic disease will have bone pain. Metastases from prostate cancer, most of which are adenocarcinomas, nearly always form osteoblastic lesions in bone; in contrast, bone metastases from kidney, lung, or breast cancers more often are osteolytic. However, metastases from the relatively uncommon neuroendocrine tumors of the prostate also produce osteolytic lesions. Approximately 90% of patients who die from prostate cancer have evidence of bone metastases.272 Radiographically, bone metastases are detected on technetium-99m (99mTc) bone scintigraphy scans. Newer modalities for detection include 18sodium fluoride PET and 18fluorodeoxyglucose PET (FDG-PET). Five-year relative survival varies with stage at diagnosis from 80% or more when malignancy is confined to the prostate to about 25% where bone metastases are present. Radium-223 (223Ra) is an α emitter with a half-life of 11.4 days. It is a calcium mimetic and forms complexes with bone mineral hydroxyapatite in areas of active bone remodeling. The 2067

α particles cause double-strand DNA break of cells. With a range of penetration of 90%) and, to a 2075

lesser degree, carcinoid tumors, leiomyosarcomas, and lymphoma. Spread to regional lymph nodes generally correlates to depth of invasion by the primary tumor and the grade of differentiation. Nodal spread occurs in 10% to 20% of tumors confined to the bowel wall. Hematogenous spread is usually to the liver via portal venous transmission. The liver is the prime organ for metastatic spread (65%); extraabdominal metastases in lung (25%) and brain and bone (10%) are much less common. Approximately, 15% to 20% of patients with CRC will present with metastatic liver disease, and half of all patient with CRC will develop liver metastases, with a median survival of 8 to 12 months in untreated patients.289 Liver imaging should be done for all patients with CRC. MRI had a significantly higher sensitivity than did CT for lesions less than 10 mm. Surgical resection represents the only chance of longterm survival, but only 20% to 25% of patients may be eligible for resection.290 Systemic chemotherapy and/or intra-arterial locoregional techniques may be options for patients not eligible for surgery. These techniques include hepatic arterial infusion, transarterial chemoembolization (TACE), embolization with drug-eluting beads (DEBTACE), selective internal radiation therapy with 90Y (SIRT), and percutaneous ablation with radiofrequency or microwave ablation. The majority of patients with stage I and II colon cancer undergo partial or total colectomy alone (84%), whereas about two-thirds of those with stage III disease (as well as some with stage II disease) receive chemotherapy in addition to colectomy to lower their risk of recurrence. For patients with rectal cancer, proctectomy or proctocolectomy is the most common treatment (61%) for stage I disease, and about one-half also receive radiation and/or chemotherapy. Stage II and III rectal cancers are often treated with neoadjuvant chemoradiation therapy.

Leukemias and Lymphomas The majority of patients with leukemia (92%) are diagnosed aged 20 years or older. Acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) are the most common types in adults. Chemotherapy with or without stem cell transplantation (SCT) is the standard treatment for AML. Approximately 60% to 85% of adults aged 60 years and younger 2076

with AML can expect to attain complete remission status after the first phase of treatment, and 35% to 40% of patients in this age group will be cured. In contrast, 40% to 60% of patients aged older than 60 years will achieve complete remission, but only 5% to 15% will be cured. The two types of lymphoma are Hodgkin lymphoma (HL) and NHL. NHLs may be indolent or aggressive and each include subtypes that progress and respond to treatment differently. Prognosis and treatment depend on the stage and type of lymphoma. The two major types of HL are classical HL (CHL) and nodular lymphocyte-predominant HL (NLPHL). CHL is the most common and is characterized by the presence of ReedSternberg cells. NLPHL comprises only about 5% of cases and is a more indolent disease with a generally favorable prognosis. The 5-year and 10year survival rates for HL are 86% and 80%, respectively. The 5-year survival rate is 94% for NLPHL and 85% for CHL. The most common types of NHL are diffuse large B-cell lymphoma (DLBCL), representing 37% of cases, and follicular lymphoma, representing 20% of cases. DLBCLs grow quickly, but most patients with localized disease and about 50% of those with advanced-stage disease are cured. In contrast, follicular lymphomas tend to grow slowly and often do not require treatment until symptoms develop, but many are not curable. Some cases of follicular lymphoma transform into DLBCL. The 5-year survival rate is 86% for follicular lymphoma and 61% for DLBCL; 10-year survival declines to 77% and 53%, respectively.

Multiple Myeloma Multiple myeloma (MM) is a clonal plasma cell malignancy that accounts for 10% of all hematologic malignancies. MM usually progresses from asymptomatic precursor stages, namely monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) with possible progression to MM. Some patients experience rapid progression from MGUS/SMM to MM, whereas others may remain indolent with minimal progression during their lifetimes. The median age of diagnosis is 69 years. The 5-year survival rate of patients with MM is 48.5%, and despite the introduction of immunomodulatory drugs and proteasome inhibitors, many patients with high-risk features still have low 2077

progression-free survival rates and poor overall survival. CT imaging is useful for detecting early bone destruction but not for detecting myeloma activity in areas of prior destruction. MRI can detect early marrow infiltration. The first biomarker for MM was the Bence Jones protein. Other markers included M protein, plasmacytosis of the bone marrow, and β2 microglobulin. Serum free light chain (FLC) assays were developed to aid the diagnosis of MM and to monitor treatment response and disease progression. Treatment plans are guided by serially measuring serum FLC levels and the FLC ratio to define a complete response or progressive disease in oligosecretory myeloma.

Tumor Markers A biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention and are important tools for diagnosis, prognosis, and management of malignancies.291 Most tumor markers are produced by normal cells (tumor-associated) as well as by cancer cells (tumor-derived); however, they are produced at much higher levels in cancerous conditions. Markers include a variety of substances like cell surface antigens, cytoplasmic proteins, enzymes, hormones, oncofetal antigens, receptors, oncogenes, and their products. These substances can be found in the blood, urine, stool, tumor tissue, or other tissues or bodily fluids of some patients with cancer. Most tumor markers are proteins, but patterns of gene expression and changes to DNA are also used as tumor markers. Predictive biomarkers, which include somatic mutations in BRAF and EGFR genes where the presence of certain molecular targets helps identify the appropriate, targeted therapy and thus predict the response to these agents. They can also be beneficial to identify patients with high susceptibility to certain cancers through detection of germline mutations, such as BRCA or somatic mutations. DNA sequencing and gene expression studies have shown that at a molecular level, almost every case of breast cancer is unique and different from other breast cancers.292 For optimal management, patients should receive treatment that is guided by the molecular composition of their tumor. Mandatory biomarkers for every newly diagnosed case of breast 2078

cancer are ER receptors and PR receptors in selecting patients for endocrine treatment and HER2 for identifying patients likely to benefit from anti-HER2 therapy.293 Examples of tumor markers in malignancy are shown in Table 42.13. TABLE 42.13 Tumor Markers in Malignancy Marker

Tissue Analyzed

Cancer Type

α-Fetoprotein β-2-microglobulin β-human chorionic gonadotropin (β-hCG) BRCA1 and BRCA2 gene mutations BRAF V600 mutations CA15-3/CA27.29 CA19-9

Blood Blood, urine, CSF Urine, blood

Liver cancer, germ cell tumors MM, CLL, some lymphomas Choriocarcinoma, germ cell tumors

Blood

Ovarian cancer

Tumor Blood Blood

CA-125 Calcitonin Carcinoembryonic antigen (CEA) Chromogranin A EGFR gene mutation Estrogen receptor (ER)/progesterone receptor (PR) HER2/neu gene amplification or protein overexpression

Blood Blood Blood Blood Tumor Tumor

Melanoma, colorectal cancer Breast cancer Pancreatic cancer, gallbladder cancer, bile duct cancer, gastric cancer Ovarian cancer Medullary thyroid cancer Colorectal cancer Neuroendocrine tumors Non–small-cell lung cancer Breast cancer

Immunoglobulins

Blood, urine

KRAS gene mutation analysis

Tumor

Prostate-specific antigen (PSA) Thyroglobulin

Blood Blood

Tumor

Breast cancer, gastric cancer, and gastroesophageal junction adenocarcinoma Multiple myeloma and Waldenström macroglobulinemia Colorectal cancer and non–smallcell lung cancer Prostate cancer Thyroid cancer

NOTE: Neu is derived from a rodent glioblastoma cell line. BRAF, gene that encodes protein B-Raf; BRCA1 and BRCA2, breast cancer gene and protein product; CA, cancer antigen; CLL, chronic lymphocytic leukemia; CSF, cerebrospinal fluid; EGRF, epidermal growth receptor factor; HER2/neu, human epidermal growth factor receptor; KRAS, proto-oncogene for Kirsten rat sarcoma viral oncogene; MM, multiple myeloma.

PATTERNS OF CANCER PAIN Cancer patients may have constant or intermittent pain. The term 2079

breakthrough pain (BTP) was popularized by Portenoy and Hagen294 in 1990 and refers to sudden increases in the base level of pain or different but recurring pains. BTP was originally defined as “a transitory exacerbation of pain that occurs in addition to otherwise stable persistent pain or one that interrupts a tolerable background level of pain” or as “a transitory exacerbation of pain that occurs on a background of otherwise stable pain in a patient receiving chronic opioid therapy.”295 However, most definitions consider BTP only after the background pain is adequately controlled. BTP should be distinguished from crescendo pain, which largely results from poorly controlled baseline pain.296 The estimated prevalence of BTP in cancer patients may be more than 50%,297 but the prevalence is difficult to estimate because of difference between studies in the definitions and diagnostic criteria and the inclusion of patients with poorly controlled background pain.298 Different terms for BTP have been used in some studies including incident pain, incidental pain, episodic pain, and transitory pain.295 The cause and anatomical site of BTP is often, but not always, the same as that of the baseline persistent pain.299 Typical features of BTP include rapid onset (the time from onset of BTP to peak severity is usually within 3 to 5 minutes), short duration (approximately 30 minutes), and of variable intensity.300 There are three types of BTP: 1. Incident pain: pain that is precipitated, stimulus dependent, or triggered such as turning in bed, weight bearing, a bowel movement, coughing, swallowing meals, etc. Often, incident pain is well defined and predictable, so that clinicians can anticipate and treat the problem prophylactically. Incident pain may be volitional or nonvolitional. 2. End of dose failure: pain that emerges because of too much time between doses of medication. This pattern is predictable for the individual patient and readily preventable by using time-contingent dosing at an appropriate interval. The key is monitoring symptoms in relation to the dosing schedule. 3. Spontaneous pain: pain that occurs spontaneously without relationship to particular events or procedures. These pains are more difficult because of their unpredictable nature and often fleeting 2080

character. Cancer-related BTP has high interference with activity, mood, ability to walk and work, social relations, sleep, and enjoyment of life.300–302 Uncontrolled or poorly controlled pain of any etiology is strongly associated with impairment of sleep, walking, daily activities, enjoyment of life, and relationships with others. It also is correlated with worsening of anxiety and depression, dissatisfaction with opioid therapy, and poor medical outcomes.303 In addition, patients with cancer-related BTP or uncontrolled pain are likely to use more health care resources, have more pain-related hospitalizations and emergency department visits, and have greater direct and indirect treatment costs than those without BTP.304

CANCER PAIN SYNDROMES Tables 42.14 to 42.17 list the common pain syndromes in the patient with cancer. TABLE 42.14 Pain Syndromes due to Tumor Involvement Primary Etiology

Pathophysiology

Tumor Invasion of Bone Vertebral body metastases Subluxation of Metastasis of atlas odontoid process of axis → fracture of atlas → compression of spinal cord or brainstem C7–T1 metastases Cancer of breast and lung → hematogenous spread or more frequently tumor originating in brachial plexus or paravertebral space → spread to adjacent vertebra and epidural space L1 metastases Frequent site of metastasis from

Characteristics of Pain

Other Symptoms and Signs

Severe neck pain radiating to back and top of skull, aggravated by flexion and other movements

Progressive sensory, somatomotor, and autonomic dysfunction beginning in upper extremity

Constant, dull, aching pain in paraspinal area radiating to both shoulders; unilateral, radicular pain with radiation to shoulder and medial (ulnar) aspect of limb Dull, aching pain in midback with

Tenderness on percussion of spinous process; paresthesia and numbness in ulnar distribution of limb; progressive weakness of triceps and hand; Horner syndrome indicating sympathetic involvement Possible numbness and weakness in the back;

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breast, prostate, or other tumors

Sacral metastases

Another frequent site of metastasis from breast, prostate, or other tumors

Base of the skull metastases Jugular foramen Metastasis to jugular foramen with involvement of cranial nerves IX– XII Clivus syndrome

Metastasis to clivus of sphenoid bone and basilar portion of occipital bone

Sphenoid sinus

Metastasis to the sphenoid sinus on one or both sides

Cavernous sinus

Metastasis to cavernous sinus syndrome from breast, prostate, and lung Metastasis from breast, lung, prostate

Occipital condyle

reference to regions of one or both sacroiliac joints and superior iliac crest; radicular pain with girdle-like distribution anteriorly or to both paraspinal areas in the sacroiliac region Dull, aching pain in the low back and/or coccygeal region exacerbated by lying or sitting and relieved by walking Occipital pain with reference to the vertex and one or both shoulders and arms, exacerbated by head movement Progressively severe vertex headache exacerbated by neck flexion Severe bifrontal headache radiating to both temples with intermittent retro-orbital pain Unilateral frontal headache and dull aching pain in supraorbital and facial region Severe localized continuous, unilateral occipital pain aggravated by neck flexion

Other bone involvement

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pain exacerbated by lying or sitting and relieved by standing

Perianal sensory loss and bowel and bladder dysfunction and impotence

Tenderness of occipital condyle and often ptosis, hoarseness, dysarthria, dysphagia, and neck and shoulder weakness Dysfunction of lower cranial nerves (VII– XII), which begins unilaterally but extends bilaterally Nasal stuffiness or sense of fullness in the head associated with diplopia Dysfunction of cranial nerves III–VI, diplopia, ophthalmoplegia, papilledema Cranial nerve XII paralysis → paralysis of tongue; weakness of sternocleidomastoid, stiff neck

Pelvis

Metastasis from breast, prostate, or other tumors

Long bones

Metastasis from breast, prostate, or other tumors

Dull, aching pain in sacrum, hips, or pubis

Dull, aching, severe pain localized to site of tumor that may be referred (e.g., reference to knee from hip metastasis); pathologic fracture produces severe pain on movement Tumor Involvement of Nerves, Plexus, or Spinal Cord Peripheral, cranial, Infiltration, Dull, aching, burning or spinal compression, or pain associated neuropathy damage to nerve with bouts of lancinating pain in distribution of affected nerve or nerves; hyperpathia Brachial plexus Compression, Progressively more infiltration, or severe, dull, damage of aching pain which brachial plexus by is first located in metastatic tumor the shoulder and or lower cervical arm and vertebral and upper thoracic border of scapula vertebra or and later extends Pancoast tumor to medial part of arm, elbow, forearm, and hand Lumbosacral Compression, Radicular pain either plexus infiltration, or in groin and damage of lumbar anterior thigh (L1, and sacral plexus L2, and L3 nerve by cancer of the involvement) or prostate, bladder, down the posterior uterus, cervix, or aspect of leg to the colon from heel (L5, S1, and extension of tumor S2 distribution) or into adjacent dull, aching lymph nodes and midline pain in the bone perianal area (S2, S3, S4

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Extension to sacral plexus with consequent motor, sensory, and/or autonomic changes

Hypesthesia, dysesthesia, motor, and/or autonomic dysfunction and reflex changes

Paresthesia, dysesthesia, hypesthesia; subjective numbness and progressive muscle weakness in C7, C8, and T1 distribution, often Horner syndrome and anhidrosis of the ipsilateral face Paresthesia followed by numbness and dysesthesia and progressive motor and sensory loss in the areas supplied by the involved nerves

Reflex sympathetic dystrophy

Compression, infiltration, or damage of major nerve or plexuses

Leptomeningeal carcinomatosis

Tumor infiltration of the cerebrospinal leptomeninges with or without invasion of the meninges of the brain

Epidural spinal cord compression

Tumor compression of cervical, thoracic, or lumbosacral parts of spinal cord and involvement of vertebra or roots of spinal nerves

Tumor Involvement of Viscera Obstruction of Contraction of hollow viscus or of smooth muscle ductal system of under isometric solid viscus conditions → intense distention of smooth muscles Rapid tumor Rapid growth of growth in solid hepatic, splenic, or viscus kidney tumors → rapid distention and stretching of investing fascia → stimulation of mechanical nociceptors Other Types of Tumor Involvement Tumor involvement

distribution) Severe burning pain not limited to a segmental or peripheral nerve distribution; aggravated by touch and emotional stress Pain in 40% of patients of two types: headache, with or without neck stiffness and pain in the low back and buttock regions Local dull, aching pain, and tenderness in the region of involved vertebral body or radicular pain, which is unilateral with cervical or lumbosacral compression and bilateral with thoracic cord compression Diffuse, poorly localized, dull, aching, or colicky pain referred to abdominal wall or chest wall Dull, aching, poorly localized pain referred to midline (liver) or in one side in lower thoracic and upper lumbar segments

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Hyperalgesia, vasomotor, and sudomotor disturbances and other symptomatology of causalgia

Malignant cells in cerebrospinal fluid, elevated protein and low glucose levels

Depends on site of epidural compression, includes motor weakness progressing to paraplegia, sensory loss, and loss of bowel and bladder function

Dyspnea and cough with thoracic viscera; abdominal distention, nausea, vomiting with abdominal visceral pathology Symptomatology of visceral dysfunction

of blood vessels Infiltration

Obstruction of large vein

Obstruction of large artery Necrosis or ulceration of mucous membrane

Perivascular lymphangitis and vasospasm Venous engorgement → progressive edema → distention of fascial compartments and soft tissue Ischemia in tissues with liberation of algesic substances Necrosis, infection, and inflammation of mucous membrane → algesic substances → lowering of nociceptors’ threshold

Burning pain in the areas supplied by the affected vessels Severe headache with obstruction of veins to head; pain in limbs with obstruction in axilla or pelvis

Signs of vasoconstriction or ischemia

Progressively severe, burning pain

Paresthesia, pallor of affected part

Excruciating local or referred pain depending on site of lesion

Signs of infection or inflammation

Edema and cyanosis of affected part

TABLE 42.15 Pain Syndromes Associated with Cancer Therapy Primary Etiology

Pathophysiology

Postsurgical Syndromes Postthoracotomy, Partial injury or postradical neck complete severance resection, of nerves during postmastectomy operation → damage to nerve membrane or neuroma formation, which becomes hypersensitive to pressure and norepinephrine → abnormal sensory input to central nervous system (peripheral-central mechanisms) Postamputation pain Persistent nociception in stump and loss of sensory input to

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Characteristics of Pain

Other Symptoms and Signs

Continuous, burning or dull, aching pain with occasional bout of lancinating pains in the areas supplied by affected nerves, aggravated by touch, movement, or emotional stress with catecholamine release

Dysesthesia, hyperesthesia in the scar area with hypesthesia in the surrounding zone

Constant aching or burning pain in stump or in

Sudomotor and vasomotor changes in stump

neuraxis → deafferentation (peripheral-central mechanism)

Postchemotherapy Pain Peripheral Symmetrical neuropathy polyneuropathy caused by vinca alkaloids (peripheral mechanism) Steroid Diffuse myalgias and pseudorheumatism arthralgias caused by withdrawal of steroid medication (peripheral mechanism) Aseptic necrosis of Aseptic necrosis of bone humoral head or femoral head as complication of chronic steroid therapy (peripheral mechanism) Mucositis Drug produces biochemical changes in mucous membranes and other structures (peripheral mechanisms). Postradiation Therapy Pain Radiation fibrosis of Radiation-induced brachial or fibrosis of lumbosacral plexus connective tissue surrounding plexus and consequent injury to nerve structures develops 6 mo to 20 y following therapy → deafferentation (peripheral-central mechanisms)

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phantom limb or cramping “proprioceptive” pain characterized by abnormal position of missing part of limb; also lancinating pain Constant burning pain in the hand and/or feet

Dysesthesia and paresthesia

Diffuse pain and tenderness in affected muscles and joints

Fatigue and general malaise; these and the pain disappear with reinstitution of steroid medication

Dull, aching pain in the shoulder or knee

Limitation of joint movement with inability to use arm or hip joint → frozen shoulder or impaired hip

Severe, excruciating pain in mouth, throat, nasal passages, and gastrointestinal tract

Difficulty or inability to eat, drink, or even talk

Progressively increasing, severe, diffuse, burning pain in a part or the entire limb, which occurs after other symptomatology

Numbness, paresthesia, dysesthesia, and motor weakness in distribution of C5 and C6 in the upper limb or in lower limb

Radiation myelopathy

Painful peripheral nerve tumors

Postherpetic neuralgia

Damage to spinal cord → Brown-Séquard syndrome progresses to complete transverse myelopathy (central pain) Radiation induces nerve sheath tumors 4–20 y after therapy Induced by radiation or after herpes zoster in the area of tumor pathology

Pain that is localized or referred to peripheral structures

Dysesthesia and other symptomatology of myelopathy

Progressively severe, burning, aching pain in distribution of involved nerves Continuous burning pain associated with intermittent lancinating pain

Progressive neurologic deficit

Dysesthesia, hypesthesia, and hyperpathia

TABLE 42.16 Pain Syndromes Caused by Cancer-Induced Pathophysiologic Changes Primary Etiology

Pathophysiology

Paraneoplastic syndromes Myofascial pain syndromes Debility, constipation, bed sores, rectal or bladder spasm, gastric distention

— — Related to specific lesions depending on involved site

Characteristics of Pain

Other Symptoms and Signs

— — Local or referred pain

— — Related to specific pathophysiology

TABLE 42.17 Pain Syndromes Unrelated to Cancer Primary Etiology

Pathophysiology

Characteristics of Pain

Examples: arthritis, migraines, osteoporosis

Pathology of affected part

Local or referred pain

Other Symptoms and Signs Related to specific pathophysiology

Table 42.18 lists the prevalence of painful manifestations of cancer and their common etiologies. Bone, viscera, and nerve are the most common sites of metastases associated with chronic cancer pain. Each of these sites will be dealt with separately. TABLE 42.18 Prevalence of Painful Manifestations of Cancer and Common Etiologies Primary Site of

Approximate Incidence of Pain

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Cancer

(%)

Common Pain Syndromes

Oropharynx

55–80

Colon–rectum

45–95

Pancreas Liver/biliary tract Lung

70–100 65–100 55–90

Breast

55–100

Uterus–cervix and ovary Prostate

40–100

Post-radical neck dissection syndrome Infection Bone metastasis Perineal pain syndrome Lumbosacral plexopathy Epidural spinal cord compression Abdominal visceral pain Abdominal visceral pain Bone metastasis Epidural spinal cord compression Brachial plexopathy Postthoracotomy syndrome Brachial plexopathy Postmastectomy syndrome Bone metastasis Epidural spinal cord compression Leptomeningeal carcinomatous Lumbosacral plexopathy

Urinary tract

60–100

55–100

Lymphoma and leukemia

5–75

Sarcoma and primary bone tumors

75–90

Bone metastasis Base of skull syndromes Vertebral body syndromes Epidural spinal cord compression Lumbosacral plexopathy Epidural spinal cord compression Leptomeningeal carcinomatosis Bone pain Mucositis Postamputation pain (stump, phantom limb) Epidural spinal cord compression

Bone Metastases Common locations for metastasis are the lung, liver, brain, and bone. Bone is the third most common site for tumor cells to spread305 and is most prevalent in advanced breast (70% to 80%), prostate (70% to 80%), thyroid (60%), lung (10% to 50%), and renal cancers (30%).306 Prostate, lung, breast, kidney, and thyroid cancer account for 80% of skeletal metastases and MM favors involvement of the bone marrow. The most common sites of bone metastases are the spine, ribs, pelvis, proximal femur, and skull. Breast cancer preferentially metastasizes to the lungs and 2088

bones, whereas prostate cancer almost exclusively metastasizes to the bones.307 Bone metastases may be classified according to the primary mechanism of interference with bone remodeling as osteolytic, osteoblastic, or mixed.308 In osteolytic lesions, bone destruction is primarily mediated by osteoclasts and not a direct effect of tumor cells, whereas osteoblastic (or osteosclerotic) lesions are characterized by the deposition of new bone. Osteolytic bone metastases are presumed to be caused by the release of osteoclastogenic agents by tumor cells in the bone microenvironment, whereas osteoblastic metastases are the result of the release of factors that stimulate osteoblast proliferation, differentiation, and uncontrolled bone formation by metastatic cancer cells. Accordingly, bone metastases are typically characterized as “lytic,” “sclerotic,” or “mixed,” according to radiographic appearances. Metastasis to the bones is facilitated by the fenestrated structure of the bone marrow sinusoid capillaries, high blood flow in the areas of red marrow, and adhesive molecules on tumor cells that bind to the bone marrow stromal cells such as osteoblasts and osteoclasts as well as the bone matrix. Bone homeostasis is maintained by balanced production of osteoblasts and osteoclasts. Tumor cells influence bone cells in two predominant ways. Most often, cancer cells stimulate the osteoclast lineage to increase osteoclast differentiation and activity while simultaneously inhibiting osteoblasts. Osteoclastic bone resorption then exceeds osteoblastic bone formation resulting in bone degradation and the formation of osteolytic lesions (as may be seen in breast, lung, and MM). In some cases, instead of inhibiting osteoblasts, tumor cells release substances to stimulate the osteoblast lineage to increase osteoblast differentiation and new bone deposition causing osteoblastic lesions. Mechanistically, osteoclasts and osteoblasts play significant roles in the formation of both lesion types. In osteolytic bone metastases, tumor cells secrete factors that stimulate osteoclast activity through the activation of the receptor activator of nuclear factor–κB ligand (RANKL)/RANK pathway, a primary mediator of osteoclast-mediated bone resorption.309 Osteoblasts secrete receptor activator of RANKL which interacts with osteoclast precursors displaying RANK receptor on their surface, resulting in their activation and finally maturation into functional osteoclasts. Osteoblasts also produce 2089

osteoprotegerin (OPG), a soluble decoy receptor which can block RANK/RANKL signaling by scavenging of RANKL. The activation of osteoclasts is triggered by the balance between RANKL and OPG. RANKL also can induce factors involved in migration, invasion, and angiogenesis such as matrix metalloproteinases 1 and matrix metalloproteinases 9 (MMP1, MMP9), matrix metalloproteinase inducer EMMPRIN/CD147, intercellular adhesion molecule-1 (ICAM-1), IL-6 and IL-8, and VEGF and decrease the expression of metastasis suppressor serpin 5b/maspin. RANKL can also promote the function of regulatory T cells (Tregs) and macrophages. Osteolysis is based on a self-perpetuating signaling system (vicious cycle) that is maintained by mitogenic factors for tumor cells such as TGF-β, insulin-like growth factor-1 (IGF-1), fibroblast growth factors (FGFs), PDGFs, and Ca-ions released from demineralized bone as well as parathyroid hormone-related peptide (PTHrP) derived from tumor cells. PTHrP acts as a promotor of osteolysis by osteoclasts (Fig. 42.8).

FIGURE 42.8 Mechanism of osteolytic bone metastases. Metastatic cancer cells are attracted to spindle-shaped N-cadherin positive osteoblasts (SNO) and remain dormant. Quiescent cells can become activated and grow giving rise to an overt metastasis. The metastatic cells produce factors, which include parathyroid hormone-related peptide (PTHrP), interleukins (ILs), PGEs, and CXCR4 that mediate their interaction with osteoblastic cells of the metastatic microenvironment. Osteoblasts, in turn, communicate with preosteoclasts, primarily via the receptor activator for

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nuclear factor κB (RANK)–receptor activator for nuclear factor κB ligand (RANKL) axis and promote osteoclastic morphologic and functional maturation. PTHrP can also induce osteoclastic maturation via non-RANK/RANKL-dependent pathways. Fully activated osteoclasts resorb bone causing osteolytic bone disease. Hypoxic conditions and factors that are released during the degradation of the bone extracellular matrix further stimulate cancer cells, feeding the “vicious circle” of lytic bone metastasis. β2AR, β2 adrenergic receptor; ECM, extracellular matrix; IGF, insulin-like growth factor; IKK, inhibitor of NF- κB kinase; MAPK, mitogen-activated protein kinase; OBL, osteoblast; OCL, osteoclast; OPG, osteoprotegerin; PGE, prostaglandin E; PLC, phospholipase C; SC, stromal cell; SNS, sympathetic nervous system; TGF-β, transforming growth factor-β; TNF-α, tumor necrosis factor-α. (From Papachristou DJ, Basdra EK, Papavassiliou AG. Bone metastases: molecular mechanisms and novel therapeutic interventions. Med Res Rev 2012;32[3]:611–636. Copyright © 2010 Wiley Periodicals, Inc. Reprinted by permission of John Wiley & Sons, Inc.)

Osteoblastic bone metastases are preferentially associated with prostate cancer but may also occur with breast, lung, carcinoid, and medulloblastoma tumors and produce sclerotic lesions. Endothelin-1 has been implicated in osteoblastic metastasis from breast cancer. It stimulates the formation of bone and the proliferation of osteoblasts in bone organ cultures, and serum endothelin-1 levels are increased in patients with osteoblastic metastasis from prostate cancer.310 Furthermore, in an animal model of osteoblastic metastasis, treatment with a selective endothelin1A–receptor antagonist decreased both osteoblastic metastasis and the tumor burden. A vicious circle may also be involved in osteoblastic metastasis in which tumors induce osteoblast activity and thus the subsequent release from the osteoblasts of growth factors that increase tumor growth. In addition to endothelin-1, PDGF, a polypeptide produced by osteoblasts in the bone microenvironment, urokinase, and PSA may also be involved. Overproduction of urokinase-type plasminogen activator (u-PA) by prostate-cancer cells increases bone metastasis. Human PC3 prostate-cancer cells produce a factor that is homologous to u-PA. Prostate-cancer cells also release PSA, a kallikrein serine protease. PSA can cleave parathyroid hormone–related peptide at the N-terminal, which could block tumor-induced bone resorption. It may also activate osteoblastic growth factors released in the bone microenvironment during the development of bone metastases, such as IGF-I and IGF-II or TGF-β (Fig. 42.9).310

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FIGURE 42.9 Mechanisms of osteoblastic bone metastases. Cancer cells secrete a series of factors that augment osteoblast activation and bone formation at the site of metastasis. Two of the major signaling cascades involved in this process are the endothelin-1A/endothelin-1A receptor and the Wnt/β-catenin, which target osteoblast-specific genes such as c-jun, runx2, osterix, and c-myc. In addition, cancer cells produce urokinase plasminogen activator (uPA) that activates proteases such as prostate-specific antigen, further enhancing the osteosclerotic process either via activation of the quiescent forms of TGF-β and IGF-1 or via degradation of parathyroid hormone-related peptide (PTHrP). ET-1, endothelin-1A; ETAR, endothelin-1A receptor; IGF, insulin-like growth factor; LRP-F, low-density lipoprotein receptor–related proteins-Frizzled complex; MAPK, mitogenactivated protein kinase; PLC, phospholipase C; TGF-β, transforming growth factor-β. (From Papachristou DJ, Basdra EK, Papavassiliou AG. Bone metastases: molecular mechanisms and novel therapeutic interventions. Med Res Rev 2012;32[3]:611–636. Copyright © 2010 Wiley Periodicals, Inc. Reprinted by permission of John Wiley & Sons, Inc.)

Imaging modalities available for diagnosing bone metastases are CT, MRI, bone scintigraphy, and PET imaging with tumor-specific or bonespecific tracers. Bone scintigraphy with 99mTc-labeled diphosphonates has limited sensitivity and poor specificity for identifying bone metastases particularly in the early stages of the disease when tumor is confined to the marrow. This is improved by the addition of single-photon emission computed tomography (SPECT), which has the advantage of providing anatomic localization of abnormal tracer uptake with better contrast resolution. An alternative strategy is PET-based radionuclide imaging. The commonly used radiopharmaceuticals are 18F-fluoro-2-deoxyglucose 2092

(FDG) and 18F/11C-choline as tumor-specific agents or sodium fluoride as a bone-specific tracer (NaF).

CHARACTERISTICS OF METASTATIC BONE PAIN Adult bone receives a restricted and unique innervation as it is only innervated largely by thinly myelinated, TrkA+ sensory nerve fibers (Aδ) and TrkA+ C fibers, and receive little, if any, innervation by the larger more rapidly conducting Aβ fibers or the TrkA-negative, unmyelinated peptide poor C fibers. Most of the sensory nerves that innervate the bone appear to only be activated by injury or damage to the bone (i.e., silent nociceptors).311 The initial sharp pain experienced from a fracture of any bone is probably detected by mechanotransducers expressed by the Aδ and C-sensory fibers. The dull aching pain following injury, bruising, or stabilization of the fractured bone is likely associated with activation of unmyelinated C fibers present in the periosteum. Cortical bone and bone marrow are also innervated by the same population of Aδ and C-sensory nerve fibers that innervate the periosteum, although the relative density of sensory nerve fibers per unit area is markedly lower.311 Osteoclasts resorb bone by forming a highly acidic resorption area between the osteoclast and bone that stimulates the TRPV1 or ASIC3 channels expressed by a significant population of nerve fibers that drive bone cancer pain.312 Tumor-associated bone pain is usually first described as dull in character and constant in nature with the pain gradually intensifying over time. Nociception from bony metastases can produce a variety of symptoms such as muscle spasms or paroxysms of stabbing pain. Hematologic malignancies (especially acute leukemias) may produce a syndrome of generalized and migrating bone pain as a result of marrow infiltration.313 Limb pain is the most common presentation, and local bone tenderness (especially on long bone diaphyses) is a frequent finding. The vertebrae are the most common sites of bone metastases. The thoracic spine is affected in more than 66% of cases, the lumbosacral spine in 20%, and the cervical spine in 10%. Multiple vertebral lesions are common. Pain from metastases involving T12 and L1 often is referred to the iliac crest or SI joint unilaterally or bilaterally. Patients with tumor invasion of the upper cervical vertebrae may present with pain in the neck that is referred to the 2093

occipital region and skull vertex. Neck flexion typically exacerbates the pain. Osteolytic bone metastases often present with bone pain, pathologic fractures, hypercalcemia, and, more rarely, swelling or neurologic complaints. The vertebrae, pelvis, ribs, femur, and skull are the sites most frequently involved.314 Pain gradually develops during a period of weeks or months, becoming progressively more severe. The pain is usually well localized in a particular area and is often strongest at night or on weight bearing. Patients describe the pain as dull in character, constant in presentation, and gradually progressive in intensity. Pain increases with pressure on the involved area. Continuous pain may be moderate on resting and then increase with different movements or positions, such as standing, walking, or sitting. BTP can result from weight bearing or instability due to incipient or actual pathologic fractures. Although the locus of bone pain usually corresponds to the site of the underlying lesion, characteristic patterns of referral to noncontiguous cutaneous areas occurs. By way of example, hip pain due to a hip lesion may refer to the knee. Fractures are common through lytic lesions in weight-bearing bones. Damage to both cortical and trabecular bone is structurally important. Radiologic features that may predict imminent fracture include large, predominantly lytic lesion that erode the cortex. The main complications of vertebral metastases are vertebral collapse, radiculopathy, and metastatic epidural spinal cord compression (MESCC). Collapse of vertebral bodies is particularly frequent in the thoracic spine metastases. Back pain is a frequent symptom in patients with advanced cancer and in 10% of cases is due to spinal instability. The pain, which can be severe, is mechanical in origin, and frequently, the patient is only comfortable when lying still. Radiculopathies can occur at any level; patients feel the pain in the spine, deep in the muscles innervated by the affected nerve root, and in the corresponding dermatome. Metastatic spinal cord compression is a serious complication of vertebral metastases (see section in the following text).

PROGNOSIS A real estimate of the impact of bone metastases is difficult to assess 2094

because incidence is influenced by factors including the sensitivity of diagnostic tools and by the length of survival of the patients. In general, the prognosis for patients presenting with bone metastases is poor (Table 42.19).

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TABLE 42.19 Incidence and Prognosis of Bone Metastases

Breast Prostate Lung Bladder Renal cell Thyroid Melanoma

Incidence of Bone Metastases in Patients with Advanced Disease (%)

Median Survival from Diagnosis of Bone Metastases (mo)

65–75 65–75 30–40 40 20–25 60 14–45

19–25 12–53 6–7 6–9 12 48 6

Reprinted from Selvaggi G, Scagliotti GV. Management of bone metastases in cancer: a review. Crit Rev Oncol Hematol 2005;56(3):365–378. Copyright © 2005 Elsevier Ireland Ltd. With permission.

Patients with fewer metastases or solitary lesions appear to have a better outlook than those with multiple metastatic deposits. Once tumor cells spread to the skeleton, the disease is usually incurable. Issues related to bone metastases include reduced survival, morbidity, and pain that negatively affect the patient’s QOL as well as skeletal-related events (SREs). In prostate cancer, skeletal metastases are associated with overall survival ranging from 12 to 53 months.315 In a Danish study of approximately 36,000 breast cancer patients, the 5-year survival was 75.8% for patients without bone metastases, 8.3% for patients with bone metastases, and 2.5% for those with both bone metastases and SREs. The adjusted mortality rate ratio (MRR) was 10.5 (95% confidence interval [CI] 9.5, 11.6) for breast cancer patients with bone metastases and 14.4 (95% CI 13.1, 15.8) for those with bone metastases and SREs, compared with breast cancer patients with no bone metastases but possibly other sites of metastases.316 Bone metastases can be a major cause for morbidity, characterized by pain, impaired mobility, pathologic fractures, spinal cord compression, myelosuppression, and hypercalcemia with the most disability caused by long bone fracture or epidural extension of tumor into the spine. Both osteolytic and osteoblastic bone metastases are prone to fracture either because of increased bone resorption or because newly deposited bone is mostly immature is less mechanically competent than mature, lamellar bone.317 2096

Factors that influence prognosis in patients with metastatic disease include the interval between primary diagnosis and the development of metastases and the Karnofsky performance status (Table 42.20). The Karnofsky score after palliative irradiation reliably predicts survival.318–320 Other factors that predict survival include the site of the primary disease and whether single or multiple bone metastases are present.321,322 The distribution of metastases on bone scans also has prognostic significance. Bone involvement offers specific measurability criteria for tumor response assessment.323 Patients with metastatic prostate carcinoma survive significantly longer if their metastases respond to therapy and do not spread beyond the pelvis or lumbar spine.324 The use of 223Ra dichloride for metastatic castration-resistant prostate cancer reduced symptomatic skeletal events325 and significantly improved survival.326 TABLE 42.20 Karnofsky Performance Status Grade

Performance Level

100 90 80 70 60 50 40 30 20 10 0

Normal, no complaints, no evidence of disease Able to carry on normal activity; minor signs or symptoms of disease Normal activity with effort; some signs or symptoms of disease Cares for self; unable to carry on normal activity or to do active work Requires occasional assistance, but is able to care for most of his or her needs Requires considerable assistance and frequent medical care Disabled, requires special care and assistance Severely disabled, hospitalization indicated; death not imminent Very sick, hospitalization necessary, active supportive treatment necessary Moribund, fatal processes, progressing rapidly Dead

SACRAL INSUFFICIENCY FRACTURES Insufficiency fractures represent a special category of stress fractures that occur in bones with reduced mineral content and elastic resistance. They are often observed in osteoporosis, rheumatoid arthritis, prolonged glucocorticoid treatment, pelvic radiation therapy, and metabolic bone diseases. Pelvic radiation therapy has a reported prevalence of 21% to 34%327–329 and may occur because of a direct effect on bone and an indirect effect associated with vascular changes.330 Following radiation therapy, the reduction of the number of osteoblasts induces a reduction of 2097

collagen production and decreased alkaline phosphatase activity, key mechanisms involved in bone mineralization. Radiation-induced occlusion of bone microvascularization also results in ischemia, which contributes to the formation of insufficiency fractures.331 Osteoporosis is also a major risk factor because of a greater susceptibility to injury with normal repetitive activities and minor trauma. Trabecular bone is more affected by osteoporosis than cortical bone, but cortical bone is also significantly attenuated; hence, the vertebral bodies, pelvis, and sacrum are particularly susceptible to fractures as the ratio of trabecular to cortical bone is highest in the sacral alae and lower in the central portion of the sacrum.332 Common areas for insufficiency fractures include weight-bearing areas such as the sacral ala, sacral body, and pubic limb. Typically, patients present with acute onset severe diffuse sacral pain and tenderness, frequently with radiation to the hips/buttocks and groin, and classically worsen with axial loading. Many patients have pain intense enough to render the patient nonambulatory. Physical examination may reveal low back or groin tenderness with restricted hip movement. Physical examination may reveal tenderness to palpation in the region of the sacral ala, but diagnosis is usually made radiologically in patients with a prior history of pelvic radiation treatment (Fig. 42.10). CT images should include coronal and sagittal reconstruction views. Patients with sacral insufficiency fractures may be misdiagnosed as having pathologic fractures from metastatic disease.333,334 Biopsy of the lesion is not recommended because of low diagnostic yield. On MRI, stress fractures present an easily recognizable edema signal in contrast to metastases that disorganize the bone and form a real replacement tissue.331 The most commonly used classification system for sacral fractures is the Denis classification and subclassification system (Fig. 42.11).335 Zone I and II fractures can cause injury to the L5 nerve root in the lumbosacral tunnel (space between the lumbosacral ligament and the S1 ala). Zone II and III fractures can cause injury to the S1 nerve root or pudendal nerve. S1 nerve injury in this setting is usually not isolated and tends to be associated with a lumbosacral plexus injury. Zone III fractures have the highest rate of neurologic deficit including bowel, bladder, and sexual dysfunction.

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FIGURE 42.10 Magnetic resonance imaging (MRI) and computed tomography (CT) images of pelvis showing sacral insufficiency fracture. A: MRI axial T1 imaging shows H-shaped sacral fracture (type 1 transverse zone 3). Green arrows indicate fractures bilaterally. B: CT images of same fracture. Minimally displaced zone 1 sacral ala fractures. The fracture on the left is intraarticular and extends into the sacroiliac joint (red arrow heads). The fracture on the right is barely visible on this view with evidence of disruption of the cortex (green arrow head).

FIGURE 42.11 Denis classification and subclassification system of sacral fractures. The classification is based on the direction, location, and level of sacral fractures. The fractures are based on the sacrum’s division into three anatomic zones: zone I (alar region), zone II (foraminal region), and zone III (region of the central sacral canal). A zone II fracture can involve zone I but cannot extend into zone III, whereas a zone III fracture can involve zones I and II. Zone 3 fractures morphologically include “H”-, “U”-, “A”-, and “T”-shaped fractures.

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GRANULOCYTE COLONY-STIMULATING FACTORS– ASSOCIATED BONE PAIN Granulocyte colony-stimulating factor (G-CSF) agents act on the hematopoietic system to stimulate the proliferation and differentiation of neutrophil precursors and produce mature functional neutrophils. Agents such as filgrastim and pegfilgrastim are used as primary or secondary prophylaxis to reduce the risk of febrile neutropenia and allow the dose maintenance in patients receiving myelosuppressive chemotherapy. Pegfilgrastim is a long-acting, pegylated formulation of filgrastim that is given as a 6-mg dose subcutaneously on a once-per-cycle administration 24 to 72 hours after the administration of cytotoxic chemotherapy. Filgrastim is administered subcutaneously once daily. Pegfilgrastim causes proliferation of immature progenitor and mature myeloid cells within the bone marrow. Bone pain is the most commonly reported adverse event associated with pegfilgrastim occurring in approximately 26% of patients336 with severe bone pain reported in 3% to 7% of patients with the highest incidence in the first cycle.337 Although the exact mechanism of associated bone pain is unknown, inflammatory processes within the bone marrow, stimulation of osteoclasts and osteoblasts, and expansion of the bone marrow are potential sources of pain.338 The incidence of bone pain between filgrastim and pegfilgrastim was similar between patients receiving either formulation of G-CSF when used as support with chemotherapy in breast cancer.339

Visceral Pain Visceral infiltration is a common cause of pain in cancer patients. Table 42.21 lists the common pain syndromes associated with tumor infiltration. TABLE 42.21 Pain Syndromes Related to Tumor Infiltration of Viscera Esophageal mediastinal pain Shoulder pain from diaphragmatic infiltration Epigastric pain from pancreatic or other upper abdominal tumor Right upper quadrant pain from hepatic capsule distention Left upper quadrant pain from splenomegaly

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Diffuse abdominal pain from abdominal or peritoneal disease with or without obstruction Pleural infiltration Gastrointestinal perforation Biliary obstruction Ureteric obstruction Suprapubic/pelvic pain from bladder infiltration Perineal pain from infiltration of rectum or perirectal tissue

MECHANISM Visceral pain is defined as pain emanating from organs in the thorax, abdomen, or pelvis. The main factors capable of inducing pain in visceral structures include abnormal distention and contraction of hollow visceral walls, rapid stretching of the capsules of solid visceral organs, ischemia of visceral musculature, formation and accumulation of algogenic substances, direct action of chemical stimuli on compromised mucosa, and traction or compression of ligaments, vessels, or mesentery.340–342 Gastric acid is a noxious stimulus that contributes to pain arising from the esophagus, stomach, and upper small intestine. Mechanical trauma to normal mucosa causes no pain, implying that preceding inflammation is necessary. There are two distinct classes of nociceptive sensory receptors in viscera.91 One population of afferents can code nonnoxious, as well as noxious stimuli, and a second population is not activated unless more intense and potentially damaging stimuli are encountered. These relatively insensitive fibers are normally silent and only become active following injury or in disease.343 The first class is composed of “high-threshold” receptors that respond to mechanical stimuli within the noxious range. These have been identified within many viscera, including the heart, lungs, gastrointestinal tract, ureters, and urinary bladder. The second class is composed of receptors that have a low threshold to natural stimuli and encode the stimulus intensity in the magnitude of their discharges, the socalled “intensity-encoding” receptors. Both receptor types are mainly concerned with mechanical stimuli such as stretch and are involved in the peripheral encoding of noxious stimuli in viscera. In the presence of local inflammation or tissue injury, these afferents become sensitized and respond to previously innocuous natural stimuli. High-threshold afferents signal acute visceral pain. Local ischemia, hypoxia, and inflammation cause pain by sensitizing high-threshold receptors and these previously 2101

“silent” or unresponsive receptors. Pain in visceral structures is not necessarily linked to tissue injury but is more dependent on the nature of the provoking stimulus. Adequate stimuli that induce pain are distention, ischemia, and inflammation. Hollow organs such as the colon are very sensitive to luminal distention or inflammation but are totally insensitive to cutting or burning stimuli. Visceral structures from the esophagus to the transverse colon are innervated not only by DRG located in the cervical, thoracic, and upper lumbar regions but also by sensory neurons arising from the superior and inferior vagal ganglia.343 Visceral structures located distal to the transverse colon, particularly the distal colon, rectum, and bladder, are also innervated by two populations of afferents; however, these are both of spinal origin arising from two different levels of the spinal cord (thoracolumbar and lumbosacral). Sensory neurons arising from these two spinal locations appear to convey different aspects of the complex sensation that humans identify as visceral pain.343 Poorly localized visceral pain may be explained by the low density of visceral nociceptors, the functional divergence of visceral input with the CNS, and viscerovisceral convergence in the spinal cord. Localization of visceral pain is difficult. Afferent nerves from viscera to the spinal cord are relatively few in number and comprise only 2% to 15% of all afferents to the spinal cord.344,345 These visceral nociceptive afferents can excite many second-order neurons in the spinal cord which in turn generate extensive divergence within the CNS, sometimes involving supraspinal loops. Such a divergent input activates several systems— sensory, motor, and autonomic—and thus triggers the general reactions that are characteristic of visceral nociception: a diffuse and referred pain and prolonged autonomic and motor activity.340 The dorsal column in the spinal cord contains an ascending excitatory pathway that plays a crucial role in the perception of visceral pain, especially under the conditions of peripheral inflammation.346 Activation of thalamic neurons by the dorsal column pathway, through a relay in the dorsal column nuclei, may be an important element in this mechanism. The dorsal column pathway may contain an ascending part of an amplification loop that enhances the responsiveness of spinal cord neurons through a descending facilitatory pathway, possibly originating in the rostroventral medulla.347 This 2102

amplification circuit could lead to potentiation of the responses of different projection neurons, including spinothalamic and postsynaptic dorsal column neurons. The effectiveness of the midline myelotomy in visceral pain patients could thus be explained by a direct reduction in the activation of thalamic neurons mediated by postsynaptic dorsal column neurons as well as by an interruption of the amplification loop, thereby preventing the potentiation of the visceral responses of other projection neurons such as spinothalamic tract cells. The origin of nociceptive impulses determines the site and type of pain. Visceral pain is either true, referred, nonreferred parietal, or referred parietal. True parietal abdominal pain is dull and poorly localized; it occurs in the region of the epigastric, periumbilical, or lower midabdominal region. Patients may describe the pain as gnawing or cramping, and often, it is associated with nausea, sweating, pallor, and, occasionally, vomiting. Referred visceral pain is more precisely localized, usually in the dermatomal or myosomal regions of the same segments of the spinal cord involved. Parietal pain may localize directly over the organ without referral. Patients locate referred parietal pain in a body region distant from the nociceptive site. For example, patients complain of pain in the shoulder area when the cause is inflammation of the middle diaphragm. Tumor invasion of adjacent blood vessels can generate nociception. Mechanisms include perivascular lymphangitis causing vasospasm, occlusion with resultant ischemia, venous engorgement, and edema. Obstruction of hollow viscera from tumor with resultant distention may cause pain. Distention causes intense contraction of smooth muscle that generates nociception. Patients experience visceral pain that is poorly localized and diffuse but usually localized in same dermatomal area of the cord segments of the viscera. Pain from tumor involvement of parenchymal viscera such as liver, spleen, pancreas, and kidney typically results from acute distention of the pain-sensitive fascia. These fascia contain many mechanical receptors, and nociception occurs when they are acutely stretched or placed under tension. This type of pain is poorly defined, dull, and generally located in the dermatomal region of the involved organ. The properties of visceral pain are discussed in Chapters 61–65. 2103

VISCERAL PAIN DESCRIPTIONS BY SITE Esophageal cancer usually elicits a history of heartburn: a burning or gnawing substernal discomfort. Patients usually describe the pain as being located in the epigastric or retrosternal areas, which often radiates to the back or interscapular region. The pain occurs often after eating and possibly relates to body position changes such as reclining or bending forward. Gastric pain has a colicky quality associated with delayed emptying and slowed motility and digestive symptoms. The pain also localizes in the epigastrium, is usually sharply focused, and may radiate into the back. Small intestine pain is usually crampy or colicky and localized in the periumbilical area. The cause of pain is usually a lesion causing distention with resultant abnormal mobility. Eating usually precipitates the pain, and defecation or fasting may afford relief. Colon pain tends to occur in the lower abdomen, varying according to which portion of the colon is affected. Change in bowel habits and occult blood in the stool often accompanies symptoms of discomfort. Peritoneal carcinomatosis is frequently found with abdominal tumors and advanced ovarian cancer. Pain may result from peritoneal irritation, mesenteric involvement, and abdominal distention with ascites. Bowel obstruction often complicates peritoneal carcinomatosis. Liver parenchyma is insensitive to tumor distention and associated chemical changes. Right upper quadrant pain from liver pathology occurs only when there is acute distention of the liver capsule. It is usually a dull, aching sensation in the right upper abdominal quadrant and flank and is often referred to the right scapula and shoulder. Perineal pain, worse when sitting and with aching and pressure-like quality is the first and, can be for a long time, the only symptom of pelvic tumors. The pain may be associated with tenesmus. Fistulas and recurrent infections can aggravate the pain syndrome. Ureteral obstruction is frequent. Direct invasion of the sacrum, sacral roots, plexus, or cauda equina are frequent complications. Pain from the fundus of the uterus typically occurs in the hypogastrium. Pain originating from the uterine cervix is commonly referred to the low back and sacral area as well as to the hypogastrium. Ovarian pain results from stretching of the surrounding 2104

peritoneum to which the ovaries adhere.

Neuropathic Pain The following are among the most common cancer pain syndromes that present with a major neuropathic component.

NEUROPATHIC PAIN SECONDARY TO CANCERRELATED PATHOLOGY IN CRANIAL NERVES Painful cranial neuralgias may occur secondary to base of skull metastases, LMs, or head and neck cancers.348 Base of skull metastases produce several well-described pain syndromes349 and are often associated with primary tumors of the breast, lung, and prostate. Constant localized aching pain from bone destruction and neurologic deficits from progressive cranial nerve palsies are cardinal manifestations. Orbital and parasellar syndromes were characterized by frontal headache, diplopia, and firstdivision trigeminal sensory loss. Proptosis may occur with the orbital syndrome. The middle-fossa syndrome was characterized by facial pain or numbness or dysesthetic neuropathic pain in the distribution of the second or third divisions of the trigeminal nerve. Associated motor deficits include weakness in the masseter or temporalis muscles or abducens palsy. The jugular foramen syndrome was characterized by hoarseness and dysphagia, with paralysis of the 9th through 11th cranial nerves and may present as glossopharyngeal neuralgia.349 This pain is distributed over the ear or mastoid region and may radiate to the neck or shoulder. Associated deficits include a Horner syndrome and paresis of the palate, vocal cords, sternocleidomastoid muscle, or trapezius muscle. It is sometimes associated with syncope.350 The occipital condyle syndrome was characterized by unilateral occipital pain and unilateral tongue paralysis with patients complaining of a continuous, severe, unilateral, occipital pain which kept them with the head rotated to the side of the pain and held with their hands351 and occipital region pain typically preceding the hypoglossal paresis by several days to 10 weeks.352 Occipital condyle syndrome, clinically mimics classical trigeminal neuralgia, can occur secondary to tumors in the middle or posterior 2105

fossa.353–356 Middle fossa tumors may present as trigeminal neuralgia but usually cause severe pain of an atypical nature and a progressive neurologic deficit. Trigeminal neuralgia secondary to tumor usually presents as a constant, dull, well-localized pain related to the underlying pathology involving bone and other somatic structures associated with paroxysmal episodes of lancinating or throbbing pain. A higher incidence of hypesthesia in the trigeminal nerve regions as well as a reduced corneal reflex was noted in patients with a mass lesion compared to those with vascular compression.355 Posterior fossa tumors are most likely to cause trigeminal neuralgia and are usually accompanied by subtle neurologic deficits.353 This association between trigeminal neuralgia and tumor is uncommon, and cancer patients with a new onset of trigeminal neuralgia should have careful imaging of the base of skull.

Cervical Plexopathy Tumor infiltration of the cervical plexus can produce several pain syndromes, depending on the pattern of nerve involvement.357 The upper four cervical ventral rami join to form the cervical plexus, which has both cutaneous and muscular branches. The plexus lies close to C1–C4 vertebrae. Cutaneous branches include the lesser occipital nerve which innervates lateral part of the occipital region; the great auricular nerve (innervates skin near auricle and external acoustic meatus); the transverse cervical nerve which innervates anterior region of the neck; and the supraclavicular nerves which innervate shoulder, suprascapularis, and upper thoracic region. The main contributor among muscular branches is ansa cervicalis. Because sensory afferents from the cervical plexus enter the spinal tract of the trigeminal along with the sensory afferents from cranial nerves V, VII, IX, and X, nociceptive referral patterns from the face and neck overlap. Symptoms usually include local pain with lancinating or dysesthetic components referred to the retroauricular and nuchal areas (lesser and greater auricular nerves), preauricular area (greater auricular nerve), anterior neck and shoulder (transverse cutaneous and supraclavicular nerves), and the jaw.348 Associated findings may include ipsilateral Horner syndrome or hemidiaphragmatic paralysis. Due to the proximity to the cervical spine, CT or MRI evaluation may be 2106

necessary to rule out associated epidural cord compression. Common clinical settings include local extension of a head and neck tumor or cervical lymph node metastases. In patients with head and neck tumors who have undergone RND followed by radiation treatment, new onset or worsening pain includes a differential diagnosis of post-RND syndrome or tumor recurrence.

Tumor-Related Mononeuropathy The most commonly described tumor-related painful mononeuropathy is intercostal nerve injury secondary to rib metastases with local extension. Patients with tumor invasion of the sciatic notch may present with symptoms resembling sciatica. Isolated mononeuropathies particularly from lymphomas are reported.358–360

Radicular Pain/Radiculopathy Radiculopathy is compression of a nerve root. Frequent signs and symptoms include varying degrees of sensory, motor, and reflex changes as well as pain, dysesthesias, and paresthesias related to nerve root(s) without evidence of spinal cord dysfunction (which is myelopathy). Patients with radiculopathy may not have pain. Evaluation includes history and physical examination. Imaging modalities commonly used for evaluation include MRI, CT, and myelography. For lower extremity issues, the most commonly used physical tests include Lasègue test* straight leg raising or crossed straight leg raising; tendon reflexes; and signs of weakness, atrophy, or sensory deficits.361 For cervical/upper extremity radiculopathy, Spurling test† is a provocative maneuver suggestive of radiculopathy. Patients with cancer-related radiculopathy may present with pain on either or both sides of the midline. The pain tends to be unilateral in the cervical and lumbosacral regions and bilateral in the thorax. Radiculopathy may result from epidural tumor mass effects with encroachment on exiting nerve roots or LMs. Coughing, sneezing, recumbency, and strain exacerbate the pain, which often has dysesthetic qualities. Radiculopathy may also develop secondary to LMs. Clinically, LMs may produce multifocal neurologic signs and symptoms at a variety of levels, including cranial neuralgias.362 2107

Leptomeningeal Metastases LM is defined as the appearance of tumor cells in the leptomeninges or CSF distant from the site of a primary tumor. It is also known as carcinomatous meningitis, neoplastic meningitis, neoplastic meningosis, leukemic meningitis (for leukemia), lymphomatous meningitis (for lymphoma), and meningeal carcinomatosis (for carcinoma). This complication occurs most commonly with cancers of the breast and lung, melanoma, lymphomas, and acute lymphocytic leukemia with an estimated survival at 1 year of approximately 10% that varies with the primary tumor.363 Clinical evaluation, MRI, and CSF assessment including cytology are the most important diagnostic measures. Neurologic dysfunction most commonly involves one or more segments of the neuraxis, including cerebral hemispheres, cranial nerves, spinal cord, or spinal roots.364 Clinical manifestations that strongly suggest the diagnosis of LM include cauda equina symptoms or signs, communicating hydrocephalus, and cranial neuropathies. Early in the disease, neurologic involvement can be subtle, such as an isolated diplopia or radicular pain. Cerebral hemisphere symptoms such as altered mental status or seizures may predominate.364 Symptoms may also include headache, back and radicular pain, and multiple cranial and spinal nerve involvement. Pain may occur in 30% to 76% of cases.365,366 Table 42.22 lists the frequency of spinal cord symptoms and signs in patients with LMs. The most common symptom is pain (80%), and patients may report a diffuse headache (25%) or pain in a spinal, radicular, or meningeal pattern (>50%). Localizing symptoms include cranial neuropathies, mononeuritis, radiculopathy, urinary incontinence, and visual disturbance. TABLE 42.22 Frequency of Spinal Cord Symptoms and Signs in Patients with Carcinomatous Meningitis Symptoms or Signs

%

Weakness Paresthesia Back pain Radicular pain Bowel/bladder dysfunction Reflex asymmetry

33 31 25 19 13 67

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Weakness Cauda equina syndrome Sensory loss Positive straight leg raise Decreased tone of anal sphincter Nuchal rigidity

 4 33 31 13 12 11

From Zachariah B, Zachariah SB, Varghese R, et al. Carcinomatous meningitis: clinical manifestations and management. Int J Clin Pharmacol Ther 1995;33(1):7–12. Reprinted by permission of Dustri-Verlag Dr. Karl Feistle GmbH & Co. KG.

Solid tumors have the propensity to adhere to neural structures and form nodules that become visible on MRI.367 MRI appearances include the presence of subarachnoid nodules, leptomeningeal enhancement, nerve root enhancement, parenchymal disease (intramedullary metastases), and epidural metastases.368 These changes may occur intracranially and along the spinal canal. T1-weighted gadolinium-enhanced sequence of the entire neuraxis (brain and spine) plays an important role in supporting the diagnosis, demonstrating the involved sites, and guiding treatment. MRI images typically show enhancing nodular lesions. Nearly all patients have some abnormality of CSF opening pressure, protein, glucose, or cell count. The finding of tumor cells in CSF establishes a definitive diagnosis. In patients with hematologic cancers, CSF flow cytometry is more sensitive than CSF cytology and additionally requires a comparatively smaller volume of CSF (4 h for additional treatment.

Follow over time and plan dose with single unit.

Wait >2 h for additional treatment.

May use multiples of 100 μg tabs and/or 200 μg tabs for any single dose; no more than 4 tabs at one time

Repeat same dose after 30 min if BTP not adequately relieved. Max doses per event = 2.

Wait >4 h for additional treatment.

Follow over time and plan dose with single unit. May use multiple tablets (one on each side of mouth in upper/lower buccal cavity) until maintenance dose achieved

2232

Lazanda

100 μg

Only 1 dose per episode

Wait >2 h for additional treatment.

Onsolis

200 μg

Single episode treatment only; no redosing

Wait >2 h for additional treatment

Subsys

100 μg (unless being converted from Actiq ≥600 μg)

Repeat same dose after 30 min if BTP not adequately relieved. Max doses per event = 2.

Wait >4 h for additional treatment.

Follow over time and plan dose with single unit. Patients should confirm dose that is adequate with second episode of BTP. Titrate with 200 μg increments. No more than 4 films at once. If inadequate pain relief after 800 μg (×4 200 μg films) and patient tolerates 800 μg dose, next episode may be treated with 1,200 μg. Follow over time and plan dose with single unit.

BTP, breakthrough pain.

The transdermal patch is widely used in the treatment of both malignant and nonmalignant chronic pain. Clinically, cachectic cancer patients may require higher transdermal doses for adequate pain relief than normal weight or obese patients. Heiskanen et al.337 studied the pharmacokinetic profile in 10 cachectic (mean body mass index [BMI] 16 kg/m2) and noted that plasma fentanyl concentrations adjusted to dose were significantly lower at 48 and 72 hours in cachectic patients than normal weight patients suggesting that the absorption was impaired in cachectic patients. The cachectic patients had a significantly thinner upper arm skin fold, but no differences were found in local blood flow, sweating, or skin temperature. Hypoalbuminemia (albumin 50%. COX-2 is expressed in 40% of human invasive breast cancers, and bone is the primary site of metastasis in cases of breast cancer.36,37 COX-2 inhibition also inhibited bone metastasis in both a prevention and treatment regimen. This suggests COX-2 produced in breast cancer cells are significant in supporting progression of osteolytic bone metastases in patients with breast cancer, and that COX-2 inhibition may halt this process. Furthermore, COX-2 inhibition may benefit iatrogenically caused tumor progression.38 COX-2 inhibitors, such as celecoxib, have also been shown 2389

to increase apoptosis and decreased progression of osteosarcoma cell lines.39 Morphine has been shown to stimulate angiogenesis supporting tumor growth in mice. COX-2 inhibition can prevent tumor growth without compromising opioid-dependent analgesia in a murine breast cancer model. Chronic morphine treatment alone stimulated angiogenesis in breast cancer with a corresponding increase in metastasis and reduced survival, whereas coadministration of a coxib prevented these morphineinduced effects and improved analgesia over either agent independently.40

CORTICOSTEROIDS Corticosteroids are established analgesics in the treatment of pain secondary to metastatic bone pain. This analgesia is thought to occur through the blockade of cytokine synthesis that contributes to both inflammation and nociception.41,42 The analgesic benefits of corticosteroids are dose-dependent and limited in their duration of activity. In a small uncontrolled study, approximately 40% of patients with metastatic prostate cancer were found to have analgesic benefit with the administration of oral corticosteroids. This was speculated to be secondary to suppression of hormone-sensitive disease that was stimulated by weak androgens of adrenal origin by negative feedback on secretion of adrenocorticotropic hormone.43 Dexamethasone is the most commonly used agent because it has the least effect on mineralocorticoid activity.

BISPHOSPHONATES Bisphosphonates are pyrophosphate analogues which bind to hydroxyapatite bone mineral surfaces acting to inhibit osteoclasts and thus bone resorption.44 The optimal dose for this class is a function of the disease stage.45 Oral clodronate given to patients with breast cancer metastatic to bone reduced the frequency of skeletal events by more than one-fourth.46 In two randomized placebo-controlled trials comparing monthly pamidronate infusions to placebo infusions showed that skeletal morbidity rate could be reduced by 30% to 40%. A large, randomized, multicenter trial using intravenous (IV) zoledronic 2390

acid demonstrated a reduction of 20% in the risk of developing skeletalrelated events compared with pamidronate for patients with breast cancer.47 Moreover, these trials demonstrated for the first time that a bisphosphonate significantly reduces the occurrence of skeletal events in hormone-refractory prostate cancer, non–small-cell lung cancer, and a large range of solid tumors. Evidence from in vitro studies have shown that bisphosphonates are able to directly affect tumor cell growth.46 Of the available bisphosphonates, IV zoledronic acid has demonstrated the broadest clinical activity and is approved in many countries for the treatment of bone metastases from all solid tumors.48,49 The indications for bisphosphonate therapy in breast cancer patients include correction of hypercalcemia and the prevention of cancer treatment-induced bone loss.50 In phase III clinical trials, denosumab, a human antibody to RANKL, is highly effective for preventing complications in patients with bone metastasis from prostate cancer, breast cancer, and other solid tumors. In addition, it decreased treatment-related bone loss in patients treated with androgen deprivation therapy for prostate cancer and women with breast cancer who are treated with aromatase inhibitors.51,52 Limited postmarketing analysis has raised concerns regarding denosumab because of the potential for osteonecrosis of the jaw.53 Bisphosphonates, although effective in decreasing bony complications due to bone metastases in prostate cancer, breast cancer, and other solid tumors, can cause extensive side effects.54 Highly selective matrix metalloproteinase inhibitors inhibit osteoclastic and bone tumor cell lines but not osteoblasts. They are also more effective in promoting tumor apoptosis compared with the standard-of-care bisphosphonate, zoledronate.55 Bisphosphonates are now a routine part of therapeutic regimen for metastatic bone pain, and at least 50% of patients report clinically relevant analgesic effect. Placebo-controlled trials with oral or IV bisphosphonates have shown that prolonged administration can reduce the frequency of skeletal-related events by 30% to 40%. The superiority of zoledronic acid compared with pamidronate has been shown by a multiple-event analysis in a large randomized trial. The short infusion time of zoledronic acid also constitutes a convenient therapy. Flu-like symptoms, which are 2391

manageable with standard treatment, do occur. Renal monitoring is recommended, with dose reductions for patients with renal dysfunction. Osteonecrosis of the mandible has been reported in patients receiving bisphosphonates and might be avoidable with appropriate dental care.56

CALCITONIN The hormone calcitonin has the potential to relieve pain and also retain bone density, leading to a decreased risk of fractures. However, there is limited evidence to support the routine use of calcitonin for pain secondary to bony metastases.57 Data suggests that calcitonin offers adjuvant analgesia in the treatment of bone pain related to metastatic disease.58,59 A human clinical trial prospectively entered 22 patients to evaluate the efficacy of salmon calcitonin in controlling pain related to bone metastasis.60 Other controlled clinical trials of salmon calcitonin in the treatment of cancer-related bone pain have shown equivocal analgesic results without evidence of reducing complications due to bone metastasis or improving quality of life or survival.57,61 Like many pain-relieving strategies, there is considerable interpatient variability in responses. In those patients who are not responding well to other first-line approaches, a trial of calcitonin may be reasonable, but close follow-up should ensure that benefits outweigh risks.

OPIOIDS/OPIATE ANTAGONISTS Opioids continue to be an important means of treating metastatic bone pain, but new research offers a challenge as to which treatment plan may be most appropriate. In a murine sarcoma model of bone cancer pain, the effects of sustained morphine found that morphine-enhanced, rather than diminished, spontaneous and evoked pain, and that the effects were dose dependent and naloxone sensitive.62 Morphine increased ATF-3 expression only in DRG cells of sarcoma mice. Morphine did not alter tumor growth in vitro or tumor burden in vivo but accelerated sarcomainduced bone destruction and doubled the incidence of spontaneous fracture in a dose- and naloxone-sensitive manner. Furthermore, morphine increased osteoclast activity and upregulated interleukin-1β within the femurs of sarcoma-treated mice suggesting enhancement of sarcoma2392

induced osteolysis. These results suggest morphine may increase pain, osteolysis, bone loss, and spontaneous fracture as well as markers of neuronal damage and expression of proinflammatory cytokines. The data from this study suggest the need to understand the long-term effects of chronic opioid therapy for cancer pain.

ADJUVANT ANALGESICS The pain of bone cancer can be refractory to traditional treatment modalities. This may be the result of neuropathic changes in involved bone tissues. In animal models of bone-invading malignancies, evidence for peripheral nerve injury provides the pathophysiologic rationale for the use of agents typically used to control neuropathic pain in the control of bone cancer pain.63

N-METHYL-D-ASPARTATE ANTAGONISM AND α2 AGONISTS Administration of α2 agonists (dexmedetomidine and clonidine), Nmethyl-D-aspartate (NMDA) antagonists (MK-801 and ketamine), and morphine were examined in a mouse sarcoma bone cancer pain model.64 As expected, morphine produced a significant analgesic effect, and the α2 agonists produced analgesic effects with an efficacy similar to that of morphine but only at doses that produced severe sedation. MK-801 demonstrated little analgesic effects, whereas ketamine yielded an analgesic effect with the same efficacy as morphine. The authors concluded that α2 agonists produce an analgesic effect only at a sedative dose. Ketamine, but not MK-801, is associated with an analgesic response without overt side effects, suggesting that non-NMDA effects may be responsible for ketamine’s analgesic efficacy in this model. Applicability of these findings to humans remains untested.

HORMONAL THERAPY Progression of metastasis from breast, prostate, and uterine malignancies is hormone dependent.65,66 Antihormonal treatment reduces an important stimulus for growth and is a common form of adjunctive therapy in breast, 2393

prostate, and endometrial cancers.67 Estrogen and estrogen analogue therapy in patients with breast cancer controls symptoms in 25% to 50% of patients temporarily.68 Antihormonal therapy improved pain in 70% of patients with widespread bone metastases from prostate cancer.69 Therapy with estrogens is efficacious but may take 30 to 60 days before complete palliation. However, serious adverse effects may exceed overall benefits. Although hormone therapy with androgen receptor antagonists (e.g., flutamide) or antigrowth factor agents (e.g., luteinizing hormone-releasing hormone analogs of somatostatin and 5-reductase inhibitor) can be used to induce tumor regression, the palliative effect may not offer long-term benefit as hormone-refractory elements continue to proliferate.70

RADIONUCLEOTIDES Analgesic effects from radionucleotides are not dependent on tumor destruction per se but are thought to result from inhibition of pain mediators from normal bone cells. Therapeutic responsiveness is greatest in osteoblastic lesions. Multiple different agents have been used for palliative treatment of cancer-related bone pain, including phosphorus-32, strontium-89, yttrium-90, samarium-153, and rhenium-186. Phosphorus-32 has been used for more than 30 years and relieves the pain from osteoblastic metastases in approximately 80% of treated patients.71 Myelosuppression caused by this agent has led to the development of newer agents. Strontium-89 is a bone-seeking radionuclide, whereas samarium-153 is a bone-seeking tetraphosphonate. Both agents have been shown to have efficacy in the treatment of painful osseous metastases from prostate cancer, breast cancer, and, perhaps, from non–small-cell lung cancer. As many as 80% of selected patients72 with painful osteoblastic bony metastases from prostate or breast cancer experience some pain relief following strontium-89 administration.73 Additionally, 10% or more may become pain free, and the average duration of clinical response typically ranges from 3 to 6 months with minimal myelosuppression as compared to phosphorus-32.74

PROCEDURAL INTERVENTIONS 2394

In addition to pharmacotherapy, interventional therapies can be used to relieve the pain associated with bone cancer. Examples include procedures such as intralesional injections, nerve blocks, intraarticular injections, radiofrequency rhizotomy, and vertebroplasty.

Intralesional Injection In a study of patients with rib metastases or involvement of the ribs by multiple myeloma, infiltration of tender areas with methylprednisolone provided significant reduction in pain-related symptoms in over half the cases.75 Of 20 assessable patients, 11 became pain free within 10 days with recurrence of pain in only 1 of these patients; in 8 others, the pain was considerably improved. The procedure was well tolerated, and there were no complications.75 This technique has also been used to treat mandibular lesions in which surgical excision of tumor would risk destabilizing the affected bone.76 This technique may be applicable to other areas of metastasis.77 Additionally, localized injection of corticosteroid, local anesthetic, and even baclofen have been reported to offer clinically meaningful relief in areas of secondary muscular spasm.78

Percutaneous Vertebroplasty/Kyphoplasty Vertebral bony metastases are seen in 30% to 70% of all bony lesions. These metastases compromise the strength of involved bone leading to pathologic vertebral fractures even in the absence of trauma. Additional causes of fractures include osteoporosis, malnutrition, radiation, and steroid administration. Vertebroplasty offers the potential of pain relief. In comparison, patients who have a nonmalignant basis for pathology of the bone such as osteoporosis, reports of analgesic benefit in cancer patients are not as high but are still significant with ranges reported between 50% and 80%.79 This may be explained by the widespread nature of metastatic disease and the multifactorial origins of pain. The mechanism by which vertebroplasty provides pain relief is not completely understood but could be secondary to fixation of mobile bone fragments and/or thermal neurolysis secondary to the exothermic reaction of methylmethacrylate cement yielding temperatures in excess of 70° C.80

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Rhizotomy Minimally invasive neurodestructive techniques have been demonstrated to be effective in a number of malignancies, specifically of visceral and neuropathic nature. Techniques involve radiofrequency lesioning, cryotherapy, and chemical neurolysis using phenol, alcohol, and hypertonic saline. Because pain from bony metastasis has a neuropathic component, these techniques offer an option in the control of cancerrelated bone pain. Other diagnoses where this approached can be applied to include chordoma, osteoid osteoma, and osseous metastasis. Studies of radiofrequency lesioning of bony and soft tissue malignancy have reported significant palliation of pain.81–84

ASSOCIATED PROCESSES Avascular Necrosis Avascular necrosis can be found in survivors of cancer who have been exposed to corticosteroid therapy. Pain is the result of weight bearing on the affected joint. In an MRI study of patients having survived childhood cancer, 67% of patients demonstrated osteonecrosis at the ankle.85 Postoperative Frozen Shoulder In postthoracotomy or postmastectomy patients, pain leads to an increased risk for the development of frozen shoulder. The site may become an independent locus of pain and can be complicated by complex regional pain syndrome. Adequate mobilization of the joint with sufficient analgesia should be implemented soon following surgery to prevent this chronic, painful, and debilitating complication.86

GRANULOCYTE COLONY-STIMULATING FACTOR RELATED PAIN Granulocyte colony-stimulating factor (G-CSF) is used to stimulate the production of granulocytes in immunocompromised patients following chemotherapy and radiation. Bone and generalized muscle pain is a common complication, which can last for 10 or more days.87 Effective analgesia can require opioids.88 G-CSF also induces an inflammatory reaction through undefined cellular signaling and histamine release.89 2396

Increased histamine levels cause nociceptive C-fiber–mediated pain and edema formation within bone leading to pain.90 Antihistamines such as terfenadine and astemizole have anti-inflammatory properties in addition to their potency as histamine-1 antagonist and can be used to treat bone pain secondary to G-CSF therapy.

Conclusion The bony skeleton is the most common location for metastatic cancer and leads to a very high incidence of morbidity including severe pain (spontaneous and provoked), hypercalcemia, pathologic fracture, and spinal cord and or nerve root compression. Bone pain is frequently undertreated. Approximately 80% of patients experienced pain before palliative therapy. Progress in understanding the prevention and treatment of cancer-related bone pain is being made. There are many therapies available to treat pain caused by infiltration of cancer into bone.91 Major skeletal-related events occur in cancer patients on average every 3 to 6 months. The prognosis of metastatic bone disease is dependent on the primary site. Breast and prostate cancer survival is measured in years; in lung cancer, survival may be measured in months. Severity and duration of tumor involvement in bone cancer are predictors of outcome and can be measured by bone-specific markers. Studies have demonstrated a significant correlation between the rate of bone resorption, clinical outcomes, skeletal morbidity, and overall life expectancy. Improved understanding and treatment will not only improve the quality of life of cancer patients but also improve long-term outcomes.7 References 1. Vigorita V. Orthopaedic Pathology. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 2008. 2. Coleman RE. Bisphosphonates: clinical experience. Oncologist 2004;9(suppl 4):14–27. 3. Buijs JT, van der Pluijm G. Osteotropic cancers: from primary tumor to bone. Cancer Lett 2009;273:177–193. 4. Li S, Peng Y, Weinhandl ED, et al. Estimated number of prevalent cases of metastatic bone disease in the US adult population. Clin Epidemiol 2012;4:87–93. 5. Halvorsan K, Sullivan L, Mantyh P. Bone pain. In: Fisch M, Burton A, eds. Cancer Pain Management. New York: McGraw-Hill; 2007:75–86. 6. Jajan N, Krishnan S, Das P, et al. Palliative radiation therapy techniques. In: Fisch M, Burton A, eds. Cancer Pain Management. New York: McGraw-Hill; 2007:271–296.

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61. 62.

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women receiving adjuvant aromatase inhibitors for non-metastatic breast cancer: subgroup analyses of a phase 3 study. Breast Cancer Res Treat 2009;118(1):81–87. Gnant M, Pfeiler G, Dubsky PC, et al. Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 2015;386(9992):433– 443. McGreevy C, Williams D. Safety of drugs used in the treatment of osteoporosis. Ther Adv Drug Saf 2011;2(4):159–172. Saad D, Saad P. Report of a jaw osteonecrosis possibly caused by denosumab. Eur J Oral Implantol 2017;10(2):213–222. Smith MR, McGovern FJ, Zietman AL, et al. Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer. N Engl J Med 2001;345(13):948–955. Tauro M, Shay G, Sansil SS, et al. Bone-seeking matrix metalloproteinase-2 inhibitors prevent bone metastatic breast cancer growth. Mol Cancer Ther 2017;16(3):494–505. Lipton A. Efficacy and safety of intravenous bisphosphonates in patients with bone metastases caused by metastatic breast cancer. Clin Breast Cancer 2007;7(suppl 1):S14–S20. Martinez-Sapata MJ, Roqué M, Alonso-Coello P, et al. Calcitonin for metastatic bone pain. Cochrane Database Syst Rev 2006;19(3):CD003223. Gennari C. Analgesic effect of calcitonin in osteoporosis. Bone 2002;30(suppl 5):67S–70S. Visser E. A review of calcitonin and its use in the treatment of acute pain. Acute Pain 2005;7(4):185–189. Mystakidou K, Befon S, Hondros K, et al. Continuous subcutaneous administration of highdose salmon calcitonin in bone metastasis: pain control and beta-endorphin plasma levels. J Pain Symptom Manage 1999;18(5):323–330. Tsavaris N, Kopterides P, Kosmas C, et al. Analgesic activity of high-dose intravenous calcitonin in cancer patients with bone metastases. Oncol Rep 2006;16(4):871–875. King T, Vardanyan A, Majuta L, et al. Morphine treatment accelerates sarcoma-induced bone pain, bone loss, and spontaneous fracture in a murine model of bone cancer. Pain 2007;132(1– 2):154–168. Donovan-Rodriguez T, Dickenson AH, Urch CE. Gabapentin normalizes spinal neuronal responses that correlate with behavior in a rat model of cancer-induced bone pain. Anesthesiology 2005;102(1):132–140. Saito O, Aoe T, Kozikowski A, et al. Ketamine and N-acetylaspartylglutamate peptidase inhibitor exert analgesia in bone cancer pain. Can J Anaesth 2006;53(9):891–898. Sant’Agnese PA. The prostatic endocrine-paracrine regulation system and neuroendocrine differentiation in prostatic carcinoma: a review and future direction in basic research. J Urol 1992;152:2. Wood BC. Hormone treatments in the common hormone-dependent carcinomas. Palliat Med 1993;7:257–272. Mike S, Harrison C, Coles B, et al. Chemotherapy for hormone-refractory prostate cancer. Cochrane Database Syst Rev 2006;(4):CD00524. Reale C, Turkiewicz AM, Reale CA. Antalgic treatment of pain associated with bone metastases. Crit Rev Oncol Hematol 2001;37:1–11. Lattouf JB, Saad F. Preservation of bone health in prostate cancer. Curr Opin Support Palliat Care 2007;1(3):192–197. Pelger RC, Soerdjbalie-Maikoe V, Hamdy NA. Strategies for management of prostate cancerrelated bone pain. Drugs Aging 2001;18(12):899–911. Silberstein EB. The treatment of painful osseous metastases with phosphorus-32-labeled phosphates. Semin Oncol 1993;20(3 suppl 2):10–21. Oosterhof GO, Roberts JT, de Reijke SA, et al. Strontium(89) chloride versus palliative local

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field radiotherapy in patients with hormonal escaped prostate cancer: a phase III study of the European Organisation for Research and Treatment of Cancer, Genitourinary Group. Eur Urol 2003;44(5):519–526. Robinson K. Strontium 89 therapy for the palliation of pain due to osseous metastases. JAMA 1995;274(5):420–424. Kraeber-Bodéré F, Campion L, Rousseau, et al. Treatment of bone metastases of prostate cancer with strontium-89 chloride: efficacy in relation to the degree of bone involvement. Eur J Nucl Med 2000;27(10):1487–1493. Rowell NP. Intralesional methylprednisolone for rib metastases: an alternative to radiotherapy? Palliat Med 1988;2(2):153–155. Adornato M, Paticoff KA. Intralesional corticosteroid injection for treatment of central giantcell granuloma. J Am Dent Assoc 2001;132(2):186–190. Lin P, Frink SJ. Intralesional treatment of bone tumors. Operative Techniques in Orthopaedics 2004;14(4):251–258. Sis T, Wong C. Difficult problems and their solutions in patients with cancer pain of the head and neck areas. Curr Rev Pain 2000;4(3):206–214. Alberico R, Ahmed AH, Husain SH. Vertebroplasty and kyphoplasty. In: de Leon Casseola O, ed. Cancer Pain Management: Pharmacologic, Interventional, and Palliative Approaches. Philadelphia: Elsevier; 2006:439–448. Fourney D, Schomer DF, Nader R, et al. Percutaneous vertebroplasty and kyphoplasty for painful vertebral body fractures in cancer patients. J Neurosurg 2003;98(suppl 1):21–30. Dupuy D, Ahmed M, Rodrigues B, et al. Percutaneous radiofrequency ablation of painful osseous metastases: a phase II trial. Proc Am Soc Clin Oncol 2001;20:385a. Locklin MA, Mannes A, Berger A, et al. Palliation of soft tissue cancer pain with radiofrequency ablation. J Support Oncol 2004;2:439–445. Wood B, Fojo A, Levy EB, et al. Radiofrequency ablation of painful neoplasms as a palliative therapy: early experience. J Vasc Interv Radiol 2000;11S:207. Goetz M, Callstrom MR, Charboneau JW, et al. Percutaneous image-guided radiofrequency ablation of painful metastases involving bone: a multicenter study. J Clin Oncol 2004;22(2):300–306. Larkin K. Practical aspects of cancer pain and symptom management and pediatric palliative care. In: Fisch M, Burton A, eds. Cancer Pain Management. New York: McGraw-Hill; 2007:209–242. Cherny N. The assessment of cancer pain. In: McMahon S, Koltzenburg M, eds. Wall and Melzack’s Textbook of Pain. 6th ed. London: Elsevier; 2006:1039–1060. Kubista E, Glaspy J, Holmes FA, et al. Bone pain associated with once-per-cycle pegfilgrastim is similar to daily filgrastim in patients with breast cancer. Clin Breast Cancer 2003;6:391–398. Gudi R, Krishnamurthy M, Patcher BR. Astemizole in the treatment of granulocyte colonystimulating factor-induced bone pain. Ann Intern Med 1995;123(3):236–237. König B, König W. Effect of growth factors on Escherichia coli-hemolysin-induced mediator release from human inflammatory cells: involvement of the signal transduction pathway. Infect Immun 1994;62:2085–2093. Bennett A. The role of biochemical mediators in peripheral nociception and bone pain. Cancer Surv 1988;7:55–67. Slatkin N. Cancer-related pain and its pharmacologic management in the patient with bone metastasis. J Support Oncol 2006;4(2 suppl 1):15–21.

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CHAPTER 47 Cancer-Related Visceral Pain MARY ALICE VIJJESWARAPU, LALITHA SUNDARARAMAN, and EDGAR ROSS

Epidemiology Review In 2004, 1.4 million Americans were diagnosed with cancer. This number equals approximately 4,000 new diagnoses per day. In the same year, over 500,000 American deaths were attributed to cancer, accounting for 22% overall mortality.1 Currently, more than 10 million individuals in the United States carry the burden of a cancer diagnosis, which is 3% of the population.2 Approximately 50% of patients who carry a diagnosis of cancer report pain as a symptom of the disease process. This percentage increases to 75% of patients reporting pain in the advanced stages of disease.3,4 In 2016, it is estimated that there are 1,685,210 new cases of cancer in the United States, and 595,690 people will die from the disease. The number of people living beyond a cancer diagnosis reached nearly 14.5 million in 2014 and is expected to rise to almost 19 million by 2024. Approximately 39.6% of men and women will be diagnosed with cancer at some point during their lifetimes (based on 2010 to 2012 data).5 The prevalence of pain in cancer varies widely depending on the stage of cancer, type of cancer, and treatment received. The pooled prevalence is about 50% with the highest prevalence in head and neck cancer patients (70% 95% CI, 55% to 80%).6 With competent management, cancer pain can be eliminated or well controlled in 80% to 90% of cases, but nearly 1 in 2 patients in the developed world receives less than optimal care. Worldwide, nearly 80% of people with cancer receive little or no pain medication.7 Trends in death rates for all cancer sites combined from 2000 to 2014 showed a decrease. Death rates decreased statistically, significantly from 2000 to 2014 by 2402

1.8% (95% CI = −1.8% to −1.8%) on average per year among men and by 1.4% (95% CI = −1.4% to −1.3%) per year among women.8 After patients come to terms with the diagnosis of cancer and the implications of their disease, most patients and their families will express concern about the pain and suffering they will experience as their disease progresses. Commonly asked questions include how much pain will there be and can it be controlled?4 Unfortunately, despite evidence that cancer pain can be controlled, it is managed poorly in many cases. Multiple factors limit adequate treatment of cancer pain, including misperceptions of disease processes, misconceptions regarding pain medications and procedures, professionals inadequately trained in pain management, failure to consult specialists trained in contemporary pain management methods, and social stigma around opioid use, including fears of addiction by patients, family members, and professional health care providers.9 Also, many common cancers in the advanced stages of disease when pain is highly prevalent are incurable, and survival may be measured in months, not years. Whereas health care professionals may only measure survival duration as a meaningful treatment outcome, patients and families may measure outcomes in terms of improvement in quality of life, alleviation of pain, and relief of other associated symptoms related to cancer and treatment.10 Because pain syndromes arise from cancer therapies (including chemotherapy, radiation therapy, or surgery), patients who survive their primary malignancy may be left with pain secondary to an iatrogenic process. Chemotherapy may induce a painful peripheral neuropathy. Neuropathy is well described with vincristine, platinum, taxanes, thalidomide, bortezomib, and other agents. Pain secondary to radiation may appear years to decades after completion of radiotherapy. Pain syndromes following surgery may present after mastectomy, amputation, thoracotomy, or other surgical approaches to malignancies (see Chapters 41, 42, 45, and 48).11

Characteristics of Visceral Pain ANATOMY AND PHYSIOLOGY 2403

Visceral pain is caused by disorders of internal organs such as the stomach, kidney, gallbladder, urinary bladder, and intestines as well as changes in the central nervous system. Pain can result from distension, impaction, ischemia, inflammation, or traction on the mesentery and can be associated with symptoms such as nausea, fever, malaise, and pain.12 Growth of visceral tumors disrupts normal physiologic processes secondary to compression and invasion of adjacent structures. Progression of disease may be asymptomatic until a critical event manifests (e.g., obstruction of a hollow viscus). Under these conditions, the first symptom a patient may experience is pain.13–15 Visceral pain is unique in quality of presentation when compared to pain that arises from musculoskeletal structures of the body. Visceral pain is usually vague in its presentation and may be confused by referral to a variety of somatic locations secondary to viscerosomatic convergence.16 The phenomenon of viscerosomatic convergence refers to the diffuse nature of visceral pain and its referral to superficial structures due to the convergence of visceral and somatic afferents on the same dorsal horn neurons and secondary hyperalgesia. Symptoms may seem out of proportion to physical examination and imaging.17 Additionally, visceral pain may be attributable both to the malignancy itself and to chemotherapeutic and radiation therapies. Increased pain following symptomatic relief may suggest the local recurrence of disease or a new locus of disease requiring repeat evaluation of the patient.18 Some features of visceral nociception may offer a better understanding of the experience of patients with visceral pain. Visceral pain is more frequently accompanied by an autonomic response than is somatic pain or pain from skin injury, unless the pain is referred visceral pain mimicking somatic pain.16 There is a poor correlation between the extent of visceral tissue damage and the severity of pain experienced. Visceral pain is poorly localized because of poor representation within the primary somatosensory cortex. The majority of visceral afferents are specific to motor or reflex responses with few neural afferents that are specialized for pain transmission. Those afferents that are specialized for pain are sparsely distributed throughout the viscera; both high-threshold nociceptors and low-threshold “silent” nociceptors are invoked in the pain experience.15 2404

Studies have demonstrated multiple visceral pain mechanisms as well as the mechanisms by which one class of visceral pain may relate to other sources of malignant pain. There are four primary classes of visceral pain: 1. Mechanical: caused by stretch of visceral structures (bowel lumen or hepatic capsule) 2. Ischemic: caused by tumor invasion or compression of visceral blood supply 3. Inflammatory: humoral mediators of inflammation released secondary to tumor infiltration of visceral structures 4. Neuropathic: compression or invasion of neural structures supplying the viscera18 Surgery, chemotherapy, or radiation therapy of cancer can also be responsible for iatrogenic damage of the viscera, associated visceral structures, or nerves. Applying a stimulus that causes tissue damage (e.g., cutting, burning, or pinching) to skin or muscle reliably produces the perception of pain, but these stimuli do not reliably evoke reports of pain when applied to visceral structures. Pain secondary to distension of a hollow viscous, such as in the case of bowel obstruction, does not necessarily produce a similar perception when applied to surface structures. In controlled studies, visceral pain can be consistently demonstrated by mechanical distension of hollow organs using distending fluids or balloon devices.19 These modalities of inducing pain most closely reproduce the natural or pathophysiologic processes causing pain. Mechanical distension can be specifically applied to a given organ structure in isolation of other structures, mimicking processes involving the gastrointestinal, biliary, and urinary tracts which may occur from tumor obstruction (or adhesions) in these sites. Distension of organ capsules, such as the splenic, renal, or hepatic capsule, has also been demonstrated to produce profound pain. On the other hand, gentle or slow but progressive distension or obstruction may not produce pain until a critical point in which ischemia or rupture results. Torsion or stretch on mesenteric structures or omentum may produce states of ischemia, infarct, and inflammatory response producing reports of severe pain.20 Inflammatory processes in visceral structures may produce pain as a result of ischemic response, but some tumors may produce inflammatory 2405

mediators with no inciting ischemic event. Both prostaglandin E2 and serotonin have been demonstrated as independent chemical stimuli in the production of pain as malignancy invades adjacent structures.21–23 Experimental studies have demonstrated that the application of inflammatory chemical stimuli can evoke pain behaviors, yet specific mechanical means of eliciting pain have been limited in their translation to studies of other visceral structures.24 Ischemic pain has also been described as occurring secondary to occlusion of visceral vasculature or by compression of visceral structures by tumor growth. When tumor growth exceeds vascular supply, necrosis may result, inducing a variety of inflammatory processes.23 Inflammatory mediators, such as hydrogen ions, kinins, prostanoids, leukotrienes, or other cytokines, are initiators of visceral pain. These chemical agents also sensitize neurologic afferents of organ structures amplifying nociception associated with mechanical stimuli. In general, healthy viscera are typically insensate to pain, whereas superficial structures are continually sensate.24 When diseased, however, visceral organs produce pain severe enough to be incapacitating to other physical activity. Pain from surface structures of the body evokes reflexive motion in the classic “fight or flight” response, whereas the sensation of visceral pain discourages motion or physical activity. Anecdotal evidence supports an association between pain of visceral origin and emotional response and is commonly held to be more anxiety-provoking than pain from somatic structures. Some argue that this anxiety comes from a patient’s inability to visualize the cause of the pain.25 Anxiety scales are reported higher in patients with visceral pain ratings of 2 on a scale of 10 when compared to a higher rated pain experience with visible cause on a superficial structure.26 Furthermore, some symptomatology is more common in patients with visceral pain. Perception of both nausea and dyspnea are more commonly associated with pain of a visceral organ. An autonomic response to visceral pain is far more common than to pain of superficial structures.27,28 Psychological processing of visceral pain is distinct from that related to somatic pain. There are a low number of visceral nociceptors compared with somatic nociceptors. There is a lack of specialization of visceral afferents. Many visceral afferents are polymodal nociceptors. Viscera have 2406

unique ascending tracts through the dorsal column and poor representation within the primary somatosensory cortex.29,30 Viscera have significant input through the medial thalamus to the limbic cortex, amygdala, anterior cingulate, and insular cortex, which influence the affective aspect of pain perception.31 Viscera also have a close association with autonomic nerves. The perception of visceral pain may be disproportionate to pathology exhibited by physical examination or imaging. As an example, a small nephrolith may offer some of the most severe pain states, whereas extensive cancer metastasis may evoke little or no discomfort. Disorders such as chronic pancreatitis demonstrate very little correlation between laboratory studies and flares in pain perception. Disorders such as irritable bowel syndrome and noncardiac chest pain syndrome appear to lack a definitive histopathologic basis for the discomfort and pain.32,33 Many models exist for visceral pain including intraperitoneal injection of a chemical, distension of hollow organs (cecum, colon, rectum), distension of the gallbladder and associated biliary system, and distention or chemical stimulation of the bladder and other urinary tract structures, as well as distension, compression, or traction on reproductive organs. However, lesions studied in one organ are limited in that they are specific to a given stimulus and do not necessarily translate to application in other visceral structures.34

SENSITIZATION Sensitization occurring secondary to the repeated presentation of visceral stimuli has been noted in human psychophysical studies as well as in animal studies. Repeated presentation of the same visceral stimuli produces increasing strength of response in neuronal, cardiovascular, and visceromotor reflex responses. Inflammation of visceral structures increases the magnitude of response to a given mechanical stimulus and decreases the stimulation thresholds for the evocation of nociceptive responses.35 Inflammation of visceral structures significantly modifies behavioral, neuronal, autonomic, and motor responses to visceral stimulation in experimental models. This model mirrors clinical circumstances because inflammation in visceral structures frequently leads to reports of pain.36 2407

Painful conditions such as mucositis, esophagitis, gastritis, pancreatitis, and colitis all exhibit mucosal inflammatory changes. The inflammatory sensitization may take place at primary afferents. These afferents are normally nonreactive to most stimuli and have been described as “silent” in nonpathologic states. However, in the context of an inflammatory tissue response, they become spontaneously active and highly reactive to mechanical stimuli. Silent afferents may comprise 50% of the neuronal sample in a visceral organ but are infrequently noted in superficial or cutaneous structures. Lack of baseline sensitivity in normal viscera may be secondary to sparsity of visceral afferentation. There are fewer afferents per unit area than similar measures of cutaneous afferents. Because of this sparse innervation, increased activity may be necessary to cross a threshold for perception. Spinal neurons responsive to visceral stimuli also change their responsiveness to visceral stimuli in the presence of inflammation. The cause of this behavior is unknown, although voltagegated sensitization by the transient receptor potential vanilloid 1 (TRPV-1) and tetrodotoxin-resistant (TTX-R) receptors may play a role.37,38 Increased afferent activity, altered intrinsic properties of dorsal horn neurons, and altered modulatory influences or some combination may all serve a role in the process. Dorsal column pathways have been demonstrated to play a role in visceral nociception but not in cutaneous nociception. The results of multiple studies suggest that visceral pain requires a sensitization process both in the periphery and the spinal cord.39

LOCALIZATION Visceral pain is classically thought of as deep and diffuse in presentation. Localization of the pain generator can be difficult to identify by physical examination. Superficial pain, in contrast, can be elicited by examination with precise localization and with consideration to the site of the body examined; pain locus can be identified within millimeters. Moreover, surface pain loci reliably localize to the same site, never migrating to other body areas, in the absence of neural injury. Visceral pain is characterized as migratory in its presentation, often perceived in several loci simultaneously or migrating regionally in spite of localization of pathology. This is evident in the presentation of 2408

appendicitis. Furthermore, the perception of pain associated with visceral pathology is not normally localized to the organ itself but to somatic structures that receive afferent inputs at the same spinal segments as the visceral afferent entry. For this reason, visceral pain is classically described as either unlocalized pain or as referred pain that may have two separate features. Sensation of the diseased viscera is transferred to a surface site (e.g., an ischemic myocardium can be felt in neck and arms) or additional sites may become hypersensitive to inputs applied directly to those other sites (e.g., flank muscle becomes sensitive to palpation with urolithiasis). This latter phenomenon is referred to as secondary somatic hyperalgesia. Psychophysical studies of internal organ sensation have focused on a given organ using simple stimuli, correlating the given stimuli to a given organ with perception at the respective site of stimulus. Other psychophysical studies using visceral stimuli have examined the referred sensations described by subjects. These studies have often failed to contrast referred pain to a body surface with cutaneous sensations at the same surface. Patient illustrations of referred sensations tend to extend over large surface areas, whereas studies using cutaneous stimuli generate pinpoint localization to highly precise sites. The phenomenon of secondary somatic hyperalgesia produced by visceral pathology has been compared to sites of sensitivity with lesions produced by herpes zoster. These initial studies were fundamental to the development of dermatomal mapping. In visceral disease processes, multiple dermatomes have been identified suggesting that secondary somatic hyperalgesia is widely distributed (i.e., poorly localized). Recent psychophysical studies have attempted to compare visceral with nonvisceral pain. In one study, the sensation produced with balloon distension of the esophagus was compared to thermal stimulation of the mid-chest skin. Subjects perceived larger areas of sensation for esophageal distension than for intensity-matched, heat-evoked sensation on body maps. Temporally, there was also a difference. A rapid response was noted with heat stimulus, whereas there was poor correlation with the esophageal stimulus and the perception of the sensation. Intense visceral discomfort remained after discontinuation of the distending apparatus but not after 2409

discontinuation of the cutaneous stimulation. Visceral sensation was concluded to be diffuse both spatially and temporally. Corollary observation of cerebral blood flow identified that similar cerebral areas were activated by both stimuli. When evaluating the patient in visceral pain with malignancy, the early presentation may be misleading with vague midline discomfort. It may be poorly localized and accompanied by both an emotional response and autonomic event. Later in the evolution of disease process, patients may complain of somatic or referred pain hypersensitivity at the spinal level of the visceral nociceptor terminus. Referred pain is sharp and localized. It is often associated with allodynia and muscle spasm. Furthermore, visceral hypersensitivity may induce the perception of pain in another organ receiving innervation from the same spinal segment.

VISCERAL AFFERENTATION Visceral primary afferents differ significantly from cutaneous primary afferents in both number and pattern of distribution. Visceral sensory pathways are organized into nerve fascicles and cell body groupings extending from prevertebral regions to contact viscera predominately via perivascular pathways. Cell bodies of visceral primary afferent nerve fibers are located in the visceral dorsal root ganglia of the thoracic and upper lumbar spine, but the peripheral axons of these neurons follow a circuitous path to visceral organs passing via the paravertebral sympathetic chain and ganglia as well as nerve fascicles that are termed the cardiac and splanchnic nerves. The splanchnic nerves are divided into the greater, lesser, least, thoracic, and lumbar divisions. The pelvic nerves arise from dorsal root ganglia at sacral levels, accepting sympathetic chain input before innervating urogenital structures. Visceral sensory processing also differs from cutaneous sensory processing because visceral neuronal synapses exist at cell bodies of prevertebral ganglia such as the celiac ganglion, superior mesenteric ganglion, and pelvic ganglion, producing changes in local visceral function outside central control. The gastrointestinal tract is also supplied by an independent enteric nervous system relating to functions of digestion and absorption. In the pelvis, structures receive dual innervation with afferents 2410

from lower thoracic to upper lumbar segments and from sacral segments. Testicle and ovary embryologically originate in the superior aspect of the abdomen and, therefore, receive thoracic innervation. The urinary bladder has a similar thoracolumbar innervation with sensory inputs extending up to the T10 level but also receives sacral inputs (the pelvic nerve) with other tissues originating from sacral dermatomes (rectum, genital structures). Pelvic organs also receive efferent and afferent connections from the vagus nerve and local ganglionic circuitry, resulting in a complex and diffuse neuroanatomy. Afferents with endings in a focal visceral site may have cell bodies in the dorsal root ganglia of 10 or more spinal levels in a bilaterally distributed fashion. In contrast, cutaneous afferents from a particular body surface arise from only 3 to 5 unilaterally located dorsal root ganglia. Visceral receptors are located in mucosa, serosa, and muscle of hollow organs as well as visceral mesentery. They are not reported in parenchyma of solid organs. The specialized receptors that discriminate a variety of stimuli in somatic structures are absent in viscera. The mesentery, however, does contain Pacinian corpuscles. Hollow organs contain specialized low-threshold and high-threshold mechanoreceptors. Lowthreshold receptors serve a basic regulatory function, whereas highthreshold receptors are activated only with noxious mechanical stimuli. Visceral nociception results from summation of nociceptive input to regulatory low-threshold receptors and noxious high-threshold and silent nociceptors rather than activation of stimulus-specific nociceptors.40

ASCENDING PATHWAYS Visceral afferent fiber activation causes an increase in nitric oxide synthase in the dorsal horn of the spinal cord, causing expression of the oncogene c-Fos in laminae I, V, VII, X of the dorsal horn within the thoracolumbar spine. Similar upregulation is seen in the amygdala and paraventricular hypothalamic nuclei and consequent elevation in norepinephrine production within the locus ceruleus. Features of visceral pain processing differing from somatic processing include dorsal column ascending secondary sensory afferents, the spinal 2411

trigeminal to parabrachioamygdaloid tract, and the spinohypothalamic pathway. In the visceral system, both ventrolateral and dorsal column postsynaptic neurons have a role in nociception. Ascending tracts synapse at the lateral thalamus first, then limbic centers, and then somatosensory cortex. Whereas somatic nociception is represented somatotopically within the primary somatosensory cortex, visceral pain is represented in the secondary somatosensory cortex and poorly represented within the primary somatosensory cortex. Visceral pain is well represented in the limbic system, including anterior cingulate gyrus, insular cortex, and amygdala, suggesting a basis for the strong emotional component of visceral pain. Whereas visceral pain elicits decreased patient activity, nausea, and hypotension, somatic pain elicits agitation, reactive activity, and hypertension. Nociceptive activity within the gastrointestinal tract induces inhibition of dorsal motor neurons of the vagus within the medulla leading to gastroparesis and nausea.

Visceral Pain Syndromes Although most pain associated with malignancy is diffuse and chronic, most acute pain syndromes in cancer are secondary to diagnostic or therapeutic interventions. Some tumors generate an acute onset of pain, which may be the result of a perforation of a hollow viscus or rupture of a visceral capsule. Any sudden onset of pain warrants a comprehensive pain assessment. Following is a list of possible pain syndromes that may be encountered by the health care provider.

ORAL MUCOSA Paraneoplastic Pemphigus Paraneoplastic pemphigus is a mucocutaneous disorder accompanying non-Hodgkin lymphoma and chronic lymphocytic leukemia. It is characterized by widespread shallow ulcers, hemorrhagic crusting of the lips, conjunctival bullae, and may be accompanied by pulmonary lesions, occurring secondary to autoantibodies directed against desmoplakins and desmogleins.41

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Oropharyngeal Mucositis and Stomatitis Mucositis and stomatitis should be distinguished as two separate processes (also see Chapter 45). Oral mucositis is an inflammation of oral mucosa resulting from chemotherapeutic agents or ionizing radiation, manifesting as erythema or ulcerations. Stomatitis is any inflammatory condition of oral tissue, including mucosa, dentition, periapices, and periodontium, including inflammation secondary to infection of oral tissues. Mucositis appears 7 to 10 days after initiation of high-dose cancer therapy and is generally self-limited when uncomplicated by infection, resolving 2 to 4 weeks after completion of chemotherapy. In order to standardize assessment, a variety of scales have been created to grade the level of stomatitis by characterizing alterations in lips, tongue, mucous membranes, gingiva, teeth, pharynx, quality of saliva, and voice. The clinical syndrome usually involves the oropharynx but may involve other gastrointestinal mucosal surfaces such as the esophagus, stomach, or intestine, producing such symptoms as odynophagia, dyspepsia, or diarrhea. Any mucosal damage may become superinfected with microorganisms, most commonly Candida albicans and herpes simplex.42 Radiotherapy may also induce mucositis. Doses of radiation in excess of 4,000 cGy frequently cause ulceration with pain lasting several weeks following treatment.43 Acute pain associated with radiotherapy can be caused by acute radiation toxicity causing inflammation and ulceration of skin or mucous membranes. The syndrome produced is dependent on the exposed field.44,45

MEDIASTINUM 5-Fluorouracil-Induced Anginal Chest Pain In patients receiving 5-fluorouracil (5-FU) infusions, ischemic chest pain may develop. Painful events are more common in patients with a history of coronary artery disease and are likely secondary to coronary vasospasm.

Pleura Lung tumors, with or without chest wall involvement, may produce visceral pain. In a large case series of patients with lung malignancies, pain was found to be unilateral in 80% of patients and bilateral in 20% of 2413

patients. Patients with hilar tumors reported sternal or scapular pain. Patients with tumors involving the upper and lower lobe experienced referral of pain into the shoulder and lower chest, respectively.46,47 Additionally, some lung malignancies generate ipsilateral facial pain, thought to be secondary to noxious stimulation of vagal afferent neurons.48–51

Pancoast Syndrome Pancoast syndrome is caused by malignant neoplasms of the superior sulcus of the lung with destructive lesions of the thoracic inlet and involvement of the brachial plexus and cervical sympathetic nerves (stellate ganglion).52,53 Patients report severe pain in the shoulder region radiating toward the axilla and scapula along the ulnar aspect of the muscles of the hand, and patients may also develop atrophy of hand and arm muscles, Horner syndrome (ptosis, miosis, hemianhidrosis, enophthalmos), and compression of the blood vessels with edema.54 Ninety-five percent of patients have either squamous cell or adenocarcinomas. Small cell carcinoma is found in fewer than 5% of cases in most series. Along with these symptoms and signs, additional predictors of poor prognosis are weight loss, supraclavicular fossa or vertebral body involvement, disease stage, and surgical treatment.55,56 These bronchopulmonary tumors may invade the bony structures of the chest. The first or second thoracic vertebra or the first, second, or third ribs may be invaded. One review has described rib erosion in 50% of patients. The tumor may invade the first or second thoracic vertebral bodies or intervertebral foramina, extending to the spinal cord, and resulting in cord compression. The subclavian vein or artery may also be invaded. Advanced tumors may involve the recurrent laryngeal nerve, phrenic nerve, or superior vena cava (SVC).

PANCREAS Midline Retroperitoneal Syndrome The most common cancer-related causes of upper abdominal retroperitoneal pain are pancreatic cancer and retroperitoneal lymphadenopathy, particularly celiac lymphadenopathy. These disease 2414

processes elicit afferent activity via injury to deep somatic structures of the posterior abdominal wall, distortion of pain-sensitive connective tissue, vascular and ductal structures, as well as local inflammation and direct infiltration of the celiac plexus. Patients report pain in the epigastrium, in the low thoracic region of the back, or both. Pain is described as diffuse and dull, exacerbated with recumbency, and improved by sitting forward. Computed tomography (CT), magnetic resonance imaging, or ultrasound scanning of the abdomen may reveal the disease process.

Pancreatic Cancer Patients with pain secondary to unresectable pancreatic cancer report severe abdominal pain radiating into the back. This pain is often refractory to analgesics, even strong opioids. Pain may be accompanied by obstructive jaundice (yellowing of the skin and eyes, itching, dark urine, clay-colored stool) and occurs more frequently when the cancer is located at the head of the pancreas. Other associated symptoms may include weight loss, anorexia, fatigue, and a change in bowel habits (constipation or diarrhea). Controlled trials support the use of neurolytic celiac plexus block with superior results in terms of pain relief over analgesics alone (see Chapter 44 and discussion of celiac plexus block in the following discussion).57

LIVER PAIN Hepatic Distension Syndrome The liver has many nociceptive structures including the liver capsule, blood vessels, and biliary tract. Afferents from these structures travel via the celiac plexus, the phrenic nerve, and the lower right intercostal nerves. Hepatic metastasis typically causes pain when the tumor stretches the capsule. Patients with intrahepatic metastases or hepatomegaly secondary to cholestasis may report discomfort in the right subcostal region or right midback or flank.58 Patients may experience referred pain to the right neck, shoulder, or scapula.59 Patients describe the pain as a dull ache exacerbated by movement, pressure in the abdomen, and deep inspiration. Associated symptoms include anorexia and nausea. Physical examination reveals a hard, irregular subcostal mass, which is dull to percussion, and 2415

descends with inspiration. Diagnostic ultrasound or CT may reveal a space-occupying lesion. Analgesics are the first line of therapy for pain control with drug selection and titration a function of the extent of hepatic compromise. Corticosteroids reduce hepatic edema and liver pain. If a tumor is chemosensitive, chemotherapy may be the treatment of choice. Hormone therapy may decrease hepatomegaly from liver metastasis but may take several months to accomplish a goal of pain relief. As with pancreatic cancer, celiac plexus block may provide definitive relief. Two randomized controlled trials (RCTs) have demonstrated hepatic irradiation to be effective in palliation of hepatic pain in 80% of patients with a reduction of systemic symptoms in half as many patients.60

INTESTINAL PAIN Chronic Intestinal Obstruction In patients with abdominal or pelvic cancers, intestinal obstruction causes diffuse abdominal pain. Pain may be secondary to smooth muscle contraction, mesenteric tension, and ischemia of the bowel wall. Obstruction may be due to tumor, autonomic neuropathy, ileus, metabolic abnormality, or medication. Pain may be continuous or intermittent (colicky) and may be associated with vomiting, anorexia, and constipation.

Peritoneal Carcinomatosis The peritoneal cavity, enclosed by visceral and parietal peritoneum, is the largest potential space in the body. Any pathologic process involving the peritoneal cavity can easily disseminate throughout this space by means of unrestricted movement of fluid and cells. Primary malignant diseases arising from the peritoneal cavity include malignant mesothelioma, cystic mesothelioma, and primary peritoneal carcinoma. Carcinomatosis can cause peritoneal inflammation, mesenteric tethering, and malignant adhesions and ascites, all of which can trigger nociceptive activity. Patients most commonly report abdominal pain and distension. Mesenteric tethering and tension appear to cause a diffuse abdominal or low back pain. Tense malignant ascites can produce diffuse abdominal discomfort and a distinct stretching pain in the anterior abdominal wall. Adhesions 2416

can also cause obstruction of a hollow viscus, with intermittent colicky pain.61 CT scanning may demonstrate evidence of ascites, omental infiltration, and peritoneal nodules.

Radiation Enteritis Acute radiation enteritis may develop in as many as 50% of patients receiving pelvic or abdominal radiotherapy. Patients with small intestinal involvement complain of cramping abdominal pain and have associated nausea and diarrhea. Patients receiving pelvic radiotherapy may develop proctocolitis, associated with pain, tenesmus, diarrhea, mucous discharge, and bleeding. These symptoms may resolve shortly after completion of therapy or may last as long as 6 months.

Intraperitoneal Chemotherapy Pain Approximately 25% of patients receiving intraperitoneal chemotherapy may develop transient mild to moderate abdominal pain and complain of fullness or bloating.62 A second group of patients (approximately 25%) may experience pain severe enough to require opioid analgesia or discontinuation of therapy. Pain is secondary to chemical serositis or infection. Infectious peritonitis is accompanied by fever and leukocytosis in blood and peritoneal fluid.

PELVIC PAIN Malignancy-related pelvic pain not due to bone metastases is most often secondary to presacral recurrence of rectal carcinoma or secondary to pelvic recurrence of cervical cancer. Lumbosacral plexus infiltration is common, resulting in severe pain with a significant neuropathic contribution. Analgesics or interventional therapies should be implemented according to protocols and guidelines (see Chapter 43).

Malignant Perineal Pain Perineal pain may be secondary to tumors of the colon or rectum, female reproductive tract, and distal genitourinary system. A report of perineal pain following therapeutic resolution of malignancy may be a precursor of recurrence and should prompt complete evaluation.63 Pain preceding 2417

evidence of disease may be secondary to microscopic perineural invasion of an insidious malignant process. Patients report pain to be constant and aching, exacerbated with sitting or standing. Associated symptoms may include tenesmus or bladder spasm.64 If tumor invades musculature of the pelvis, patients may complain of a constant aching in the pelvis, which is exacerbated with standing. Examination of the pelvic floor may demonstrate tumor.

Ureteral Obstruction Patients with tumor involving the pelvis may have pain due to tumor compression or infiltration of the distal ureter.10 Obstruction of the proximal ureter is less common and is associated with retroperitoneal lymphadenopathy, an isolated retroperitoneal metastasis, mural metastases, or intraluminal metastases. Cancers of the cervix, ovary, prostate, and rectum are most commonly associated with this complication. Other rare causes of ureteral obstruction include retroperitoneal fibrosis resulting from radiotherapy or graft-versus-host disease. Pain is described as dull, chronic discomfort in the flank often with associated radiation into the inguinal region or genitalia.10 However, patients may have obstruction without evidence of pain.

Ovarian Cancer Pain Patients experiencing severe chronic abdominal or pelvic pain may be experiencing the harbinger of ovarian cancer. It is the most common presenting symptom and most common symptom of recurrence.10 Twothirds of patients experience pain in the 2 weeks prior to the onset or recurrence of the disease. In patients who have been previously treated, it is an important symptom of potential recurrence.10

Tumor-Related Gynecomastia In patients complaining of breast pain or tenderness, there is a risk of occult tumor of the testes or lung. Human chorionic gonadotrophin (HCG)-secreting tumors of testis, including malignant and benign types as well as other HCG-secreting tumors, may produce breast tenderness or gynecomastia.65 Approximately 10% of patients diagnosed with testicular 2418

cancer complain of gynecomastia or breast tenderness.66

Intravesical Chemotherapy or Immunotherapy Patients receiving intravesical Bacillus Calmette-Guérin (BCG) therapy for urinary bladder transitional cell carcinoma experience a syndrome of bladder irritability. Patients report urinary frequency and painful micturition. In rare cases, patients receiving BCG therapy may develop a painful polyarthritis.67 Other intravesical chemotherapies, such as doxorubicin, may also cause a painful chemical cystitis.68

Corticosteroid-Induced Perineal Discomfort In patients receiving high-dose corticosteroid therapy, some may report an uncomfortable sensation of burning perineal pain.69

ADRENAL PAIN SYNDROME Patients with adrenal metastases of considerable size, common in lung cancer, may develop unilateral flank pain or abdominal pain. Patients report pain from this condition as highly variable, describing it as dull and aching to severe in presentation.70

Vascular Obstruction Hypercoagulability with thrombosis is the most frequent complication associated with malignancy and the second most frequent cause of mortality in malignant disease. A thrombotic event may occur in advance of the diagnosis of cancer by months or years; therefore, thrombosis should be considered as a marker for occult malignancy. Chemotherapy and hormone therapy are associated with an increased thrombotic risk. Additionally, deep vein thrombosis (DVT) is a more common postoperative complication in patients with malignancies than in other postoperative populations. Hypercoagulability in malignancy is secondary to tumor cell expression of tissue factor and cancer procoagulant. Apoptosis of malignant cells or penumbra of nonmalignant cells affected by invading malignant tissue activates normally dormant tissue factor, initiating a coagulation cascade and formation of thrombus. Tumor proliferation, chemotherapy, hormonal 2419

therapy, radiation therapy, and hematopoietic growth factors all increase apoptotic activity and increase the risk of thrombus. Factors contributing to the formation of thrombus include cytokine release, acute phase reaction, and neovascularization. Tumors associated with higher risk of hypercoagulability include tumors of the pelvis, pancreas, stomach, breast, and brain.

Venous Thrombosis Patients with DVT most often present with pain and swelling of the lower extremity. Patients often report that pain is mild, dull and crampy, or a diffuse perception of pressure or heaviness. The calf is most often involved, but the sole of the foot, heel, thigh, groin, or pelvis may be the site of thrombus and pain. Exacerbating factors include standing or walking. Physical examination may reveal signs of DVT, including swelling, warmth, dilation of superficial veins, tenderness along venous tracts, and pain with stretching of the affected limb. Rarely, a patient may present with ischemia of the lower extremity or in worse cases, a gangrenous limb. This presentation may occur in the absence of arterial or capillary occlusion (phlegmasia cerulea dolens). Signs include severe pain, extensive edema, and cyanosis of the affected leg. Mortality varies but may be as high as 40% secondary to ischemia of the affected extremity or progression of thrombus to cause pulmonary emboli. Only 2% of DVT cases involve the upper extremity with a low rate of associated pulmonary embolism. On physical examination, upper extremity DVT most often presents with edema, dilated collateral circulation, and pain.69 In patients with malignancy, central venous catheterization is the most frequent cause along with extrinsic compression by tumor.71,72

Superior Vena Cava Obstruction For patients with lung cancer and lymphoma, SVC obstruction develops with extrinsic compression of the SVC by tumor expansion or by enlarged mediastinal lymph nodes.71 Intravascular catheters are an iatrogenic cause, especially with left-sided ports where the catheter tip rests in the upper portion of the vessel.73 Physical examination reveals facial swelling, 2420

dilated neck veins, and dilated chest wall veins. Less common patient reports of symptoms associated with SVC obstruction include chest pain, headache, and mastalgia.74

Acute Mesenteric Vein Thrombosis Acute thrombosis of the mesenteric veins is most commonly associated with hypercoagulability secondary to malignancy and more rarely secondary to venous compression by lymphadenopathy, extension of venous thrombosis, or iatrogenic hypercoagulable states.

PAIN SYNDROMES RELATED TO INTRAVENOUS CHEMOTHERAPEUTIC AGENTS Chemotherapeutic agents may cause vascular pain secondary to venous spasm, chemical phlebitis, vesicant extravasation, and anthracyclineassociated flare. Venospasm pain is not secondary to inflammation or phlebitis. Attenuation of symptoms may come from application of a warm compress or reduction of chemotherapeutic infusion rate. Agents causing chemical phlebitis include amsacrine, dacarbazine, carmustine and vinorelbine, potassium chloride, and hyperosmolar solutions. The pain and erythema associated with chemical phlebitis should be monitored closely because it shares many of the early features of vesicant cytotoxic extravasation that in later stages presents as desquamation and ulceration of cutaneous structures. Venous flare reaction is often associated with the use of anthracycline or doxorubicin and presents with local urticaria, pain, or stinging.

Hepatic Artery Infusion Pain Patients receiving cytotoxic infusions directly into the hepatic artery often report diffuse abdominal pain.73 Pain is attributed to gastric ulceration, gastric erosion, or cholangitis. With no persistence of complications, resolution of pain occurs with completion of therapy.

COMPLEX VISCERAL PAIN SYNDROMES Nontraumatic rupture of a visceral tumor may cause sudden, severe abdominal or pelvic pain and is most commonly associated with 2421

hepatocellular carcinoma.75 Metastases from other tumors also cause visceral ruptures (e.g., kidney rupture from a metastasis from adenocarcinoma of the colon or metastasis-induced perforated appendicitis).76,77 Torsion of pedunculated visceral tumors may cause cramping abdominal pain.78

POSTRADIATION VISCERAL PAIN Postradiation therapy pain syndromes often involve both somatic and visceral structures, regardless of the target organ. Late effects, including connective tissue fibrosis, neural damage, and secondary malignancies, can occur long after completion of radiotherapy. A recent large retrospective cohort study revealed an association between previous pelvic radiation and hip fractures, with an increase in lifetime fracture rate from 17% (control) to 27% (radiation group). Pelvic pain after radiotherapy may be due to pelvic insufficiency fracture, enteritis, visceral dysfunction, or neural damage. Chronic pelvic pain has been reported as a consequence of prostate brachytherapy. Twenty percent of patients receiving brachytherapy have been reported to complain of dysuria 1 year after treatment.

Radiation Enteritis and Proctitis In 2% to 10% of patients receiving pelvic or abdominal radiation therapy, chronic enteritis and proctocolitis may occur.79 The rectum and distal colon are more frequently sites of involvement. Onset may be as early as 3 months or as late as 30 years.80 Presentations may include proctitis (bloody diarrhea, tenesmus, and cramping pain), obstruction due to stricture formation, or fistulae to the bladder or vagina.10 Small bowel radiation damage typically causes colicky abdominal pain, which can be associated with chronic nausea or malabsorption. Barium studies may demonstrate a narrow tubular bowel segment resembling Crohn’s disease or ischemic colitis. Endoscopy and biopsy may be needed to identify recurrent cancer.

Burning Perineum Syndrome Perineal discomfort may develop 6 to 18 months following pelvic 2422

radiotherapy. Patients complain of burning pain in the perianal region and may involve the vagina or scrotum. For those patients with postabdominoperineal resection, phantom anus pain and recurrent tumor should be considered.

Radiation Cystitis Radiation therapy used in the treatment of tumors of the pelvic organs (prostate, bladder, colon/rectum, uterus, ovary, and vagina/vulva) may produce chronic radiation cystitis.10 Symptoms of radiation injury to the bladder may be as minor as temporary irritation with voiding or asymptomatic hematuria, or as severe as gross hematuria, a contracted nonfunctional bladder, persistent incontinence, and fistula formation. Other signs and symptoms may include frequency, urgency, dysuria, hematuria, incontinence, hydronephrosis, pneumaturia, and fecaluria.10

POSTCHEMOTHERAPY VISCERAL PAIN Painful peripheral neuropathy is frequently a dose-limiting side effect of some chemotherapeutic regimens. Once the therapy is stopped, the neuropathic pain will resolve with or without symptomatic treatment. However, in a small number of patients, the neuropathy does not resolve and may continue to be intensely painful. Prevalence during treatment varies from agent to agent, with the intensity of treatment (dose intensity and cumulative dose), with other concurrent therapies such as surgery and radiotherapy, and with the use of combination chemotherapy. Estimates of prevalence range from 4% to 76% during chemotherapy treatment.

Treatment In general, treatment for cancer-related visceral pain syndromes should adhere to standard cancer pain treatment guidelines (e.g., World Health Organization (WHO) Analgesic Ladder; American Pain Society Guidelines). The reader is referred to Chapters 43, 44, and 48 for details of various pharmacotherapeutic, radiotherapeutic, and interventional treatment modalities. Therapies that target visceral pain mechanisms with some specificity that are not covered in detail in other chapters are

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elaborated in the following discussion.

N-METHYL-D-ASPARTATE RECEPTOR ANTAGONISTS Ketamine, which blocks N-methyl-D-aspartate (NMDA) receptors, can influence visceral hypersensitivity. Primary visceral hypersensitivity is attributed to a reduction in peripheral nociceptive thresholds. Two central processes mediate secondary visceral hypersensitivity: (1) plasticity of activated C fibers and (2) convergence of afferents at multiple levels and maintained by glutamate release that binds to NMDA receptors. NMDA receptor activation results in nitric oxide synthase expression, nitric oxide production, and prostaglandin production. Through these mechanisms (and perhaps others), ketamine has been found to be useful in the management of pain states that are either poorly responsive to opioids and other analgesics or when there are dose-limiting adverse effects to other pain treatments. Ketamine use has been described, with variable success, in adults, pediatric patients, via intrathecal, parenteral, and oral routes, and in inpatient as well as outpatient settings.81–90

CORTICOSTEROIDS Dexamethasone inhibits neuronal nitric oxide synthase gene expression. It has been effective in treating visceral pain and bowel obstruction.91

GABAPENTIN Gabapentin has been demonstrated to reduce glutamate levels and reduces hypersensitivity associated with celiac pain.92

SHORT INTERFERING RNA THERAPEUTICS The discovery that short double-stranded RNA molecules can be used to induce RNA interference (RNAi) in mammalian systems has opened up several possible new avenues in treatment of pain. Gene silencing by small interfering RNAs (siRNAs) has been demonstrated in neurons, and several targets involved in pain perception have been identified can be modulated by these siRNAs. In the past decade, hundreds of molecular targets have 2424

been identified for their roles in pain modulation, but most molecular targets are not readily amenable to drugs with small molecules. In the past years, RNAi has become the most widely used technology to suppress gene expression. Effective delivery of nucleic acid-based therapeutic molecules to the central nervous system remains a limiting step for RNAi, and currently, transfection agents are being used via the intrathecal route to deliver siRNA into spinal cord cells as well as dorsal root ganglion cells and hence act on many possible targets for gene expression and modulation including nerves and spinal cord regions affected by cancer pain.93–95

T-TYPE CALCIUM CHANNEL ANTAGONISTS T-type calcium channels are expressed in many diverse tissues, including neuronal, cardiovascular, and endocrine. T-type calcium channels are known to play roles in the development, maintenance, and repair of these tissues but have also been implicated in disease when not properly regulated. T-type calcium channels found on peripheral and central endings of primary afferent neurons are involved in nociception. Voltagegated calcium channels can be divided into two groups: high-voltage activated calcium channels (L, N, P/Q, and R types) and low-voltage activated calcium channels (T types).96 Li et al.97 showed that paclitaxelinduced neuropathy causes hyperexcitability in dorsal root ganglion neurons that is paralleled by increased expression of low voltage–activated calcium channels or namely the T-type channels. Hence, there was great excitement that antagonism of these channels could be of great promise in the treatment of neuropathic pain. Additionally, Le Blanc et al.98 proved that these T-type calcium channel blocker (CCB) antagonists restore synchrony in thalamic burst firing and possibly alter the affective pathway of pain. Preclinical studies with ABT-639, a peripherally acting highly selective T-type Cav3.2 CCB, showed dose-dependent reduction of pain in multiple pain models including arthritic, neuropathic, cancer- and capsaicininduced pain. However, the initial study results are still to be validated through repeat studies. Wallace et al.99 compared the pharmacodynamic effects of a single 100-mg dose of ABT-639, a peripherally active, 2425

selective T-type Cav3.2 channel blocker, with pregabalin. They used an intradermal capsaicin model to assess drug efficacy and demonstrated that a single 100-mg dose of ABT-639 had no effect on experimental pain induced by intradermal capsaicin injection. Hence, the jury remains out on T-type calcium channel antagonists.

AMPA/KAINATE ANTAGONISTS Glutamate activates three subtypes of ligand-gated ion channel: the NMDA, (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl) propionic acid (AMPA), and kainate receptors. Animal studies suggest that AMPA and kainate receptors are involved in epilepsy, pain, and psychiatric disorders. Kainic acid activates nociceptors, and consequently, kainate receptor antagonists have a potential as analgesics. Receptors for AMPA (GluR1-4) are found throughout all superficial laminae of the dorsal horn pre- and postsynaptically. AMPA agonists augment responses of spinal neurons to noxious and nonnoxious stimuli. Kainate receptors (Glu 5-7; KA2) are expressed diffusely in the dorsal horn, mostly in lamina.100,101 Gormsen et al.102 investigated the efficacy of NS1209, a test AMPA receptor antagonist and lidocaine in nerve injury pain. In a three-way RCT involving 13 patients comparing lidocaine, NS1209, and placebo, the authors found that like lidocaine, NS1209 was superior to placebo in alleviating some key symptoms of neuropathic pain (i.e., evoked types of pain, including mechanical and cold allodynia but not superior in alleviating spontaneous current pain). Possibly, more work is needed to delineate the disease mechanisms influenced by AMPA/kainate receptors before antagonists can be developed for the treatment of pain.

P38 KINASE INHIBITORS p38 mitogen-activated protein kinases (MAPK) are serine/threonine protein kinases involved in the regulation and synthesis of inflammatory mediators and show great potential for the development of cytokinetargeted anti-inflammatory drugs. p38 inhibitors have been shown in preclinical models to decrease neuropathic pain, particularly where there is a substantial inflammatory component.103 In a randomized control trial involving 43 patients with carpal tunnel 2426

syndrome, radiculopathy or other causes of nerve trauma, Anand et al.104 demonstrated lower pain scores with acceptable side effects for the new drug dilmapimod. However, other clinical trials of these medications have found prolongation of QT intervals by these agents and have largely been unsuccessful. Further studies require results to be ratified for use in cancer neurogenic pain.

CHEMOKINE RECEPTOR TYPE 2 ANTAGONISTS Chemokine receptor type 2 (CCR2) is a chemokine receptor that mediates monocyte chemotaxis and hence is thought to play a crucial role in inflammatory and neuropathic pain states. Abbadie et al.105 proved that mice with chronic pain showed activated CCR2-positive microglia in the spinal cord. They suggested that the recruitment and activation of macrophages and microglia peripherally and in neural tissue may contribute to both inflammatory and neuropathic pain states. Accordingly, blockade of the CCR2 receptor may provide a novel therapeutic modality for the treatment of chronic pain. However, many trials including a recent one by AstraZeneca have failed. Newer emerging evidence suggests that alternate applications for CCR2 antagonists are possible. It has been shown that spinal CCR2 is upregulated in several neuropathic pain models and expressed by neuronal and glial cells in the spinal cord. Hu et al.106 investigated the expression changes and cellular localization of spinal CCR2 in a rat model of bone cancer induced by Walker 256 cell inoculation. The results indicated that mechanical allodynia progressively increased in bone cancer pain rats with increased CCR2 expressed by both microglia and neurons in the spinal cord. These results suggest that CCR2 may be involved in the development of cancer pain, and that targeting CCR2 may be a new strategy for the treatment of cancer pain.

P2X PURINOCEPTOR 3 ANTAGONISTS P2X purinoceptor 3 (P2X3) receptor subunits are expressed prominently and relatively selectively in so-called C- and Aδ-fiber primary afferent neurons in most tissues and organ systems, including skin, joints, and hollow organs, suggesting a high degree of specificity to the pain sensing 2427

system in the human body. P2X3 antagonists block the activation of these fibers by adenosine triphosphate (ATP) and reduce ATP sensitization of peripheral pain neurons. In addition, P2X3 is expressed presynaptically at the central terminals of C-fiber afferent neurons, where upregulation and sensitization of pain signals by ATP occurs. This is also potentially blocked by P2X3 receptor antagonists. Another exciting prospect offered by these agents is the potential of decreased side effects due to the selective expression of P2X3, with a lesser risk of affecting the gastrointestinal and renal systems that remain limiting factors for many other existing medications.107 Gilchrist et al.108 also suggested in their murine model study that there is increased expression of P2X3 receptors in tumor growth in rats with hence increased potential for ATP activation and bone cancer pain. This study opens avenues for possible use of P2X3 antagonists in bone cancer pain. Newer research has suggested that a potentially significant pathway for the transmission of cancer visceral pain would be the highly specific postsynaptic dorsal column, which have been shown to express neurokinin receptors (neurokinin-1 [NK-1]) in the event of visceral stimulation that help propagate cancer visceral pain. Surgical lesioning of the dorsal column is potentially difficult, and hence, pharmacologic lesion of the pathway may be an alternate choice. Evidence has shown that spinal dorsal column neurons start to express NK-1 receptors after visceral stimulation, suggesting new targets for the development of pharmacologic strategies for the control of visceral pain. Wang et al.109 suggested that targeted cytoxin composed of substance P coupled to the cytotoxic ribosome inactivating protein, saporin, might selectively destroy spinal postsynaptic dorsal column neurons expressing NK-1 receptors, to help improve intractable visceral pain of cancer origin. Gillespie et al.110 also demonstrated that there is increased NK-1 receptor signaling in colitis associated with cancer further suggesting that there is potential in antagonizing this transmission in the treatment of visceral cancer pain. However, this therapeutics is still in its infancy, and many more studies are needed for further ratification before this group of drugs can be of clinical significance.

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NEWER OPIOID DERIVATIVES FOR THE TREATMENT OF CHRONIC PAIN Opioid agonists act on the µ, κ, and δ receptors. Of the µ, δ, and κ subtypes of opioid receptors, most analgesia is thought to derive from mu activation.

Cebranopadol Cebranopadol is a new opioid agonist that is under development by the Grünenthal company in collaboration with Depomed of United States. It is a full agonist at the nociceptin/orphanin pathway (NOP) and at µ and δ receptors, whereas being a partial agonist at the κ receptor. Conventional opioids are currently the mainstay of visceral cancer pain treatment. However, their efficacy is limited by potential side effects due to effects on the gastrointestinal, respiratory, and central nervous systems as well as the potential of addiction and tolerance.111,112 In animal studies, drugs acting at the nociceptin/orphanin receptors do not generate typical opioid-like side effects and may even ameliorate supraspinal opioid-related side effects when administered concurrently with an opioid. Hence, an agonist at the NOP and the opioid receptors would be particularly useful in the treatment of visceral pain with a more favorable side effect profile.113 In a bone cancer pain murine model, Linz et al.114 demonstrated that cebranopadol caused dose-dependent increased pain withdrawal thresholds that reached statistical significance after 30- and 60-minute intervals. However, there is evidence to suggest that cebranopadol is more effective in neuropathic rather than nociceptive bone cancer pain. Animal studies indicate that cebranopadol is more effective in experimental models of chronic neuropathic pain (e.g., streptozotocin-induced diabetic polyneuropathy and spinal nerve ligation models) compared to acute nociceptive pain (bone cancer pain and tail-flick test).115 In the rat, there are strong indications that cebranopadol shows limited depression of breathing also which has been shown to be significant in comparison to conventional opioids.116 Moreover, tolerance and addiction are less likely with cebranopadol than with conventional opioids due to slower metabolism and pharmacokinetic profile.117 2429

In the rat, tolerance to morphine develops quickly, and in a study by Lambert et al.,117 rats were completely tolerant to morphine (8.8 mg/kg intraperitoneal [IP] daily) in 11 days. In contrast, an equianalgesic dose of cebranopadol (only 0.8 µg/kg IP daily) was still effective for a further 15 days, or 26 days in total.118 Hence, cebranopadol presents great potential in the treatment of cancer pain with a better side effect, tolerance, and dependence profile.

PROCEDURAL INTERVENTIONS Ganglion Impar Block The ganglion impar is a solitary retroperitoneal structure located at the level of the sacrococcygeal junction. This unpaired ganglion marks the end of two sympathetic chains. The ganglion receives sympathetic and parasympathetic fibers at the lumbar and sacral levels, providing sympathetic innervation to portions of the pelvic viscera and genitalia.119 Visceral pain in the perineal area associated with malignancies may be effectively treated with neurolysis of the ganglion impar (also known as Walther ganglion).120 Patients who will benefit from this block frequently present with a vague poorly localized pain that is frequently accompanied by sensations of burning and urgency. The ganglion impar block is useful to the management of sympathetically mediated pain in the perineum, rectum, and genitalia. It has been primarily used for malignancy; however, it has been used for treatment of associated syndromes such as radiation enteritis, proctalgia fugax, and reflex sympathetic dystrophy. The ganglion impar is close in proximity to the rectum. There is increased risk of contamination through the needle track as the needle is removed. Infection and fistula are possible complications in patients who are already immunocompromised or have received radiation to the perineum.

Thoracic Sympathetic Ganglion Block Preganglionic fibers of the thoracic sympathetics exit with respective thoracic paravertebral nerves from the intervertebral foramen. After exiting the intervertebral foramen, thoracic paravertebral nerves branch looping dorsal through the same foramen to provide innervation to the 2430

spinal ligaments, meninges, and respective vertebra. The paravertebral nerve at this level also affects the thoracic sympathetic chain through myelinated preganglionic fibers of the white rami communicantes. Preganglionic and postganglionic fibers synapse at the level of thoracic sympathetic ganglia. Postganglionic fibers provide sympathetic innervation to the vasculature, sweat glands, and pilomotor muscles of the skin as well as the cardiac plexus and terminate in distal ganglia as they course up and down the thoracic sympathetic trunk.121 Block of the thoracic sympathetic ganglion is useful for evaluation of sympathetically mediated pain to the thoracic and upper abdominal viscera, the thorax, and the chest wall. Differential blockade may serve as a prognostic indicator of the benefit to be expected from lesioning of the thoracic sympathetic ganglion. The block has been used in the past to treat intractable abdominal pain as well as intractable cardiac pain. It has also been demonstrated to be effective in the treatment of acute herpes zoster, postherpetic neuralgia, and phantom breast pain following mastectomy. Thoracic sympathetic chain destruction may be used to relieve pain in pain syndromes that have been improved by local anesthetic block.122 Because of the close proximity to the pleural space of the exiting nerve roots at the thoracic level from sympathetic ganglion, pneumothorax is a possible complication. The pleural space lies lateral and anterior to the thoracic sympathetic chain. The lower cervical ganglion fuses with the first thoracic ganglion to make the stellate ganglion. Caudad in the thoracic chain, thoracic ganglia move further anterior resting along the posterolateral surface of the vertebral body. Other possible complications include accidental injection of the epidural, subdural, and subarachnoid space. Infection is of greater concern in patients with malignancy because of their immunocompromised state.

Interpleural Catheters The role of interpleural analgesia (IPA) in both acute and chronic pain management is still undergoing clinical scrutiny. Original work with this technique showed that IPA could provide analgesia in patients with subcostal incisions and fractured ribs. The technique for insertion of an interpleural catheter is relatively easy, 2431

and an epidural tray can be utilized. Local anesthetics (0.5% bupivacaine or 2% lidocaine) have been traditionally utilized via intermittent bolus or a continuous infusion. Interpleural phenol has been described as an alternative for the treatment of visceral pain associated with esophageal cancer. This may be an effective technique to treat visceral pain associated with cancer of the esophagus, liver, biliary tree, stomach, and pancreas. For analgesia associated with cancer, continuous infusions of bupivacaine or intermittent bolus doses of bupivacaine may also provide adequate analgesia. Higher concentrations of bupivacaine increase the risk of toxicity. Complications are secondary to needle or catheter injury or are secondary to the neurolytic agent injected in the interpleural space. Pneumothorax may occur in 2% of patients, and lung injury has been reported when a rigid catheter is used. Phrenic nerve palsy may occur following this block resulting in respiratory failure. Thus, bilateral blocks should be avoided. Doses of phenol should be limited; systemic effects from drug absorption may occur because the pleural membranes are highly vascularized.

Surgery Referral for surgical options should be pursued with diagnosis and treatment of pain in malignancy at any time during the course of care. Surgical objectives in the palliation of cancer include staging of disease, control of disease, control of pain and associated symptoms, reconstruction, and rehabilitation.123 Patients interested in and capable of tolerating surgical options should be referred to a surgeon for consideration of options, even if there are nonsurgical options available. If no intervention is recommended, the patient will have an understanding for the surgical referral and have a sense of closure with regard to the variety of options available for palliation. Surgical consult is particularly valuable in the areas of wound management, complicated issues with regard to nutrition, and discussion of progression of disease.122 There is no standard set of procedures for the palliation of malignant visceral pain. The operations available are a reflection of the subjective pain experience of the patient, the specific stage of the disease, and the 2432

anatomic effects of the disease. Often, other distressing symptoms may be the reason for surgical management as well as the complaints of pain. The given surgical option should palliate as many symptoms as possible without altering benefit–risk ratios.122 The most important preoperative measure involves reassurance to the patient that preparation is complete and that postoperative analgesia has been considered. This is best achieved with close coordination with the partnering anesthesia team and preoperative consultation regarding analgesic options. Furthermore, the operative encounter may be the foundation for continued postoperative pain management options. Malignancy presenting with pain is likely to be advanced in nature. Resection of an organ or portion of an organ for management of pain is reasonable even in the case of uncontrollable disease, especially if the disease is resectable or partially resectable. There is little data, however, comparing the efficacy of resection with nonoperative approaches. In visceral disease, surgical resection has proven effective for the relief of dysphagia, odynophagia, and chest pain in patients with esophageal carcinoma; the relief of painful ulceration in those with gastric carcinoma; and the preemptive control of jaundice, pain, and duodenal obstruction in those with pancreatic carcinoma.122 Surgery can promote comfort as well as eliminate pain. Mechanical bowel obstruction may be expected in as many as 15% of cancer patients. Pain is a reflection of the severity of the distension, the nature of the primary neoplasm, and the level of obstruction. Resection has also been offered on occasion for relief of pain associated with carcinoma of the kidney. In some situations, nephrectomy may be considered to prevent pain, hematuria, and constitutional effects of the disease. In patients with large bladder masses, total or partial organ resection may be a consideration in cases where more conservative options have been considered. Stent placement may relieve severe pain secondary to malignant ureteral obstruction by tumors of the prostate, cervix, bladder, and colon. If stent placement is not an option, percutaneous nephrostomy may be effective.122 Debulking of functional tumors of the liver may be beneficial in patients with carcinoid to decrease such symptoms as flushing and diarrhea. 2433

Debulking has also been used in patients with metastatic gastrinoma, ovarian cancer, and large and small bowel malignancies. Finally, drainage of ascites, which may develop in as many as half of cancer patients, may relieve associated symptoms such as bloating, diffuse abdominal pain, dyspnea, nausea, early satiety, and gastric reflux.

Dorsal Myelotomy for Treatment of Intractable Visceral Cancer Pain Neurosurgical interruption of midline visceral pain pathway can help control severe visceral pain without causing significant adverse neurologic sequelae in patients with advanced visceral cancer. However, surgery is not without side effects, and often, this approach is used when conventional pharmacologic treatment has failed. Hwang et al.122 demonstrated a technique of punctate midline myelotomy (PMM) for the treatment of cancer pain refractory to opioids. In their study, a PMM at the T3 level was performed in six patients who experienced severe visceral pain caused by hepatobiliary or pancreatic cancer. In a small study involving six patients, follow-up periods ranged from 2 to 18 weeks after operation. All six patients had immediate pain relief after operation. Although the pain recurred from 2 to 12 weeks later in three patients, the severity of recurrent cancer pain was markedly decreased.122 Kim et al.124 also attempted a high thoracic myelotomy in their palliation attempt in the treatment of severe pain due to stomach cancer. Under general anesthesia, patients received high thoracic midline dorsal column myelotomies after T1 or T2 laminectomy. In their study, they demonstrated clinically significant decrease in pain scores after the procedure, although one patient developed paresthesia and posterior column signs below the level of myelotomy without analgesia and another paresthesia responsive to corticosteroids. They concluded that dorsal column myelotomy at a high thoracic cord level effectively controls severe abdominal pain and should be considered as a new palliative operation for patients with severe visceral pain.125

Hypophysectomy and Cancer Pain Destruction of the pituitary stalk has been a long established palliative 2434

approach to the treatment of severe refractory cancer pain especially due to widespread metastases and also in bone cancer pain in breast cancer. Surgical, stereotactic instillation of alcohol in to the sella turcica and other methods of chemical hypophysectomy have been long established in cancer pain treatment. A proposed mechanism is that or its associated neurophysins act as central pain transmitters. The production of these transmitters is decreased or abolished by chemical or surgical hypophysectomy through the destruction of hypothalamic nuclei.126–128

Conclusion Failure to assess and treat cancer pain, whether of somatic, visceral, neuropathic, or mixed types, is still a common problem among patients in all stages of malignant disease. Barriers to adequate care have been discussed in previous chapters. Notwithstanding needed improvements in clinician education, access to pain and supportive care specialists, among other needed systems improvements, and similar to other causes of cancer pain, relief of pain in patients with visceral malignancies or treatmentrelated visceral pain syndromes should be organized as part of a comprehensive interdisciplinary approach to care. Visceral pain cannot be exclusively managed with pharmacotherapy, and the resources of several medical and supportive care disciplines should be considered with each patient so that pain management can be tailored to the individual requirements of each patient according to his or her unique constellation of clinical and social circumstances. References 1. Goudas LC, Bloch R, Gialeli-Goudas M, et al. The epidemiology of cancer pain. Cancer Invest 2005;23(2):182–190. 2. Burton AW, Cleeland CS. Cancer pain: progress since the WHO guidelines. Pain Pract 2001;1(3):236–242. 3. Miguel R. Cultural and family issues. In: de Leon Casseola O, ed. Cancer Pain Management: Pharmacologic, Interventional, and Palliative Approaches. Philadelphia: Elsevier; 2006:25– 32. 4. Mantyh P. Cancer pain: causes, consequences and therapeutic opportunities. In: McMahon S, Koltzenburg M, eds. Wall and Melzack’s Textbook of Pain. 5th ed. London: Elsevier; 2006:1029–1038. 5. National Institutes of Health. NIH National Cancer Institute SEER Cancer Statistics Review. Available at: https://www.cancer.gov/about-cancer/understanding/statistics. Accessed

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CHAPTER 48 Radiotherapy and Chemotherapy in Cancer Pain Management NORA JANJAN

Introduction “Cancer pain is best controlled by removing the cancer or causing it to regress.”1 This succinct principle stated by palliative medicine specialist Dr. Neil MacDonald is a useful framework from which to consider the role of palliative chemotherapy and radiotherapy in the management of symptomatic disease. In the year 2016, 1,685,210 new cancer cases were diagnosed, and about 595,690 cancer-related deaths occurred. National expenditures for cancer care in the United States totaled nearly $125 billion in 2010 and are projected to reach $156 billion in 2020.2 There has been substantial progress in cancer incidence and mortality. The incidence of cancer from 2009 to 2013 was stable in women but decreased by 2.3% per year in men. An overall 13% decrease in cancer deaths occurred between the years 2004 and 2013.2,3 Death rates decreased for 11 of the 16 most common cancer types in men and for 13 of the 18 most common cancer types in women; this decline in cancer death rates included lung, colorectal, female breast, and prostate cancer. The 5-year survival rate for breast cancer increased from 18.7% between 1975 and 1977 to 33.6% between 2006 and 2012. The improvements in 5-year survival rates also included meaningful increases in survival with distantstage disease.3 Deaths due to breast cancer declined almost 40% between 1989 and 2015, averting 322,600 deaths.4,5 This trend can be attributed to the persistent efforts in research, early detection of disease, and treatment advances. Cancer and its treatment, however, still result in a significant burden of symptoms like pain. Cancer has a negative impact on almost all cancer patients’ domains of 2442

daily living. Quality-of-life measurements have been shown to predict survival and add to the prognostic information derived from the Karnofsky performance status (KPS) and extent of disease. Physical symptoms including pain, dry mouth, constipation, change in taste, lack of appetite and energy, feeling bloated, nausea, vomiting, weight loss, and feeling drowsy or dizzy often portend a poorer prognosis.6 Palliative care is an integral component of cancer treatment with a goal to effectively and efficiently relieve symptoms and maintain the maximum functional and emotional well-being for the duration of the patient’s life.7–13 Recognizing the value of the early integration of palliative care, an American Society of Clinical Oncology clinical practice guideline states that the standard for oncology care includes the control of the symptoms of cancer and its treatment from diagnosis to death. Data supporting this guideline includes nine randomized controlled trials and five secondary analyses from these trials that demonstrate the effectiveness of dedicated palliative care services early in the treatment of cancer. Essential components of palliative care may include symptom management, education about the cancer and its prognosis, clarification of treatment goals and assistance with medical decision making, coping needs, and coordination of care.14 Applying these principles, a prospective trial in 171 newly diagnosed advanced lung or noncolorectal gastrointestinal cancer patients evaluated the key elements of early palliative care from 2,921 clinic visits. The initial cancer therapy was chemotherapy (80.7%) or radiotherapy (19.3%). Patients randomly assigned to at least monthly visits in the palliative care clinic had assessments performed at baseline and at 24 weeks. Most of these palliative care visits addressed symptom management (74.5%) and coping (64.2%). By 24 weeks, patients who more frequently addressed treatment decisions were less likely to initiate chemotherapy (P = .02) or be hospitalized (P = .005) in the 60 days before death. With a higher proportion of visits addressing advanced care planning, hospice care was more frequently used (P = .03) (Fig. 48.1).15

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FIGURE 48.1 Content of palliative care (PC) visits across the illness trajectory. PC clinicians recorded the content they addressed after each visit. Reported proportions for the final three visits are restricted to decedents. Reported proportions for the initial three visits exclude visits that were also among the final three visits. Reported proportions for middle visits represent averages across all available middle visits. Relative to the initial three visits, the final three visits increasingly addressed treatment decisions (P < .001), advance care planning (P < .001), and disposition (P < .001) but decreasingly addressed rapport (P < .001) and illness understanding (P < .001). (From Hoerger M, Greer JA, Jackson VA, et al. Defining the elements of early palliative care that are associated with patient-reported outcomes and the delivery of end-of-life care. J Clin Oncol 2018;36[11]:1096–1102. Reprinted with permission. Copyright © 2018 American Society of Clinical Oncology. All rights reserved.)

Application of palliative care principles has a profound impact on the physical and psychological comfort of the patient and their caregivers. These palliative care principles also have a profound socioeconomic impact given that the highest costs incurred in health care are at the end of life. Referral to a specialty palliative care service only occurred in 298 (30%) of 978 patients. Of these 298 patients, only 94 (9.6% of the total) had an early referral, whereas the remaining 204 patients (21% of the total) had a late referral to the palliative care service. Early delivery of palliative care resulted in lower rates of inpatient admission in the last month of life (33% vs. 66%), lower rates of intensive care unit (ICU) stay in the last month of life (5% vs. 20%), fewer emergency department visits in the last month (34% vs. 54%), fewer instances of hospice service less than 3 days (7% vs. 20%), and lower rate of inpatient death (15% vs. 34%). The direct 2444

cost of inpatient medical care in the last 6 months of life with early palliative care was less than among those with late palliative care ($19,000 vs. $25,700).16 At the Johns Hopkins Medical Institutions, the palliative care unit and palliative care consults had a positive financial impact of $3,488,863.10. Palliative care consultations alone, with 60% of these involving cancer patients, saved $2,765,218.00. The 30-day readmission rate was cut from 15% to 10%. Hospice care was arranged in 57% of palliative care consultation patients as compared to only 27% if a palliative care consult was not requested.17 The early integration of palliative care services significantly reduces health care utilization during end-of-life care. Insurance claims during the last month of life from 6,568 cancer patients from a Surveillance, Epidemiology, and End Results (SEER) database between 2007 and 2015 were reviewed. At baseline, at least one imaging scan was performed in 48.9%, and 56.3% of patients were hospitalized; only 31.4% of patients younger than 65 years were enrolled in hospice. With changes in health care and reimbursement policies over this time frame, the administration of chemotherapy and/or radiotherapy, diagnostic imaging, and hospitalization rates declined (Fig. 48.2).18

2445

FIGURE 48.2 Trends in health care use in the last 30 days of life by year of death and percentage of decedents. A: Chemotherapy or radiation use. B: Imaging use. C: Hospitalization and emergency department (ED) visits. D: Hospice and opioid use. Overall, 963 patients died between 2007 and 2009, 2,628 between 2010 and 2012, and 2,977 between 2013 and 2015. aStatistically significant trend over time. bFor people under 65 years of age: 426 died between 2007 and 2009, 1,088 died between 2010 and 2012, and 1,064 died between 2013 and 2015. cUnder 65 years, not enrolled in hospice. CT, computed tomography; MRI, magnetic resonance imaging; PET, positron emission tomography. (From McDermott CL, Fedorenko C, Kreizenbeck K, et al. End-of-life services among patients with cancer: evidence from cancer registry records linked with commercial health insurance claims. J Oncol Pract 2017;13[11]:e889–e899. Reprinted with permission. Copyright © 2017 American Society of Clinical Oncology. All rights reserved.)

Palliative chemotherapy has been an ambiguous term and mostly refers to chemotherapy given when the likelihood of cure was minimal. In the true sense, palliative chemotherapy means that systemic therapy is delivered to relieve symptoms and improve quality of life regardless of stage of disease or the likelihood of remission or cure. The primary outcomes of most studies involving disease-modifying systemic agents, however, do not have symptom relief as a major endpoint. Although virtually all systemic agents used in cancer have been surveyed for impact on quality-of-life, the results of these quality-of-life surveys are rarely reported. Reduction in the size of the tumor, which is the intended goal of 2446

chemotherapy, should intuitively decrease cancer pain. However, because the therapeutic benefits of chemotherapy are limited by their own toxicities, the risks versus benefits need to be weighed as part of treatment planning and decision making on a case-by-case basis. Palliative radiation often is used near the end of life to relieve pain and obstruction from tumor. To achieve the most benefit, palliative radiation should be administered to prevent or relieve symptoms before they become severe. If referral for palliative radiation is delayed until the patient becomes extremely debilitated and/or the lesion has progressed significantly, often the possibility of any benefit from palliative radiation is lost. Demonstrating this, a retrospective study of 1,424 patients with metastatic cancer was conducted between 2010 and 2015 found that 11.3% had received palliative radiation therapy before ICU admission. The inhospital mortality rate was 36.7% for palliative radiation patients compared to 16.6% of other patients with metastatic cancer. After ICU admission, only 21.1% of patients previously treated with palliative radiation received additional cancer treatment.19 The median length of survival is critical to evaluating response to and determining the appropriate recommendations for palliative therapy. The most common application of palliative radiation is in management of pain related to bone metastasis. Seventy percent of metastatic bone lesions are painful and debilitating. The goal of treatment is to relieve pain, restore functional ability, and prevent pathologic fractures. In prostate cancer, the distribution of bone metastases has prognostic significance. Survival is longer when the metastases are restricted to the pelvis and lumbar spine or if there is a response to salvage hormone therapy, but lower if metastatic involvement is outside the pelvis and lumbar spine irrespective of response to salvage hormone therapy.20–22 Survival rapidly declines once visceral metastases develop.23–25 The location of the metastasis can also be a limitation in the effectiveness of a palliative radiation. Metastatic involvement of weightbearing bones and those used in functional activities are often less likely to respond completely to palliative interventions due to applied mechanical forces put on them. Pain relief is achieved in 73% of spine metastases, 88% of limb lesions, 67% of pelvic metastases, and 75% of metastases to 2447

other parts of the skeleton.26–28 Palliative therapy has become a recognized subspecialty within radiation oncology.29 Despite the establishment of multiple palliative medicine programs in the country and the proven efficacy of palliative radiotherapy for symptoms, radiotherapy is often underutilized due to long radiation treatment schedules.26 Even with a relatively short life expectancy, palliative radiotherapy may be helpful, but less than 3% of the patients in hospice care received radiation in one survey.30 Conducting randomized trials among large patient cohorts, shorter radiation treatment regimens have enhanced quality of care by achieving equivalent symptom reduction when compared to longer radiation regimens and have significantly reduced the lengths of hospitalization (P = .01).31 Among 181 patients hospitalized for bone metastases between 2010 and 2016, a palliative care radiation oncology consult service recommended shorter palliative radiation schedules, increased palliative care utilization, and reduced hospital stays by 8.5 days. Median total hospitalization costs were $76,792 for patients with bone metastases before a palliative radiation oncology consult service was available and were reduced to $50,582 after the palliative radiation oncology consult service was formed.32 Cost of outpatient radiation therapy was evaluated from claims-linked data from 207 breast and 233 prostate cancer patients in 98 cancer treatment centers in 16 US states between 2008 and 2010. The mean total cost of radiation for bone metastases was $7,457 for breast cancer and $7,553 for prostate cancer patients.33 More sophisticated and costly radiation techniques, like stereotactic and proton radiation, are available to treat patients expected to have a longer survival or those with complicated clinical presentations, like those near critical structures and in/near previously irradiated sites. Stereotactic radiation is not cost-effective for routine cases having an incremental costeffectiveness ratio of $124,552 per quality-adjusted life years. However, stereotactic radiation does become cost-effective, with an incremental cost-effectiveness ratio of less than $100,000 per quality-adjusted life years, among patients with a median survival of over 10 months.34 More abbreviated radiation courses result in cost savings for less complicated clinical presentations. Ineffective therapy, however, incurs more personal 2448

and economic cost resulting from the continued need for analgesics and the functional limitations caused by unrelieved pain and disability.35,36 The most common barriers to radiotherapy still relate to the costs of radiation therapy and transportation difficulties. The selection of a radiation course or technique, like that for a systemic therapy, is dependent on the patient wishes, prognosis, and comorbidities.

BONE DISEASE The annual prevalence of bone metastasis was determined to be 256,137 in the years 2000 to 2004. The direct cost for patients with bone metastasis was $75,329, and the incremental cost was $44,442 compared to patients with cancer without bone metastasis. The national cost burden for patients with skeletal metastasis was estimated at $12.6 billion which is 17% of the $74 billion total direct medical cost estimated by National Institutes of Health (NIH).37 The prevalence of metastatic bone disease totaled 279,679 as determined by claims-based data from 2004 to 2008, with breast, prostate, and lung cancer accounting for 68% of these cases.38 Multidisciplinary evaluation of patients with metastatic disease to the bone allows comprehensive management of the associated symptoms, determines the risk for pathologic fracture, and helps coordinate administration of a wide range of available antineoplastic therapies (also see Chapter 46).39,40 Bone metastases can be treated with localized, systemic, or both kinds of therapies. Because localized treatments, like radiation and surgery, provide treatment only to a localized symptomatic site of disease, it is frequently used in coordination with systemic therapies such as chemotherapy, hormonal therapy, and bisphosphonates. Radiopharmaceuticals provide another systemic option that treats diffuse symptomatic bone metastases.39,41 Because the radiation is deposited directly at the involved area in the bone, radiopharmaceuticals, such as strontium 89 or samarium 153, can also be used to treat diffuse bone metastases or when symptoms recur in a previously irradiated site. Radiopharmaceuticals can also act as an adjuvant to localized external beam irradiation and reduce the development of other symptomatic sites of disease. A study was conducted among patients referred to a multidisciplinary bone metastases clinic between 2007 and 2015. 2449

Independent of age, 62% of patients received palliative radiation, whereas surgical stabilization was required in 30% over the age of 66 years and in 39% of patients 65 years of age or younger.42 Control of cancer-related pain with the use of analgesics is imperative to allow comfort during and while awaiting response to therapeutic interventions. Pain represents a sensitive measure of disease activity. Close follow-up should be performed to ensure control of cancer and treatmentrelated pain and to initiate diagnostic studies to identify progressive or recurrent disease. Pain, risk for pathologic fracture, and spinal cord compression are the most common indications to treat bone metastases with localized therapy including radiation and surgery.

CLINICAL APPLICATIONS OF RADIATION THERAPY Radiotherapy can be delivered with curative or palliative intent. Curative treatment attempts to render the patient disease free of either primary or metastatic disease. Treatment with palliative intent is intended to control the symptoms of disease when the disease cannot be eradicated. A number of clinical, prognostic, and therapeutic factors must be considered to determine the most optimal treatment regimen for a course of palliative radiotherapy. Although any site of disease can be effectively palliated, treatment of bone metastases is one of the most common indications for palliative irradiation with external beam therapy. During the last year of life, one-third of patients receive radiation therapy, which decreased to 24.3% in the last 3 months of life and 8.5% during the last month of life. Although radiation with curative intent was delivered at a constant rate in 25% of patients, palliative radiation was administered at a supralinear rate over the last year of life in which the treatment of bone metastases and use of single-fraction radiation increased closer to death.43 The limited radiation tolerances of normal tissues, such as the spinal cord, make it impossible to administer a large enough dose of radiation to completely eradicate most tumors. Palliative radiation should result in sufficient tumor regression to relieve symptoms for the duration of the patient’s life. Palliative radiotherapy is often combined with chemotherapy and/or surgery to optimize therapeutic outcomes from tumor-related pain, bleeding, visceral obstruction, or lymphatic and vascular obstruction. 2450

Common sites include respiratory system structures, pelvis, skin and subcutaneous tissues, brain, and all bony structures. Potential relief of symptoms is a more important determinant for palliative radiation than whether lesions result from locally advanced or metastatic disease. Symptoms that recur after palliative radiation most commonly result from localized regrowth of tumor in the radiation field.44 The palliative interventions recommended depend on the patient’s clinical status, burden of disease, and location of the symptomatic site. For either locally advanced or metastatic disease, these factors are indexed to the relative effectiveness, durability, and morbidity of each palliative intervention. Each patient’s prognosis represents the single most important factor in deciding the approach to palliative therapy.45 Because patients with metastatic disease have a limited life expectancy, the number of radiation fractions prescribed for treatment with palliative intent depends on prognosis and not primary histology, so a lower total dose is given with palliative radiation over 1 to 2 weeks (hypofractionated radiation schedule). Based on the radiation tolerance of normal tissues, a low daily radiation dose (1.8 to 2.0 Gy) is given with conventional radiation; in contrast, large daily radiation fractions are given with hypofractionated radiation schedules. Hypofractionated radiation schedules for palliative therapy can range from 2.5 Gy per fraction administered over 3 weeks for a total dose of 35 Gy to a single 8-Gy dose of radiation. Most frequently, 30 Gy is administered in 10 fractions over 2 weeks. Especially among patients with short life expectancies, many centers administer 20 Gy in 1 week or a single fraction of radiation because the rates of pain relief, mobility, and frequency of pathologic fractures are similar to more protracted radiation schedules.46,47 Palliative interventions not only should be limited in time relative to the patient’s life expectancy but should also be focused to limit toxicity. Available radiation techniques that focus the radiation to the symptomatic site should be applied to limit toxicity. Although the relative cost of more advanced radiation planning and treatment may be higher, the tolerance to palliative radiation is better, avoiding the costs of treating toxicities, especially for radiation portals that include mucosal surfaces. Among the radiation techniques that more precisely focus the delivery of radiation to 2451

the tumor are intensity-modulated radiation therapy (IMRT), proton radiation therapy, and stereotactic radiation therapy (SRT).48

Response of Tumors to Radiotherapy TRACHEA, BRONCHI, AND LUNGS Locally advanced primary or metastatic involvement of the lung often requires palliative intervention because cure is possible in only a few of these cases. A variety of symptoms, some of them emergent, can manifest because of tumor involvement of the lung. Pain can result from tumor invasion of the ribs and nerve roots of the chest wall. Vertebral involvement can be associated with spinal cord compression. Lower respiratory tract obstruction, bleeding, and pneumonitis can result from tracheobronchial tumor growth. Mediastinal infiltration can cause superior vena cava syndrome. All of these clinical presentations can be palliated with external beam radiation that encompasses the disease that is evident on diagnostic images and that treats pain referred along involved nerve roots. Radiation schedules that administer 30 Gy in 10 fractions over 2 weeks, 20 Gy in 5 fractions, 2 fractions of 8.5 Gy 1 week apart, or 1 fraction of 10 Gy (depending on the patient’s life expectancy and ability to tolerate multifraction therapy) are typically prescribed to previously unirradiated sites.48 Optimal palliation of patients with incurable lung cancer requires coordinated interdisciplinary care. For patients with stage III non–smallcell lung cancer who have a life expectancy of at least 3 months, have a good performance status, and no comorbidities excluding the administration of chemotherapy, administration of a platinum-containing chemotherapy concurrent with hypofractionated palliative thoracic radiation therapy is recommended over treatment with either modality alone.49 Hemoptysis and chest pain can be effectively palliated with external beam radiation, although dyspnea and dysphagia are not as effectively relieved. If the area has been previously irradiated, techniques that exclude critical anatomic structures, such as the spinal cord, are applied. Other 2452

approaches, like brachytherapy, stereotactic radiation, and proton therapy, can be used when the symptomatic site is well localized and accessible. Brachytherapy can be used to treat bronchial obstruction and bleeding by placing a radioactive source directly against the tumor under bronchoscopic guidance. In these cases, large doses of radiation can be delivered over a few minutes by a high-dose rate brachytherapy unit.48,49

PANCREATIC CANCER Palliative doses of radiation for unresectable pancreatic cancer have minimal to no impact on survival. Randomized trials have not shown any significant survival benefit when conventional radiation is used after chemotherapy for unresectable pancreatic cancer. Results from nonrandomized studies of 3 to 5 fractions that deliver a biologic equivalent dose (BED) of 53 Gy of stereotactic radiation (SRT) not only have less toxicity and a shorter treatment time but also a minimal impact on survival. However, when 15 to 25 fractions of SRT, which deliver a BED of 100 Gy, longer survival can be achieved with low toxicity. Based on the anatomic disease extension and the patient’s performance status and wishes, SRT can be tailored to effectively relieve cancer-related symptoms, and in specific circumstances, extend life.50

PELVIS Hemorrhage with or without obstruction or compression of viscera, lymphatics, vascular structures, and nerves commonly occurs with locally advanced or metastatic disease in the pelvis. Treatment may require emergent radiotherapeutic, surgical interventions, or both. Hemorrhage is commonly associated with tumors involving the rectum and genitourinary tracts. As with tumors in the lung, radiation is an effective means of stopping active bleeding. Colorectal cancers are often diagnosed among patients with unexplained bleeding. In patients who have locally advanced tumors with months to years of life expectancy, 40 Gy in 2.5 Gy fractions to 50 Gy in 2 Gy fractions have been used with the intent to stop bleeding, render the patient operable, and provide a chance for cure. With extensive metastatic disease, 30 Gy in 10 fractions or 20 Gy in 5 fractions is used to palliate symptoms of bleeding and obstruction. Colorectal tumor 2453

involvement may also result in obstruction requiring stent placement to maintain the integrity of the visceral lumen while administering radiation. Diverting colostomy is occasionally required but is reported to have been avoided after chemohypofractionated irradiation.51 Tumors involving the cervix can hemorrhage and require emergent radiotherapeutic intervention. Superficial radiographs are applied directly to the bleeding cervix through a cone to treat the bleeding site and do not compromise later radiation of other pelvic structures. Usually, radiation doses between 5 and 10 Gy are administered in one to three applications of cone therapy. Brachytherapy also can be used to treat gynecologic tumors, especially in the vagina, cervix, and endometrium.51 Bladder cancers or tumors that secondarily invade the bladder can also result in significant bleeding that can be palliated by external beam radiation. Urinary obstruction commonly occurs with locally advanced pelvic cancers, especially with bladder, rectum, prostate, and cervical cancers. Occasionally, placement of a urinary stent, urostomy, or nephrostomy is required until sufficient tumor regression can be accomplished by radiation to reestablish integrity of the urinary tract. As with the bowel and gynecologic tracts, a bladder fistula, resulting from either the tumor itself or from tumor regression, is a concern. The pelvic lymph nodes and major blood vessels may become obstructed by tumor. This is most frequently seen when tumors arise in pelvic structures but can also occur with pelvic metastases from breast and other cancers. Lymph-vascular obstruction results in painful edema that is refractory to diuretic and other therapies. Other than pain and functional interference, when severe, fluid and electrolyte imbalances can occur. Pelvic radiation can relieve lymph-vascular obstruction through tumor regression.51 Pelvic tumors can also invade the sacral plexus and result in intractable pain. Tumor can track along nerve roots and can be associated with bony invasion of the sacrum. Pain caused by visceral, lymph-vascular, or both kinds of obstructions often respond more rapidly to palliative radiation than the more refractory neuropathic pain seen with sacral plexus involvement. Other radiotherapeutic approaches, such as brachytherapy, are extremely limited when the cancer persists or recurs after external 2454

beam radiation. Interventional pain management techniques are frequently required to control pain associated with sacral plexus involvement (see Chapter 44). The use of palliative radiation in colorectal, prostate, and breast cancer is common. Using SEER data of 39,619 patients between 2004 and 2011, half of the patients received radiation in the last 6 months of life, defined as the last 6 months of life. Of the patients who received radiation during the end of life (19,586), only 46% had not previously been treated with radiation. Surgery was performed at the end of life in 35% of the patients, with proportionately more patients undergoing both surgery and radiation. Radiation was administered during the last 14 days of life, in 5,723 patients (14%). Administration of radiation during the end of life strongly correlated with end-of-life chemotherapy use, including the last 14 days of life (36% of chemotherapy patients); by comparison, only 15% of patients were treated with radiation in the group that did not receive chemotherapy during the last 14 days of life. Especially during the last 14 days of life, treatment may cause increased burden without improving quality of life.52

SKIN AND SUBCUTANEOUS TISSUES Tumors can cause ulceration of the skin and subcutaneous tissues that are often painful and distressing because of constant drainage. Representing a source for the development of sepsis in immunocompromised patients, localized radiation can be applied to destroy tumor and allow reepithelialization of the skin. Radiation that treats only the skin and subcutaneous tissues (electron beam therapy) is generally used to avoid radiation side effects to underlying uninvolved normal structures. Although usually 10 radiation treatments are given, the course of radiation can be abbreviated further, ranging from 1 to 5 days. Occasionally, these lesions are treated with brachytherapy. The radioactive sources can be placed in a mold that sits on top of the tumor and delivers treatment over a few minutes (high-dose rate) or a few days (low-dose rate).

BRAIN METASTASES Radiation is used to relieve the symptoms of headache, seizure, nausea and vomiting, and neurologic dysfunction associated with brain metastases. In 2455

patients with good performance status, surgery or radiosurgery followed by postoperative whole brain radiation is commonly administered. Radiation is generally with a total of 30 Gy in 10 fractions or 20 Gy in 5 fractions.53 Management of newly diagnosed single or multiple brain metastases, however, depends on the estimated prognosis and the aims of treatment, including survival, local treated lesion control, distant brain control, and neurocognitive preservation. Prognostic systems, such as recursive partitioning analysis and diagnosis-specific graded prognostic assessment, may assist in predicting prognosis. Single brain metastasis greater than 3 to 4 cm in size with a good prognosis (expected survival of 3 months or more), the lesion should be surgically resected followed by whole brain radiotherapy (WBRT) or surgical resection followed by intraoperative radiation or an SRT boost to the resection cavity. For a single metastasis less than 3 to 4 cm in size, multiple options exist including SRT alone, WBRT and SRT, WBRT and surgery, surgical resection, and SRT or intraoperative radiation boost. For anatomically unresectable or incompletely resected single brain metastases less than 3 to 4 cm in size, WBRT and SRT or SRT alone should be considered. With an unresected brain metastasis larger than 3 to 4 cm, WBRT should be considered.54 Multiple brain metastases, all of which are less than 3 to 4 cm in size with a good prognosis SRT alone if the multiple lesions are limited in number and location, WBRT and SRT, or WBRT alone are options. Other alternatives include WBRT alone or resection of large brain metastasis or metastases if it can be accomplished without causing significant mass effect or morbidity followed by postoperative WBRT. With poor prognosis, patients with either a single or multiple brain metastases should be considered for palliative care with or without WBRT.

Bone Metastases There are two major historical sets of experience with palliative radiation for bone metastases. The Radiation Therapy Oncology Group (RTOG) conducted a prospective trial that included a variety of treatment schedules (Table 48.1). To account for prognosis, patients were stratified on the basis 2456

of whether they had a solitary or multiple sites of bony metastases. The initial analysis of the study concluded that low-dose, short-course treatment schedules were as effective as high-dose protracted treatment programs.55 For solitary bone metastases, no difference existed in the relief of pain when 20 Gy using 4-Gy fractions was compared with 40.5 Gy delivered as 2.7 Gy fractions. Relapse of pain occurred in 57% of patients at a median of 15 weeks after completion of therapy for each dose level. In patients with multiple bone metastases, the following dose schedules were compared: 30 Gy at 3 Gy per fraction, 15 Gy given as 3 Gy per fraction, 20 Gy using 4 Gy per fraction, and 25 Gy using 5 Gy per fraction. No difference was identified in the rates of pain relief among these treatment schedules. Partial relief of pain was achieved in 83%, and complete relief occurred in 53% of the patients studied. More than 50% of these patients developed recurrent pain, the fracture rate equaled 8%, and the median duration of pain control was 12 weeks for all the radiation schedules used for multiple bony metastases. Prognostic factors for response included the initial pain score and site of the primary cancer. TABLE 48.1 Dose–Response Evaluation from the Reanalysis of the Radiation Therapy Oncology Group Bone Metastases Protocol55 Dose per Fraction (Gy)

Total Dose (Gy)

Solitary Bone Metastases 2.7 40.5 4 20 Multiple Bone Metastases 3 30 3 15 4 20 5 25

Tumor Dose at 2 Gy per Fractiona

Complete Response Rate (%)b

P Value P < .0003

42.9 23.3

55 37 P < .0003

32.5 16.2 23.3 31.25

46 36 40 28

a

The radiobiologic equivalent dose if administered at 2 Gy per fraction. complete response rate using the definition that excludes the use of analgesics and that accounts for retreatment.

bThe

In a reanalysis of the data, a different definition for complete pain relief was used and excluded the continued administration of analgesics. Using this definition, the relief of pain was significantly related to the number of 2457

fractions and the total dose of radiation that was administered.56 Complete relief of pain was achieved in 55% of patients with solitary bone metastases who received 40.5 Gy at 2.7 Gy per fraction as compared with 37% of patients who received a total dose of 20 Gy given as 4 Gy per fraction. A similar relationship was observed in the reanalysis of patients who had multiple bone metastases. Complete relief of pain was achieved in 46% of patients who received 30 Gy at 3 Gy per fraction versus 28% of patients treated to 25 Gy using 5-Gy fractions. In most cases, the interval to response was 4 weeks for both complete and minimal relief of symptoms. Three important issues are identified from the RTOG experience. First, the results of the reanalysis demonstrate the importance of defining what represents a response to therapy. Second, this revised definition of response showed that the total radiation dose did influence the degree that pain was relieved.55,56 The response rates and the radiobiologically equivalent doses are listed from the reanalysis in Figure 48.1 for each of the treatment schedules used. Patients treated with total doses of 40 Gy or more had a 75% rate of complete pain relief versus a 62% rate of complete pain relief for patients treated with total doses of less than 40 Gy.27,57 Third, the RTOG experience identified the amount of time that was needed to experience relief of pain after radiation for bone metastases (Table 48.2). It is important to note that only one-half of the patients who were going to respond had relief of symptoms at 2 to 4 weeks after radiation.55,56 This underscores the need for continued analgesic support after completing radiation. Consistently, it took 12 to 20 weeks after radiation to accomplish the maximal level of relief. That period of time may reflect the time needed for reossification. Radiographic evidence of recalcification is observed in approximately one-fourth of cases, and in 70% of cases, recalcification is seen within 6 months of completing radiation treatments.60–63 Recalcification is the basis of stabilization and prevention of fractures in the future. For pain relief, a short course of radiation is adequate; however, a longer schedule is recommended for adequate recalcification.58,59 Again, clinical context, with a focus on life expectancy, is a key determinant of radiation type, dose, and fractionation schedule. 2458

TABLE 48.2 Percentage of Patients Who Responded to Radiation Relative to Time, Designated in Weeks after Completion of Radiation Therapy Weeks after Radiation Total Dose (Gy)

Dose per Fraction (Gy)

Solitary Metastases 40.5 2.7 20 4 Multiple Metastases 30 3 15 3 20 4 25 5

Tumor Dose at 2 Gy per Fraction

5 d 0.1 mg/kg/h IV infusion with titration 1 g PO preoperative

NOTE: Dosing guidelines listed herein refer to children > 1 year of age. Maximum dose acetaminophen: 75 mg/kg/day. Further modifications in dosing are required for use of these agents in term and preterm neonates and in infants. Modifications are detailed in the text. IV, intravenous; PO, orally.

KETAMINE Ketamine is increasingly used in both acute and chronic pain, especially in the postoperative period. Ketamine has anti-N-methyl-D-aspartate (NMDA) activity, which acts to decrease wind-up, central sensitization, opioid-induced hyperalgesia, and opioid tolerance. Multiple studies in the adult population have shown that ketamine has not only opioid-sparing effects but also analgesic and antihyperalgesic effects.56 Literature supporting the use of ketamine in the perioperative period in children is not as clear. A 2016 meta-analysis of perioperative ketamine use in children did not find that ketamine beneficial in decreasing the amount of opioids used postoperatively.57 Although the meta-analysis was not 2592

favorable, individual studies favor the use of ketamine in the postoperative period. This study showed decreased opioid use and lower pain scores following Nuss procedure in the group that received ketamine in addition to fentanyl.58 One study published in 2016 did not find that low-dose ketamine postoperatively in posterior fusion spine surgery in children decreased opioid use postoperatively.59 This particular study also did not find benefit in preventing long-term postoperative pain, although the incidence of persistent postoperative pain in this demographic is not clearly known. It is reasonable to consider use of ketamine in children, particularly in those with difficult to control pain or a history of chronic opioid use. The data for use in adults is well-established and thus is an area that can be further explored in pediatrics.

ANTICONVULSANTS The use of anticonvulsants in chronic pain is well established; however, their use in acute pain, especially in children, is not as well established. There is evidence to support perioperative use of gabapentin for spine surgery in children. A study published in 2010 did show benefit to perioperative use of gabapentin 15 mg/kg prior to posterior spine fusion.60 Gabapentin (continued at 5 mg/kg three times a day for a total of 5 days) decreased opioid requirements and postoperative pain scores only in the first 48 hours after surgery. Therefore, some clinicians only provide a preoperative oral loading dose. Valproic acid is another anticonvulsant that finds limited use in the acute treatment of pediatric migraine with one study finding approximately 50% of patients receiving significant relief from their headache.61 There is some evidence to support its efficacy in the treatment of acute migraine; however, the studies are few and also complicated by the fact that valproic acid was not the first-line treatment; thus, other medications, treatments, and factors likely played a role in the reported relief.62

Opioids Opioids are among the most widely used analgesics for treating moderate to severe pain in infants and children. As with adults, they are extremely 2593

useful but require careful patient selection, titrated dosing, and active treatment of side effects.

ONTOGENY OF OPIOID ACTIONS The ontogeny of opioid actions has been studied in human clinical trials, in case series, and in a number of infant animal models. Infant animal models have provided useful information, although there are marked differences among species in opioid actions. There are age-related differences in analgesia and side effects involving pharmacokinetic and pharmacodynamics differences. Opioids (except for remifentanil) have prolonged actions in neonates and infants due to immature hepatic enzyme systems and immature renal excretion of active metabolites. Effects of hepatic and renal dysfunction on opioid clearance are discussed in a separate section in the following text. Additional factors that influence opioid pharmacokinetics include developmental changes in expression of P-glycoproteins, both in the gastrointestinal tract and in the blood–brain barrier, and changes in protein binding. Pharmacodynamic studies of opioids in neonates and younger infants have examined analgesia and side effects, with a major emphasis on measures of respiratory depression. These studies are made difficult by a number of factors, including the imprecision inherent in observational pain measures in neonates, on the state dependence of behavioral responses, on the confounding effects of critical illness on measures, and on the variability of painful stimuli. Major sites of opioid actions, including the periaqueductal grey matter and descending pathways of the dorsolateral funiculus, appear immature in infant rats. Conversely, opioids administered systemically or via the epidural route show strong analgesic responses in infant rats at developmental stages corresponding to preterm neonates. In human studies, there are mixed results with use of opioids in studies of procedural pain in neonates, and studies randomly assigning ventilated neonates to receive morphine infusions versus placebo infusions (with both groups receiving morphine for painful procedures) have not shown clear advantages in the morphine infusion groups.63,64 Children who are at particular risk for respiratory depressant effects of opioids include those with tonsillar hypertrophy, obstructive sleep apnea, 2594

certain neurologic conditions, and craniofacial abnormalities as well as neonates and young infants. Neonates and infants, particularly premature infants, have an increased risk of apnea and hypoventilation in response to opioids on a pharmacodynamic as well as pharmacokinetic basis. Careful dosing, cardiorespiratory monitoring, and close nursing observation are warranted for neonates and younger infants receiving opioids.

CODEINE Codeine is an opioid previously used widely to treat mild to moderate pain. It is available as an elixir in pill and parenteral forms. Although it has seen a declining use for pain, it remains commonly used in cough suppressant formulations. For reasons to be detailed in the following text, our opinion is that codeine is in general a suboptimal choice as an analgesic in children in most settings, and we recommend against its use.65 Codeine is a prodrug extensively metabolized in the liver. It is demethylated to morphine, which accounts for the analgesic effect.66 A study of children undergoing surgery, receiving a fairly large dose of codeine, found that roughly one-third of the subjects generated undetectable blood concentrations of morphine, which would result in no discernible analgesic effect. Conversely, there are genotypes associated with ultrarapid metabolism of codeine to morphine.67,68 In these subjects, standard recommended codeine doses can produce apnea. Standard dosing is 0.5 to 1 mg/kg every 4 hours. Dose escalation beyond this range appears to generate a higher incidence of side effects, particularly nausea and vomiting. In standard doses, codeine is a very weak analgesic. Studies in adult patients comparing efficacy of codeine to ibuprofen have shown that 30 to 45 mg codeine has less analgesic effect than 600 mg of ibuprofen. Because of the relatively high incidence of the impaired inability to demethylate codeine and higher incidence of side effects, other oral opioids such as oxycodone, morphine, hydromorphone, and hydrocodone are preferred. Intramuscular (IM) codeine has the double disadvantage of being a weak and inconsistent analgesic delivered by a noxious route. Codeine is often dispensed in combination with acetaminophen to increase efficacy. When prescribing codeine combined with acetaminophen, care is required to avoid inadvertent administration of 2595

toxic doses of acetaminophen, particularly when increased dosages are prescribed for pain or when patients are taking other over-the-counter preparations containing acetaminophen. Codeine is also commonly prescribed as an antitussive. As of 2013, the FDA has issued a new contraindication for the use of codeine to treat pain or cough in children younger than 12 years as well as a warning against its use the 12- to 18-year-old age group of children who have sleep apnea and/or are obese.69

TRAMADOL Tramadol has both opioid and nonopioid properties. It exists in a racemic mixture where the positive enantiomer has opioid and serotoninergic properties and its negative enantiomer exerts noradrenergic reuptake properties.70 Like codeine, it is metabolized to O-desmethyltramadol by the P450 isoenzyme CYP2D6. It exerts its analgesic effect via the µ-opioid as well as acting as a serotonin and norepinephrine reuptake inhibitor. In the United States, it is available only in the oral form. In other countries, it is also available in an intravenous preparation. Although not approved for use in children under the age of 12 years, it is widely used for postoperative pain as well as acute pain in children.71 Tramadol is also associated with many reports of toxicity in children. Overall, the incidence of these adverse reactions is low, but they do occur. Toxicity for tramadol, like opioids, not only can result in respiratory depression but can also result in seizures. As of 2017, the FDA has issued new black box contraindication for the use of tramadol to treat pain or cough in children less than 12 years of age. They have also included a contraindication to the use of tramadol in children undergoing tonsillectomy and/or adenoidectomy in patients under the age of 18 years. In addition to these contraindications, a new warning against the of tramadol in the 12- to 18-year-old age group in children with sleep apnea or who are obese is also in place. These were put in place after the recognition of the implications of genetic variability in P450 2D6 metabolism and the potential for life-threatening reactions.72

OXYCODONE 2596

Oxycodone can be used for moderate pain in doses of 0.05 to 0.1 mg/kg every 4 hours and for moderate to severe pain in starting doses of 0.1 to 0.2 mg/kg every 4 hours in infants and children >1 year of age. Less information regarding the use of oxycodone in neonates and small infants is available. Recent review and modeling suggests the use of lower doses in preterm neonate and small infants starting as low as 0.035 mg/kg and increasing to 0.065 mg/kg in term neonates.73,74 Although historically prescribed in smaller doses, oxycodone dosing can be escalated as needed much like any of the so-called strong opioids. Oxycodone is generally well tolerated by children either alone or in combination with acetaminophen. Our impression is that it is associated with fewer side effects than codeine when used to treat moderate to severe pain. Oxycodone is metabolized in the liver to oxymorphone, which is metabolically active.75 Because oxymorphone is eliminated by the kidneys, it can accumulate in patients with renal failure. Oxycodone is commonly used in children postoperatively when transitioning from parenteral opioids to oral opioids in preparation for discharge. A sustained-release preparation of oxycodone (OxyContin) is available for use in the treatment of chronic pain and was approved use in children age 11 to 16 years in 2015. Recently, the trend at our institution is away from the use of long-acting oxycodone for postoperative pain. It has a bioavailability of approximately 60% and reaches peak analgesic effect after 60 to 90 minutes.76

MORPHINE Morphine is often the first-line opioid chosen for parenteral use in children. It has a long track record in pediatrics; it has received extensive pharmacologic study at all age groups; it is inexpensive; and it can be administered via oral, sublingual, intravenous, subcutaneous, rectal, and neuraxial routes. The duration of morphine’s clinical effects are related in a complex manner to distribution into and out of the central nervous system, hepatic metabolism, and excretion of active metabolites, including morphine 6glucuronide. Morphine primarily undergoes glucuronidation by the UDP glucuronosyltransferase (UGT) pathway in the liver to morphine-32597

glucuronide, which has predominantly excitatory actions, and morphine-6glucuronide, which has analgesic, sedative, and respiratory depressant actions more potent than morphine.77 Because morphine-6-glucuronide is renally eliminated, it can accumulate in patients with renal failure, producing delayed sedation and hypoventilation. In addition, accumulation of morphine 3-glucuronide can contribute to delirium, agitation, and seizures. The elimination half-life of morphine in older children and adults is approximately 3 to 4 hours. The elimination half-life is approximately 7 hours in full-term newborns and even longer in premature infants.78,79 Long-acting preparations of morphine, such as MS Contin or KADIAN, are typically used for children with sickle cell pain, cancer pain, and other types of chronic pain. Dosing of morphine in children, as with all opioids, should be titrated to effect and individualized based on severity of pain, underlying medical conditions, age, side effects, and weight. See Table 50.3 for dosing guidelines for oral and parenteral morphine. TABLE 50.3 Initial Dosing Guidelines for Opioids Parenteral Dosing Equianalgesic Doses and Intervals

Drug

Parenteral

Oral

Codeine

120 mg

Morphine

10 mg

200 mg 30 mg (long term)

Oxycodone

NA

15–20

Oral Dosing

Usual Starting Intravenous or Subcutaneous Doses

Usual Starting Oral Doses and Intervals Ratio Parenteral to Oral

Child 50 kg

NR

NR

Bolus: 0.1 mg/kg every 2– 4h

Bolus: 5–8 1:3 mg (long term) every 2– 4h

Infusion: 0.03 mg/kg/h

Infusion: 1.5 mg/h

NA

NA

2598

1:2

1:6 (single dose)

NA

Child 6 months of age, with reductions to 0.015 mg/kg/hour from 1 to 6 months, ranging down to 0.005 mg/kg/hour for preterm neonates at 32 weeks postconception. These recommendations should be taken as population averages; individual rates should be adjusted according to clinical conditions, expected intensity of painful stimuli, and behavioral and physiologic signs.

PATIENT-, NURSE-, AND PARENT-CONTROLLED ANALGESIA PCA is widely used among pediatric centers for variety of acute painful conditions such as cancer pain, sickle cell pain from vasoocclusive crises, trauma, and acute postoperative pain. Most children 8 years of age and older have the cognitive ability to understand cause and effect relationships of pushing the PCA button and obtaining pain relief. In rare cases, experienced children younger than 6 to 8 years, who have had longstanding pain, are able to use PCA. For most children younger than 6 to 8 years, PCA has a higher failure rate in part because of the inability to understand the causal connection between button-pressing and delivery of medication to provide pain relief. However, nurse-controlled analgesia (NCA) or PNCA has been shown to provide effective analgesia with good 2605

patient, parent, and caregiver satisfaction in younger children. PNCA is also used for children with cognitive and physical limitations who are unable to use the PCA.96–98 In our hospital, PNCA is the most common method of systemic opioid administration following major surgery in infants and in children with cognitive or physical limitations to selfadministration.99,100 At our institution, we have also adopted the use of PNCA in our neonatal population. In this population, we recommend starting your opioid dose lower at 10 µg/kg. Commonly used opioids for PCA/NCA are morphine, hydromorphone, and fentanyl. Use of a basal infusion along with PCA boluses has been a subject of controversy and some controlled studies in adults and children. In some studies, a basal infusion improves pain scores, patient satisfaction, and the quality of nighttime sleep. In other studies, a basal infusion increased surrogate measures of hypoventilation, including brief respiratory pauses. Our view is that the recommendations regarding addition of a basal infusion depend on patient medical conditions and risk factors, on psychological factors, on expected intensity of painful stimuli, and on history of previous opioid use. For example, a basal infusion may be omitted for children who have received a regional block intraoperatively, for children with increased respiratory risks, or for those undergoing surgical procedures expected to be only moderately, but not severely, painful. Conversely, we generally include a basal infusion for patients who are opioid-tolerant or for procedures expected to cause severe pain. For those undergoing very painful operations, such as scoliosis surgery, open lateral thoracotomy, or major hip surgery, we generally maintain a basal infusion at least through the first postoperative night. Parent-controlled analgesia is widely accepted for use among children with advanced cancer or children in palliative care. There have been several serious adverse events reported, including apnea and death with the use of parent-controlled analgesia in children with risk factors and with insufficient protocols for patient observation and education on proper use. Our view is that parent-controlled analgesia for opioid-naive children should be restricted to institutions which have formal programs for parent education, protocols for frequent assessments by nurses, and protocols for cardiorespiratory. Please see Tables 50.4 and 50.5 for PCA dosing. 2606

TABLE 50.4 Typical Starting Doses for Patient-Controlled Analgesia (for >10 kg) Drug

Bolus Dose (μg/kg)

Continuous Rate (μg/kg/h)

Hourly Limit (μg/kg)

Morphine Hydromorphone Fentanyl

10–30 2–6 0.25–1

4–20 1–4 0.25

120 24 2–4

NOTE: The usual lockout interval is 6 to 10 minutes.

TABLE 50.5 Typical Starting Doses for Patient-Controlled Analgesia (for V1 200 mg per day) of indomethacin and raised cerebrospinal fluid (CSF) pressure should be suspected in apparent bilateral PH. It is worth noting that indomethacin reduces CSF pressure by an unknown mechanism.107 It is appropriate to image patients, with MRI if practical, when a diagnosis of PH is being considered.

SHORT-LASTING UNILATERAL NEURALGIFORM HEADACHE ATTACKS WITH CONJUNCTIVAL INJECTION AND TEARING OR CRANIAL AUTONOMIC ACTIVATION Sjaastad and colleagues108 reported three male patients whose brief attacks of pain in and around one eye were associated with sudden conjunctival injection and other autonomic features of cluster headache. The attacks 3232

lasted only 15 to 60 seconds and recurred 5 to 30 times per hour and could be precipitated by chewing or eating certain foods, such as citrus fruits. They were not abolished by indomethacin. Brain imaging has suggested that they share with cluster headache and PH the feature on activation studies of involvement of the posterior hypothalamic region.109 Of the patients recognized with this problem, males dominate slightly and the paroxysms of pain may last between 5 and 300 seconds, although longer duller interictal pains are recognized, as are longer attacks with a sawtooth pattern.104 The conjunctival injection seen with SUNCT is often the most prominent autonomic feature, and tearing may be very obvious. If one of either conjunctival injection or tearing is absent, or neither is present but another cranial autonomic symptom is seen, the term short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) is used.6 The two key clinical features of SUNCT/SUNA are the attacks being triggerable with no refractory period to triggering. The latter serves as a very useful distinction between SUNCT/SUNA and trigeminal neuralgia. SUNCT/SUNA can be treated very often with lamotrigine and if that is unhelpful topiramate or gabapentin.110 Carbamazepine often has a useful but incomplete effect. Given what has been reported, cranial MRI with pituitary and posterior fossa views is highly recommended when SUNCT/SUNA is considered as a diagnosis.110

OTHER PRIMARY HEADACHES Primary Stabbing Headache Short-lived jabs of pain, defined by the Headache Classification Committee of the IHS as primary stabbing headache,6 are well documented in association with most types of primary headache. The essential clinical features are: • Pain confined to the head, although rarely is it facial • Stabbing pain lasting from 1 to many seconds and occurring as a single stab or a series of stabs • Recurring at irregular intervals (hours to days) These pains have been called ice-pick pains or jabs and jolts. They generally respond to indomethacin (25 to 50 mg twice to three times daily). The symptoms tend to wax and wane, and after a period of control 3233

outcome. Most patients will not want treatment when the nature of the problem is explained, and they are reassured that the attacks are not sinister in any way.

Primary Cough Headache Sharp pain in the head on coughing, sneezing, straining, laughing, or stooping has long been regarded as a symptom of organic intracranial disease, commonly associated with obstruction of the CSF pathways. The presence of an Arnold-Chiari malformation or any lesion causing obstruction of CSF pathways or displacing cerebral structures must be excluded before cough headache is assumed to be benign. Cerebral aneurysm, carotid stenosis, and vertebrobasilar disease may also present with cough or exertional headache as the initial symptom. The term benign Valsalva’s maneuver–related headache covers the headaches provoked by coughing, straining, or stooping, but cough headache is more succinct and so widely used it is unlikely to be displaced.6 The essential clinical features of primary cough headache are: • Bilateral headache of sudden onset, lasting minutes, precipitated by coughing • May be prevented by avoiding coughing • Diagnosed only after structural lesions, such as posterior fossa tumor, have been excluded by neuroimaging Indomethacin is the medical treatment of choice in cough headache. Raskin111 followed up an observation of Sir Charles Symonds reporting that some patients with cough headache are relieved by lumbar puncture.112 This is a simple option when compared to prolonged use of indomethacin. The mechanism of this response remains unclear.

Primary Exertional Headache The relationship of this form of headache to cough headache is unclear and certainly much is shared. Indeed, the relationship to migraine also requires delineation. The clinical features are6: • Pain specifically brought on by physical exercise • Bilateral and throbbing in nature at onset and may develop migrainous 3234

• Bilateral and throbbing in nature at onset and may develop migrainous features in those patients susceptible to migraine • Lasts from 5 minutes to 24 hours • Prevented by avoiding excessive exertion, particularly in hot weather or at high altitude The acute onset of headache with straining and breath holding as in weightlifter’s headache may be explained by acute venous distension. The development of headache after sustained exertion, particularly on a hot day, is more difficult to understand. Anginal pain may be referred to the head, probably by central connections of vagal afferents and may present as exertional headache, so called cardiac cephalgia.113 The link to exercise is the important clinical clue. Pheochromocytoma may occasionally be responsible for exertional headache. Intracranial lesions or stenosis of the carotid arteries may have to be excluded as discussed for benign cough headache. Headache may be precipitated by any form of exercise and often has the pulsatile quality of migraine. The most obvious form of treatment is to take exercise gradually and progressively whenever possible. Indomethacin at daily doses varying from 25 to 150 mg is generally very effective in benign exertional headache. Indomethacin 50 mg or frovatriptan 2.5 mg po are useful short-term preventive measures.

Primary Sex Headache Sex headache may be precipitated by masturbation or coitus and usually starts as a dull bilateral ache while sexual excitement increases, suddenly becoming intense at orgasm. The term orgasmic cephalgia is not accurate because not all sex headaches require orgasm. Two types of primary sex headache are recognized: a dull ache in the head and neck that intensifies as sexual excitement increases and a sudden severe (“explosive”) headache occurring at orgasm.6 Low CSF volume headache may also be precipitated by a sexual activity and is considered as a form of new daily persistent headache (NDPH) (see the following text). The essential clinical features of sex headache are: • Precipitation by sexual excitement • Bilateral at onset • Prevented or eased by ceasing sexual activity before orgasm 3235

Headaches developing at the time of orgasm are not always benign, and consideration of a diagnosis of subarachnoid headache is essential. Sex headache affects men more often than women and may occur at any time during the years of sexual activity. It may develop on several occasions in succession and then not trouble the patient again, despite no obvious change in sexual technique. In patients who stop sexual activity when headache is first noticed, it may subside within a period of 5 minutes to 2 hours, and it is recognized that more frequent orgasm can aggravate established sex headache. About one-third of the patients with sex headache have a history of exertional headaches, but there is no excess of cough headache in patients with sex headache. In about 50% of patients, sex headache will settle in 6 months. Migraine is reported in about 25% of patients with sex headache. Primary sex headaches are usually irregular and infrequent in occurrence, so management can often be limited to reassurance and advice about ceasing sexual activity if a milder, warning headache develops. When the condition recurs regularly or frequently, it can be prevented by the administration of propranolol; the dosage required varies from 40 to 200 mg daily. An alternative is the calcium channel blocking agent diltiazem 60 mg three times daily, which this author finds particularly useful in such patients. Indomethacin (25 to 50 mg) or frovatriptan (2.5 mg) taken about 30 to 45 minutes prior to sexual activity can also be helpful.

Hypnic Headache This syndrome was first described by Raskin114 in patients aged from 67 to 84 years who had headache of a moderately severe nature that typically came on a few hours after going to sleep.114 These headaches last from 15 to 30 minutes, are typically generalized, although may be unilateral, and can be throbbing. Patients may report falling back to sleep only to be awoken by a further attack a few hours later with up to three repetitions of this pattern over the night. In a series of 19 patients, 16 (84%) were female, and the mean age at onset was 61 ± 9 years.115 Headaches were bilateral in two-thirds and unilateral in one-third and in 80% of cases mild or moderate. Three patients reported similar headaches when falling asleep 3236

during the day. None had photophobia or phonophobia, and nausea is unusual. Patients with this form of headache generally respond to a bedtime dose of lithium carbonate (200 to 600 mg) and in those that do not tolerate this, verapamil at bedtime may be alternative strategies).116 Dodick and colleagues115 reported that one to two cups of coffee or caffeine 60 mg orally at bedtime was helpful. This is a simple approach that is effective in about one-third of patients. An important secondary cause of hypnic headache is hypertension which should be carefully pursued and appropriately investigated as treatment of the blood pressure will arrest the headache problem.117

Primary Thunderclap Headache Sudden-onset severe headache may occur in the absence of sexual activity, and the differential diagnosis includes the sentinel bleed of an intracranial aneurysm, cervicocephalic arterial dissection, and cerebral venous thrombosis. Headaches of explosive onset may also be caused by the ingestion of sympathomimetic drugs or tyramine-containing foods in a patient who is taking monoamine oxidase inhibitors and can also be a symptom of pheochromocytoma. Whether thunderclap headache can be the presentation of an unruptured cerebral aneurysm is unclear. Day and Raskin118 reported a woman with three episodes of sudden-onset very severe headache who was found to have an unruptured aneurysm of the internal carotid artery, with adjacent areas of segmental vasospasm. In the absence of CT scan or CSF evidence of subarachnoid hemorrhage, studies indicate that such patients do very well, and there indeed seems a form of benign or primary thunderclap headache. Wijdicks and colleagues119 followed up 71 patients for an average of 3.3 years whose CT scans and CSF findings were negative. Twelve patients had further such headache, and 31 (44%) later had regular episodes of migraine or TTH. Factors identified as precipitating the headache were sexual intercourse in 3 cases, coughing in 4, and exertion in 12, whereas the remainder had no obvious cause. A history of hypertension was found in 11 and of previous headache in 22. Markus120 compared the presentation of 37 patients with subarachnoid hemorrhage 3237

and could not discern any characteristic to distinguish the two conditions. Investigation of any sudden-onset severe headache, be it in the context of sexual excitement or isolated thunderclap headache, should be driven by the clinical context. The first presentation should be vigorously investigated with x-ray CT and CSF examination and, where possible, MRI/magnetic resonance venography (MRV)/magnetic resonance angiography (MRA). Formal cerebral angiography should be reserved for when no primary diagnosis is forthcoming, and the clinical situation is particularly suggestive of intracranial aneurysm. Bearing in mind the entity of diffuse multifocal reversible cerebral vasospasm,121 which may be seen in apparent primary thunderclap headache without there being an intracranial aneurysm, caution in interpretation of findings is crucial.

Hemicrania Continua Two patients were initially reported with this syndrome, a woman aged 63 years and a man of 53 years, who developed unilateral headache without obvious cause. Both patients were relieved completely by indomethacin, whereas other NSAIDs were of little or no benefit. Newman and colleagues122 reviewed the 24 previously reported cases and added 10 of their own, including some with pronounced autonomic features resembling cluster headache. They divided their case histories into remitting and unremitting forms. Of the 34 patients reviewed, 22 were women and 12 men with the age of onset ranging from 11 to 58 years. The symptoms were controlled by indomethacin 75 to 150 mg daily. The essential features of hemicrania continua are6: • Unilateral pain • Pain is continuous but with exacerbations that may be severe • Complete resolution of pain with indomethacin • Exacerbations may be associated with autonomic features Apart from analgesic overuse as an aggravating factor, and a report in an HIV-infected patient, the status of secondary hemicrania continua is unclear. Antonaci and colleagues123 proposed the “indotest” by which the intramuscular injection of indomethacin 50 mg could be used as a diagnostic tool. In hemicrania continua, pain was relieved in 73 ± 66 minutes and the pain-free period was 13 ± 8 hours. A placebo-controlled 3238

minutes and the pain-free period was 13 ± 8 hours. A placebo-controlled modification of this test is preferred where possible to the open-label version. Using the latter method in conjunction with PET, it has been shown that there is activation of the contralateral posterior hypothalamus and ipsilateral dorsal rostral pons in association with the headache of hemicrania continua as well as activation of the ipsilateral ventrolateral midbrain.124 The alternative is a trial of oral indomethacin, initially 25 mg 3 times daily, then 50 mg 3 times daily, and then 75 mg 3 times daily. One should allow up to 2 weeks for any dose to have a useful effect. Acute treatment with sumatriptan has been employed and reported to be of no benefit. Cyclooxygenase 2 (COX-2) antagonists seem effective, although undesirable now, and topiramate is helpful in some patients as is greater occipital nerve injection. nVNS is helpful in these patients and well tolerated.106

New Daily Persistent Headache NDPH is a clinically useful concept with a range of important possible causes because some are very treatable (Table 61.11). From a nosologic point of view, all that are mentioned here could be placed within various categories of the IHS classification,6 and indeed, the IHS refers to primary NDPH. However, the term as employed here serves both patients and clinicians by highlighting a group of conditions, some of which are curable and encompasses the IHS term under as the primary featureless form of NDPH.125 TABLE 61.11 Differential Diagnosis of New Daily Persistent Headache Primary

Secondary

Migrainous-type Featureless (tension-type)

Subarachnoid hemorrhage Low CSF volume headache Raised CSF pressure headache Posttraumatic headachea Chronic meningitis

aIncludes

postinfective forms. CSF, cerebrospinal fluid.

The patient with NDPH presents with a history of headache on most if 3239

not all days that began from one day to the next. The onset of headache is abrupt, often moment-to-moment but at least in less than a few days where three is suggested as an upper limit. The typical history is for the patient to recall the exact day and circumstances, so from one moment to the next, a headache develops that never leaves them. This presentation triggers certain key questions about the onset and behavior of the pain. The pressing issues arise from considering the secondary headache possibilities. Although subarachnoid hemorrhage is listed for some logical consistency, as the headache may certainly come on from one moment to the next, it is not likely to produce diagnostic confusion in this group of patients. Suffice to say that subarachnoid hemorrhage is so important that it must always be considered if only to be excluded, either by history or appropriate investigation. Primary new daily persistent headache: Case series of primary NDPH showed it to occur in both males and females.126 Migrainous features are common, with unilateral headache in about one-third and throbbing pain in about one-third. Nausea was reported in about half the patients, as was photophobia and phonophobia observed again in about half. A number of these patients have a previous history of migraine but not more than one might expect given the population prevalence of migraine.126,127 It is remarkable that the initial report noted that 86% of patients were headache free at 24 months. It is general experience among those interested in headache management that primary NDPH is perhaps the most intractable and least therapeutically rewarding form of headache. In general, one can classify the dominant phenotype, migraine or TTH, and treat with preventives according to that subclassification. Secondary new daily persistent headache: The secondary causes of the syndrome of NDPH are worthy of consideration, as they have distinctive clinical pictures that can guide investigation (see Table 61.11).

Low Cerebrospinal Fluid Volume Headache The syndrome of persistent low CSF volume headache is an important diagnosis not to miss. The more immediately obvious version of this problem is encountered commonly after lumbar puncture. In that situation, the headache usually settles rapidly with bed rest. In the chronic situation, 3240

the next. The pain is generally not present on waking, worsens during the day, and is relieved by lying down. Recumbency usually improves the headache in minutes, and it takes only minutes to an hour for the pain to return when the patient is again upright. The patient may give a history of an index event: lumbar puncture or epidural injection or a vigorous Valsalva, such as with lifting, straining, coughing, clearing the Eustachian tubes in an aeroplane, or multiple orgasms. Patients may volunteer, or a history may be obtained, that soft drinks with caffeine provide temporary respite. Spontaneous leaks are recognized, and the clinician should not be put off the diagnosis if the headache history is typical when there is no obvious index event. As time passes from the index event, the postural nature may be less obvious; certainly, cases whose index event was several years prior to the eventual diagnosis are recognized. The term low volume rather than low pressure is used because there is no clear evidence at which point the pressure can be called low. Although low pressures, such as 0 to 5 are often identified, a pressure of 16 cm CSF has been recorded with a documented leak. One should be aware of the possibility of the development of subdural collections in patients with low CSF volume headaches, which makes imaging before any invasive studies all the more important. The investigation of choice is MRI with gadolinium (Fig. 61.5), which produces a striking pattern of diffuse pachymeningeal enhancement,128 although in about 10% of cases a leak can be documented without enhancement.129 The finding of diffuse meningeal enhancement is so typical that in clinical context immediate treatment is appropriate. It is also common to see Chiari malformations on MRI with some degree of descent of the cerebellar tonsils. This is important because surgery in such settings simply worsens the headache problem. It seems appropriate that any patient being considered for such surgery for a headache indication should be reviewed by a neurologist first. To investigate further, CSF pressure may be determined or preferably a leak sought with 111In-DPTA CSF studies that can demonstrate the site, early emptying of tracer into the bladder, or lack of progression of tracer over the cerebral convexities, although with MR-myelography, this method is becoming redundant.130

3241

FIGURE 61.5 Magnetic resonance image showing diffuse meningeal enhancement after gadolinium administration in a patient with low cerebrospinal fluid volume (pressure) headache.

Treatment is bed rest in the first instance. False-positive transient improvement in persistent low CSF volume headache with chiropractic and other similar therapies is recognized where the treatment necessitates the patient lying down for a prolonged period for the therapy. Intravenous caffeine (500 mg in 500-mL saline administered over 2 hours) is the standard and often very efficacious treatment. The ECG should be checked for any arrhythmia prior to administration. A reasonable practice is to carry out at least two infusions separated by 4 weeks after obtaining the suggestive clinical history and MRI with enhancement. Because intravenous caffeine is safe, and can be curative, by an unknown mechanism, it spares many patients the need for further tests. If that is unsuccessful, an abdominal binder may be helpful. If a leak can be identified, either by the radioisotope study, or by CT myelogram, or spinal T2-weighted MRI, an autologous blood patch is usually curative. In more intractable situations, theophylline is a useful alternative that offers outpatient management, although its onset of action is rather slow. An important phenotypically identical headache can be seen in the postural orthostatic tachycardia syndrome (POTS)131 and should be considered 3242

when investigating this group of patients.

Raised Cerebrospinal Fluid Pressure Headache As is the case for low CSF pressure states, raised CSF pressure as a cause of headache is well recognized by neurologists. Brain imaging can often reveal the cause, such as raised pressure due to a space-occupying lesion. The particular setting in which patients enter the spectrum of NDPH are those with idiopathic intracranial hypertension who present with headache without visual problems, particularly with normal fundi. It is recognized that intractable chronic migraine can be triggered by persistently raised intracranial pressure.132 These patients typically give a history of generalized headache that is present on waking and gets better as the day goes on. It is generally worse with recumbency. Visual obscurations are frequently reported. Fundal changes on raised intracranial pressure would make the diagnosis relatively straightforward, but it is in those without such changes that the history must drive investigation. Patients often report a curious whooshing sensation in the occipital region. Brain imaging is mandatory if raised pressure is suspected, and it is most simple in the long run to obtain an MRI and include MRV. The CSF pressure should be measured by lumbar puncture taking care to do so when the patient is symptomatic so that both the pressure and response to removal of CSF can be determined. A raised pressure and improvement in headache with removal of CSF is diagnostic of the problem. The fields should be formally documented even in the absence of overt ophthalmic involvement. Initial treatment can be with acetazolamide (250 to 500 mg twice daily). The patient may respond in weeks with improvement in headache. If this is not effective, topiramate has many actions that may be useful in this setting: carbonic anhydrase inhibition, weight loss, and neuronal membrane stabilization, probably through actions on phosphorylation pathways. A small number of severely disabled patients who do not respond to medical treatment will come to intracranial pressure monitoring and even shunting. This is exceptional and not undertaken without careful work up.

Posttraumatic Headache 3243

NDPH may be seen after a blow to the head but more commonly after an infective episode, typically viral, or even malarial meningitis. A recent series identified one-third of all patients with NDPH reported the headache starting after a flu-like illness. The patient may note a period in which they had a significant infection: fever, neck stiffness, photophobia, and marked malaise. The headache starts during that period and never stops. Investigation reveals no current cause for the headache. It has been suggested that some patients with this syndrome have a persistent EpsteinBarr infection,133 but this syndrome is anything but clearly delineated. A complicating factor will often be that the patient had a lumbar puncture during that illness, so a persistent low CSF volume headache needs to be considered first. Posttraumatic headache may be seen after carotid artery dissection, subarachnoid hemorrhage, and following intracranial surgery for a benign mass. The underlying theme seems to be that a traumatic event involving the dura mater can trigger a headache process that lasts for many years after that event. The treatment of this form of NDPH is substantially empirical. Tricyclics, notably amitriptyline, and anticonvulsants, valproate, topiramate, and gabapentin, have been used with good effects.

OTHER IMPORTANT FORMS OF SECONDARY HEADACHE Giant Cell Arteritis This is an important cause of headache because delay in steroid treatment may result in blindness due to retinal artery ischaemia (Table 61.12). It is also known as temporal arteritis or cranial arteritis. Patients are usually elderly with focal tenderness of the scalp which may be provoked markedly by resting the head on the pillow. Jaw claudication provoked by chewing is a characteristic but relatively uncommon feature. Constitutional symptoms are common, particularly weight loss, malaise, or polymyalgia rheumatica. An elevated erythrocyte sedimentation rate (ESR) is a strong pointer to the diagnosis. The temporal artery may be tenderly inflamed, swollen, or pulseless. On suspicion of this diagnosis, steroid treatment should be started pending the result of temporal artery biopsy. Treatment is very often long term and requires careful monitoring for reactivation and 3244

the side effects of corticosteroids. TABLE 61.12 Other Secondary Headaches Giant cell arteritis Cervicogenic headache Reader’s paratrigeminal neuralgia139 Tolosa-Hunt syndrome140,141 Headache as a presentation of cervical dystonia5 Headache in temporomandibular dysfunction Cardiac cephalalgia113 Headache with endocrine disturbance, particularly pituitary tumor26 Neck-tongue syndrome142 Red-ear syndrome143

Cervicogenic Headache It is a time-honored concept that the neck is responsible for much headache. Unfortunately, as with much of history, the good story is often ruined by the facts. Although there is little doubt that there is a rich overlap between the innervation of intracranial pain-producing structures by the ophthalmic division of the trigeminal nerve, and the posterior fossa and high cervical innervation by branches especially of the C2 dorsal root,134 causality is another issue. The Headache Classification Committee of the IHS recognizes that head pain can arise from the neck and labels this cervicogenic headache.6 The term has been used by others to define a syndrome135 that is so poorly described as to be useless in practice.136 Most patients with neck discomfort and headache referred to specialty practice have migraine. They will have neck stiffness or discomfort as a premonitory symptom that can clearly persist in all stages of the attack.137 They may respond to local therapies, such as greater occipital nerve injection138; however, this implies no more than triggering and is to be expected. The pursuit of neck pathology and the treatment of patients who have migraine by manipulative or physical means has no support in the controlled literature and is rarely of long-lasting value.

ACKNOWLEDGMENT PJG is funded by the NIHR-Maudsley Biomedical Research Centre. 3245

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csf/volume syndromes compared to myelography. Cephalalgia 2016;36:1291–1295. Mokri B, Low PA. Orthostatic headaches without CSF leak in postural tachycardia syndrome. Neurology 2003;61:980–982. Mathew NT, Ravishankar K, Sanin LC. Coexistence of migraine and idiopathic intracranial hypertension without papilledema. Neurology 1996;46:1226–1230. Diaz-Mitoma F, Vanast WJ, Tyrrell DLJ. Increased frequency of Epstein-Barr virus excretion in patients with new daily persistent headaches. Lancet 1987;1:411–415. Bartsch T, Goadsby PJ. Anatomy and physiology of pain referral patterns in primary and cervicogenic headache disorders. Headache Curr 2005;2:42–48. Antonaci F, Fredriksen T, Sjaastad O. Cervicogenic headache: clinical presentation, diagnostic criteria, and differential diagnosis. Curr Pain Headache Rep 2001;5:387–392. Goadsby PJ. A critical view of cervicogenic headache. In: Sjaastad O, Fredriksen TA, Bono G, et al, eds. Cervicogenic Headache. London: Smith-Gordon; 2004:131–136. Giffin NJ, Ruggiero L, Lipton RB, et al. Premonitory symptoms in migraine: an electronic diary study. Neurology 2003;60:935–940. Afridi SK, Shields KG, Bhola R, et al. Greater occipital nerve injection in primary headache syndromes- prolonged effects from a single injection. Pain 2006;122:126–129. Goadsby PJ. Raeder’s syndrome: “paratrigeminal” paralysis of oculo-pupillary sympathetic system. J Neurol Neurosurg Psychiatry 2002;72:297–299. Tolosa E. Periarteritic lesions of the carotid siphon with the clinical features of a carotid infraclinoidal aneurysm. J Neurol Neurosurg Psychiatry 1954;17:300–302. Hunt WE, Meagher JN, LeFever HE, et al. Painful ophthalmoplegia. Its relation to indolent inflammation of the cavernous sinus. Neurolgy (Minneap) 1961;11:56–62. Bogduk N. An anatomical basis for the neck-tongue syndrome. J Neurol Neurosurg Psychiatry 1981;44:202–208. Lance JW. The red ear syndrome. Neurology 1996;47:617–620. Bahra A, Matharu MS, Buchel C, et al. Brainstem activation specific to migraine headache. Lancet 2001;357:1016–1017. Afridi S, Giffin NJ, Kaube H, et al. A positron emission tomographic study in spontaneous migraine. Arch Neurol 2005;62:1270–1275. Matharu MS, Bartsch T, Ward N, et al. Central neuromodulation in chronic migraine patients with suboccipital stimulators: a PET study. Brain 2004;127:220–230. Afridi S, Matharu MS, Lee L, et al. A PET study exploring the laterality of brainstem activation in migraine using glyceryl trinitrate. Brain 2005;128:932–939.

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CHAPTER 62 Noncardiac Chest Pain RONNIE FASS and TAKAHISA YAMASAKI Noncardiac chest pain (NCCP) is defined as recurring angina-like retrosternal chest pain of noncardiac origin. A patient’s history and characteristics do not reliably distinguish between cardiac and esophageal causes of chest pain.1 This is compounded by the fact that patients with a history of coronary artery disease (CAD) may also experience chest pain of noncardiac origin. The heightened awareness about the potentially devastating ramifications of chest pain may drive patients to seek medical attention despite a negative cardiac workup.2 Furthermore, almost half of NCCP patients are not convinced by their negative cardiac diagnosis, and reassurance alone has proved to be an ungratifying therapeutic strategy.3 There are many causes for NCCP, and they are not limited to the esophagus (Table 62.1).4 Compared to patients with cardiac angina, those with NCCP are usually younger, less likely to have typical symptoms, and more likely to have a normal resting electrocardiogram.5 Additionally, levels of anxiety of NCCP patients seen in a rapid access chest pain clinic significantly exceeded those of patients with cardiac angina and remained above community norms for at least 2 months after clinic visit.6 NCCP patients view their condition as significantly less controllable and less understandable than those whose pain is of cardiac origin.6 TABLE 62.1 Noncardiac, Nonesophageal Etiologies for Chest Pain Musculoskeletal Tietze syndrome Costochondritis Fibromyalgia Precordial catch syndrome Slipping rib syndrome Gastrointestinal Eosinophilic esophagitis

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Gastric Biliary tree Pancreatic Intra-abdominal masses (benign and malignant) Pulmonary Pneumonia Pulmonary embolus Lung cancer Sarcoidosis Pneumothorax and pneumomediastinum Pleural effusions Intrathoracic masses (benign and malignant) Miscellaneous Aortic disorders Pericarditis and myocarditis Pulmonary hypertension Herpes zoster Drug-induced pain Sickle cell crisis Psychological disorders Reprinted from Fass R, Achem SR. Noncardiac chest pain: epidemiology, natural course and pathogenesis. J Neurogastroenterol Motil 2011;17:110–123, with permission.

NCCP may be the manifestation of non-gastrointestinal (GI) or GIrelated disorders (Fig. 62.1). An important step toward understanding of the underlying mechanisms of NCCP was the recognition that gastroesophageal reflux disease (GERD) is the most common contributing factor for chest pain. Although chest pain has been considered an atypical manifestation of GERD, it is an integral part of the limited repertoire of esophageal symptoms. In patients with non–GERD-related NCCP, esophageal motility disorders and functional chest pain (FCP) are the main underlying mechanism for symptoms. The Rome IV Committee uses the term functional chest pain to describe recurrent episodes of substernal chest pain of visceral quality with no apparent explanation (Table 62.2). As with all other functional esophageal disorders, GERD, major esophageal motor disorders, and eosinophilic esophagitis should also be ruled out before the diagnosis is established.7

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FIGURE 62.1 The different underlying mechanisms of noncardiac chest pain.

TABLE 62.2 Rome IV Diagnostic Criteria for Functional Chest Pain of Presumed Esophageal Origin Must include all of the following: Retrosternal chest pain or discomfort Absence of associated esophageal symptoms, such as heartburn and dysphagia Absence of evidence that major esophageal motility disorders, gastroesophageal reflux, or eosinophilic esophagitis are the cause of the symptom Criteria must be fulfilled for the last 3 months with symptoms onset at least 6 months prior to diagnosis with a frequency of at least once a week.

Up to 20% of the patients with FCP exhibit other functional disorders, primarily irritable bowel syndrome (IBS) (27%) and abdominal bloating (22%).8 The mechanisms responsible for FCP include abnormal mechanophysical properties of the esophagus, central and peripheral hypersensitivity, altered central processing of visceral stimuli, and psychological comorbidity (Table 62.3). The latter may include depression, anxiety, panic attack, and somatization.9 TABLE 62.3 The Main Proposed Underlying Mechanisms of Functional Chest Pain Abnormal mechanophysical properties Hyperactive esophagus ↓ Compliance Visceral hypersensitivity Peripheral and central sensitization Altered central processing of visceral stimuli (altered autonomic activity) Psychological abnormalities Panic attack Anxiety Depression

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Epidemiology Information about the epidemiology of NCCP in the United States and around the world is relatively limited. Presently, chest pain is the second most common presentation to hospital emergency departments; however, only 25% of individuals who experience chest pain actually present to a hospital.10 The mean annual prevalence of NCCP in six population-based studies was approximately 25%. However, these studies differ in many aspects such as NCCP definition, geography, sample size, sampling order, and ethnic disparities.11 A population-based survey in the United States assessed the prevalence of GERD in Olmsted County, Minnesota, and reported an overall NCCP prevalence of 23%.12 Gender distribution among NCCP patients was similar (24% among males and 22% among females). Using the Rome criteria for functional GI disorders, Drossman et al.13 reported a prevalence of 13.6% in 8,250 households in the United States. In this study, FCP was diagnosed rather than NCCP. Eslick14 and Eslick et al.15 recently evaluated the prevalence of NCCP in Australia by using a mailing of a validated Chest Pain Questionnaire to 1,000 randomly selected individuals. The study demonstrated a prevalence rate of 33% with almost equal gender distribution (32% in males vs. 33% in females). This study also showed that the population prevalence of NCCP decreases with increasing age.14,15 A nationwide population-based study from South America found that the annual prevalence of NCCP was 23.5% and that NCCP has been equally reported by both sexes.16 In this study, frequent typical GERD symptoms (at least once a week) were significantly and independently associated with NCCP. Another recently published epidemiologic study demonstrated that the annual prevalence of NCCP in a Chinese population was 19%.17 Although females with NCCP tend to consult health care providers more often than men, the disorder affects both sexes equally.12,14,16 Additionally, females are more likely to present to hospital emergency departments with NCCP than males, but there are no sex differences regarding chest pain intensity.18 Overall, women tend to use terms like burning and frightening more often than men.19 3256

Epidemiologic studies report a decrease in the prevalence of NCCP with increasing age. Women under 25 years of age and those between 45 and 55 years of age have the highest prevalence rates.15 Patients with NCCP are younger, consume greater amounts of alcohol and tobacco, and are more likely to suffer from anxiety than their counterparts with ischemic heart disease. Patients with NCCP continue to seek treatment on a regular basis after the diagnosis was established for both chest pain and other unrelated symptoms, but few are in contact with hospital services.20 A meta-analysis of the epidemiology of NCCP in the community revealed pooled prevalence of 13%, lack of age and gender predilection, and increased prevalence in subjects with GERD (odds ratio [OR], 4.71).21 In one study, almost a fourth of individuals with NCCP had sought health care for chest pain within the previous 12 months. None of the GI (heartburn, dysphagia, and acid regurgitation) or psychological (anxiety, depression, and neuroticism) risk factors was significantly associated with pursuing consultation for NCCP.15 A recent US-based survey revealed that cardiologists manage by themselves about half of the patients who are diagnosed with NCCP.22 Of those NCCP patients who were referred, 45.9% were sent back to the primary care physician (PCP) and only 29.3% to a gastroenterologist (Fig. 62.2).

FIGURE 62.2 A: A survey of 246 cardiologists determined that approximately half self-managed

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noncardiac chest pain patients. (Reprinted with permission from Wong WM, Risner-Adler S, Beeler J, et al. Noncardiac chest pain: the role of the cardiologist—a national survey. J Clin Gastroenterol 2005;39[10]:858–862, with permission.)B: A similar survey of 205 primary care physicians demonstrated that the majority self-managed noncardiac chest pain patients. (Redrawn after Wong WM, Risner-Adler S, Beeler J, et al. Noncardiac chest pain: the role of the cardiologist—a national survey. J Clin Gastroenterol 2005;39[10]:858–862, with permission.)

In a survey of PCPs, Wong et al.23 demonstrated that most NCCP patients were diagnosed and treated by PCPs (79.5%) without being referred to a gastroenterologist. The most preferred subspecialty for the initial diagnostic evaluation of a patient presenting with chest pain was cardiology (62%), followed by gastroenterology (17%). The mean percentage of such referrals was only 22%. The most preferred subspecialty for further management of NCCP was gastroenterology (76%), followed by cardiology (8%). The mean percentage of the actual referral rate was 29.8% for gastroenterologists and 14% for cardiologists.23 A study by Eslick and Talley24 reported that 78% of patients who presented to a hospital emergency department with acute chest pain had seen a health care provider in the last 12 months. The most common health care provider seen was a general practitioner (85%), followed by cardiologist (74%), gastroenterologist (30%), pulmonologist (14%), alternative therapist (8%), and psychologist (10%).24 A multiple logistic regression analysis revealed that patients with chest pain who are also suffering from heartburn were 16 times more likely to see a general practitioner (OR, 16.40; 95% confidence interval [CI], 1.98 to 135.99) and 3 times more likely to consult a gastroenterologist (OR, 3.10; 95% CI, 1.26 to 7.62). Additionally, work absenteeism rates (29%) and interruptions to daily activities (63%) were high because of NCCP. Many patients with NCCP report poor quality of life and admit taking cardiac medications despite lack of evidence for a cardiac cause. Only a small fraction of patients feels reassured. Consequently, the economic burden of the disease has been proposed to be very high, although studies evaluating the cost impact of NCCP on the health care system are very scarce. In one study, the health care cost for NCCP was estimated to be more than $315 million annually primarily because of multiple clinic visits, emergency room visits, hospitalizations, and prescription medications.25 This cost estimate does not include indirect costs such as 3258

lost days of work or the impact of symptoms on patients’ quality of life, which have been demonstrated to be more significant when evaluating the economic burden of patients with functional bowel disorders. In Australia, the annual cost associated with NCCP presentations to the Nepean Hospital amounts to approximately $1.4 million.26 The researchers extrapolated these costs to the Australian health care system and conservatively estimated that NCCP accounts for at least a $30 million of the health care budget annually.

Natural History Thus far, very few studies have prospectively evaluated the natural course of NCCP. Obviously, the main concern is the likelihood of these patients developing true ischemic heart disease if followed long term. One of the early studies by Wielgosz et al.27 followed 821 patients with chest pain and normal coronary arteries for a period of 1 year. The authors demonstrated that only three (0.3%) patients died, and all were due to nonischemic reasons.27 However, most of the patients (67%) continued to experience chest pain to some degree (39% less pain, 26% the same pain, and 2% more severe pain). In a study that followed 46 NCCP patients over a period of 11 years, only 2 (4.3%) of the subjects died from a cardiovascular-related event (stroke and ischemic heart disease). Again, as in the previous study, 74% of the surviving NCCP patients continued to report chest pain 11 years later, and of those, 34% reported chest pain symptoms weekly.28 Other studies also documented a very limited longterm mortality in NCCP patients but with continuous debilitating symptoms, impaired functional status, chronic use of drugs (GI, cardiac, and psychiatric), repeated admissions to the hospital, and repeated cardiac and noncardiac procedures.20,29–33 In a survey study, 119 NCCP patients, of which 63 were diagnosed as having pain from the esophagus, were followed for a period of 21.8 months.34 Patients with esophageal-related chest pain usually continued to have recurrent pain. Interestingly, a specific diagnosis did not significantly increase the likelihood of pain resolution. However, patients who understood that the esophagus was the source of their pain were significantly less likely to feel disabled by their 3259

pain and therefore were less likely to require continued physician evaluation. This study was published prior to the proton pump inhibitor (PPI) era. It is unlikely that patients with NCCP due to GERD will continue to have symptoms long term if they are compliant with their antireflux treatment. In another study that compared long-term natural history between NCCP and GERD patients, the authors found no significant difference in survival between the two groups (hazard ratio, 1.1; 95% CI, 0.8 to 1.5). Interestingly, the diagnosis of NCCP disappeared from the electronic hospital record in 96% of the patients within 2 years of follow-up.35 In a recent study that followed 355 NCCP patients, the authors demonstrated that 49% sought care in the emergency department, 42% underwent repeated cardiac workup, and only 15% were seen by a gastroenterologist.36 Survival free of cardiac death in the subset with NCCP and a GI disorder was 90.2% at 10 years and 84.8% at 20 years compared to 93.7% at 10 years and 88.1% at 20 years for those with NCCP of unknown origin. Less than a handful of studies reported similar mortality between patients with NCCP and those with CAD.33,37 A more recent study by Eslick and Talley38 followed 126 NCCP and 71 cardiac patients who were seen in the emergency room for a period of 4 years. The majority of the NCCP (71%) and the CAD patients (81%) continued to have symptoms 4 years later. The authors found no difference in the mortality rate between the two groups (CAD, 11.0%, vs. NCCP, 5.5%; P = .16). However, the study may suffer from type II error, and the results need to be confirmed in a larger cohort of patients. Overall, the aforementioned data support the overall conclusion that increased mortality is uncommon in NCCP patients. However, patients with NCCP demonstrate poor quality of life primarily due to continuation of symptoms many years after diagnosis.

Pathophysiology GASTROESOPHAGEAL REFLUX DISEASE Many studies have shown an association between GERD and NCCP. However, association does not confer causality. Resolution or 3260

improvement of chest pain symptoms in response to treatment with antireflux medications provides the missing causal link. Locke et al.12 have demonstrated that NCCP is more commonly reported by patients (37%) who experience heartburn symptoms at least weekly, as compared with 30.7% of those who have infrequent heartburn (less than once a week) and 7.9% of those without any GERD symptoms. In another community-based study, the authors found that 53% of all patients with NCCP experienced heartburn and 58% acid regurgitation.15 Stahl et al.39 found in a small sample of NCCP patients that 61.5% had GERD-related symptoms. In three different studies evaluating the role of the PPI test in patients with NCCP, the authors found GERD-related symptoms in 68% to 90% of the patients.40–42 Ambulatory 24-hour esophageal pH testing studies have demonstrated that about half of NCCP patients have an abnormal esophageal acid exposure. Stahl et al.39 evaluated 13 consecutive NCCP patients and found that 69.2% had an abnormal pH test. Beedassy et al.43 evaluated 104 patients with NCCP and documented that 48% of them had an abnormal pH test. It should be noted that only 21% of the 52 patients who reported chest pain during the study had a concomitant acid reflux event. Interestingly, only 10 of the 52 subjects had a positive symptom index (>50%). Similarly, DeMeester et al.44 demonstrated that 46% of patients with chest pain had symptoms associated with an acid reflux event as documented during pH testing. Pandak et al.45 found an abnormal pH test in 42% of NCCP patients. In three different studies evaluating the role of the PPI test, the authors found abnormal pH test in 37.5% to 67% of the NCCP patients.40–42 In a study from Asia, 34.3% of the NCCP patients had at least one abnormal pH parameter.46 Even in patients with CAD who continued to have atypical chest pain symptoms, 49% to 67% had some of their painful episodes associated with acid reflux.47,48 The presence of esophageal mucosal abnormalities consistent with GERD appears to be less common in NCCP patients than GERD symptoms or excess esophageal acid exposure. From different studies, the range has been between 2.5% and 75%.46,49–52 In three different studies evaluating the role of the PPI test in patients with NCCP, the authors found GERD-related endoscopic findings in 44% to 75% of the NCCP 3261

patients.40–42 In all of these studies, low-grade erosive esophagitis was the main GERD-related endoscopic finding. A recent study by Dickman et al.53 evaluated upper GI findings in patients with NCCP as compared with those having only GERD-related symptoms using a large multicenter consortium. Of the NCCP group, 28.6% had hiatal hernia, 19.6% erosive esophagitis, 4.4% Barrett esophagus (BE), and 3.6% esophageal stricture/stenosis. The prevalence of these findings was significantly lower in the NCCP group when compared with the GERD group. From this study, it appears that GERD-related mucosal abnormalities are not uncommon in the esophagus of NCCP patients. However, the prevalence of these anatomical findings is lower than what has been observed in GERD patients. Importantly, NCCP patients may also demonstrate BE, albeit uncommonly. The mechanism by which gastroesophageal reflux causes NCCP remains poorly understood. It is still unclear why esophageal exposure to gastric content in some patients causes heartburn, and in others, chest pain. This is compounded by the fact that some patients may experience chest pain at one time and heartburn at other times. Characteristics of the individual reflux episodes (duration and pH) have been proposed to influence patients’ symptoms. Smith et al.54 studied 25 individuals with NCCP to determine the relation between the sensation of pain in GERD and pH of the refluxate. They found that all 25 patients had reproduction of their pain during intra-esophageal infusion of solutions with pH 1 and 1.5. Reflux events resulting in pain were significantly longer than those without pain and were more often associated with a recently preceding painful episode. Esophageal hypersensitivity has been suggested to be another important mechanism for chest pain in patients with GERD. In one study,55 healthy subjects underwent perfusion of the distal esophagus with normal saline or 0.1 N hydrochloric acid. Perceptual responses to intraluminal esophageal balloon distension were evaluated using an electronic barostat. As compared with saline, acid perfusion reduced the perception threshold (innocuous sensation) and tended to reduce the pain threshold (aversive sensation). This study demonstrated short-term sensitization of mechanosensitive afferent pathways by transient exposure to acid. The 3262

authors suggested that in patients with NCCP, acid reflux induces sensitization of the esophagus, which may subsequently alter the way the esophagus perceives otherwise normal esophageal distention. Sarkar et al.56 recruited 19 healthy volunteers and 7 patients with NCCP. Hydrochloric acid was infused into the distal esophagus over 30 minutes. Sensory responses to electrical stimulation were monitored within the acid-exposed distal esophagus and the nonexposed proximal esophagus before and after infusion. In the healthy subjects, acid infusion into the distal esophagus lowered the pain threshold in the upper esophagus. Patients with NCCP already had a lower resting esophageal pain threshold than healthy subjects. After acid perfusion, their pain threshold in the proximal esophagus fell further and for a longer duration than was the case for the healthy subjects (Fig. 62.3). Additionally, there was a decrease in pain threshold after acid infusion in the anterior chest wall. This study demonstrated the development of secondary allodynia (visceral hypersensitivity to an innocuous stimulus in normal tissue that is in proximity to the site of tissue injury) in the proximal esophagus by repeated acid exposure of the distal esophagus. The concurrent visceral and somatic pain hypersensitivity is most likely caused by central sensitization (an increase in excitability of spinal cord neurons induced by activation of nociceptive C fibers in the area of tissue injury). The patients with NCCP demonstrated visceral hypersensitivity and amplified secondary allodynia in the esophagus.

FIGURE 62.3 Mean change in pain threshold in the upper esophagus after 5 minutes infusion of

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acid or saline into the lower esophagus (noncardiac chest pain vs. control). (Redrawn after Sarkar S, Aziz Q, Woolf CJ, et al. Contribution of central sensitization to the development of non-cardiac chest pain. Lancet 2000;356[9236]:1154–1159. Copyright © 2000 Elsevier. With permission.)

Another explanation how GERD may cause chest pain was provided by studies using high-frequency, intraluminal ultrasonography. Balaban et al.57 demonstrated a temporal correlation between sustained contractions of the esophageal longitudinal muscle and spontaneous as well as provoked esophageal chest pain. In a follow-up study, the authors suggested that the duration of sustained esophageal contraction determines the type of symptom perceived by patients.58 Heartburn was associated with shorter duration contractions, whereas chest pain was associated with contractions of longer duration. In a recent study, the authors suggested that esophageal muscle thickness per se, in the absence of esophageal motility abnormality, can lead to chest pain symptoms.59 Utilization of pH impedance in patients with GERD-related NCCP suggested that the presence of gas in the refluxate may drive the chest pain symptom.60 Studies have demonstrated that NCCP patients with evidence of GERD (endoscopic findings and/or abnormal pH test) commonly respond to antireflux treatment. Between 78% and 92% of NCCP patients with objective evidence of GERD demonstrated symptoms improvement on antireflux treatment.40,42,45,46 In contrast, response to PPI treatment in NCCP patients without objective evidence of GERD ranged between 10% and 14%.40–42 Kushnir et al.61 have demonstrated that a positive symptom association probability and elevated acid exposure time predicted response to PPI treatment in patients with NCCP. When used hierarchically, response to antireflux treatment was best predicted when GERD parameters (acid exposure time, symptom association probability, and symptom index) were all abnormal and poorest when all normal. These data suggest a causal relationship between patients’ GERD and chest pain symptoms. In patients with CAD and atypical chest pain, a higher incidence and longer duration of ischemic events were more commonly observed in those with GERD.48

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It is well known that the esophagus and the heart share similar sensory innervation, and several studies have demonstrated that acidification of the distal esophagus may influence the flow of the coronary circulation.62–64 Chauhan et al.65 have shown a reduction in coronary artery blood flow in response to acid perfusion into the distal esophagus in patients with syndrome X. Syndrome X is defined as typical chest pain and electrocardiographic changes suggestive of myocardial ischemia on stress test but patent coronary arteries on angiogram.64 The reduction in coronary blood flow was also associated with typical anginal pain, suggesting the presence of an esophagocardiac inhibitory reflex.65 These findings were later confirmed by Rosztoczy et al.66 who showed a decrease in coronary artery blood flow in 19 out of 42 (45%) patients undergoing acid perfusion of the esophagus.

ESOPHAGEAL DYSMOTILITY Several large studies demonstrated that approximately 30% of NCCP patients had abnormal esophageal manometry.67–69 In one study that included 910 NCCP patients, the authors found that 70% had normal esophageal motility (Fig. 62.4).67 Nutcracker esophagus (14.4%) was the most commonly documented esophageal motility abnormality, followed by nonspecific esophageal motor disorder (10.8%). Diffuse esophageal spasm (DES), achalasia, and hypertensive lower esophageal sphincter (LES) were very uncommon in this NCCP group. In another study, Dekel et al.68 evaluated 140 NCCP patients using the Clinical Outcomes Research Initiative database. Unlike the previous study that included patients from one major center with interest in esophageal motility, the study by Dekel et al.68 included patients from more than 60 academic, veteran affairs, and private centers from around the United States. The authors also found that 70% of the subjects had a normal esophageal motility test. Hypotensive LES (61%) was the most common motility abnormality diagnosed, followed by hypertensive LES, nonspecific esophageal motor disorder, and nutcracker esophagus (10% each). In this study, achalasia and DES were also very uncommon. The difference in the distribution of motility abnormalities between the two studies reflects the different study designs. In the first study, only non–GERD-related NCCP patients were included, 3265

whereas all newcomers were enrolled into the second study. A recent study from Chile evaluated 100 newly diagnosed NCCP patients and found that 8% of them had an abnormal esophageal manometry.70 In this study, 36% of patients had nutcracker esophagus, 28% hypotensive LES, and 16% nonspecific esophageal motor disorder. The reason for the discrepancy between the results of this study and the other two is unclear. It appears, however, that the high rate of esophageal motility abnormalities recorded in NCCP patients in this study may reflect a local referral bias.

FIGURE 62.4 Distribution of esophageal motility abnormalities in noncardiac chest pain patient without gastroesophageal reflux disease (N = 910). (Redrawn after Katz PO, Dalton CB, Richter JE, et al. Esophageal testing of patients with noncardiac chest pain or dysphagia. Results of three years’ experience with 1161 patients. Ann Intern Med 1987;106[4]:593–597. Copyright © 1987 American College of Physicians. All Rights Reserved. Reprinted with the permission of American College of Physicians, Inc.)

There are very few studies assessing NCCP patients with highresolution esophageal manometry (HREM). One study demonstrated impaired peristalsis in 60% of NCCP patients, including ineffective esophageal motility, fragmented peristalsis, and absent contractility.60 The relationship between NCCP and esophageal dysmotility remains an area of intense controversy because documentation of esophageal dysmotility during manometry is rarely associated with reports of chest pain symptoms.71 In addition, unlike GERD, we are still devoid of highly effective pharmacologic compounds that can eliminate esophageal dysmotility and thus can be used to demonstrate a causal relationship.72 Furthermore, in NCCP patients who underwent simultaneous esophageal manometry and pH testing, chest pain was more commonly associated 3266

with acid reflux events than motility abnormalities.69,73 Even the past usage of ambulatory 24-hour esophageal manometry was unable to improve the sensitivity of the test in NCCP. In fact, studies have demonstrated that 27% and 43% of patients did not report any chest pain symptoms during the test.69,74 Moreover, the investigators were able to relate pain episodes to recorded esophageal dysmotility in only 13% to 24% of patients. Consequently, the routine usage of ambulatory 24-hour esophageal manometry has been questioned, and the technique is rarely performed in clinical practice. In one study, the authors were able to demonstrate improvement of NCCP symptoms in patients with nutcracker esophagus receiving antireflux treatment but with no effect on esophageal motility.75 Some authorities have proposed using esophageal motility abnormalities in NCCP patients as a marker for an underlying motor disorder that may be responsible for patients’ symptoms.76 However, it is plausible that our current evaluative techniques of the esophagus provide only crude information about esophageal motor function. Future tests will require providing a more comprehensive evaluation of anatomical structure and biomechanics of the esophagus and their relationship to pain.

SUSTAINED ESOPHAGEAL CONTRACTIONS High-frequency intraluminal ultrasonography, a technique useful for the evaluation of smooth muscle contraction, has been employed to assess the esophageal motor corollary of chest pain in NCCP patients.57 By using high-frequency intraluminal ultrasonography, Balaban et al.57 have shown a close correlation between longitudinal muscle contractions and reports of chest pain. When evaluating the 10 participating subjects, the authors demonstrated esophageal longitudinal muscle contractions preceding 18 of 24 spontaneous chest pain events. These muscle contractions cannot be detected by conventional esophageal pressure recordings that solely evaluate the esophageal circular muscle. Balaban et al.57 further showed that edrophonium-induced chest pain was also preceded by sustained esophageal muscle contractions.57 The authors also demonstrated that swallow-associated contractions of the longitudinal muscles lasted an average of 6.4 seconds, whereas contractions associated with chest pain 3267

lasted a mean of 68.0 seconds. Pehlivanov et al.58 demonstrated that the duration of the sustained esophageal muscle contractions might be correlated with the type of symptom perceived by patients. Shorter durations of these contractions were associated more with heartburn, whereas longer durations were linked more with chest pain.58 Furthermore, sustained esophageal muscle contractions were observed in patients who reported heartburn that was unrelated to an acid reflux event giving further credence to the hypothesis that sustained esophageal contractions are responsible for the generation of esophageal-related symptoms such as chest pain. Unfortunately, high-frequency intraluminal ultrasonography is highly operator-dependent and consequently may not always be an objective evaluative tool. None of the initial studies have been replicated by other investigators. Although sustained esophageal muscle contractions appear to be predictable markers for chest pain, it is still unclear if they are the direct underlying mechanism or just an epiphenomenon.

ESOPHAGEAL HYPERSENSITIVITY Studies have consistently documented alteration in pain perception regardless of whether dysmotility was present or absent in patients with NCCP. Visceral hypersensitivity is a phenomenon in which conscious perception of visceral stimulus is enhanced independently of the intensity of the stimulus.77 Peripheral and central mechanisms have been proposed to be responsible for visceral hypersensitivity in patients with NCCP. It has been hypothesized that peripheral sensitization of esophageal sensory afferents leads to subsequently heightened responses to physiologic or pathologic stimuli of the esophageal mucosa.78 Additionally, central sensitization at the brain level or the dorsal horn of the spinal cord may modulate afferent neural function and thus enhance perception of intraluminal stimuli.79 What causes peripheral or central sensitization remains to be determined. Studies have shown that acute tissue irritation results in subsequent peripheral and central sensitization, which is manifested as increased background activity of sensory neurons, lowering of nociceptive thresholds, changes in stimulus response curves, and enlargement of receptive fields.80 Peripheral sensitization involves the 3268

reduction of esophageal pain threshold and increase in the transduction processes of primary afferent neurons.81 Esophageal tissue injury, inflammation, spasm, or repetitive mechanical stimuli can all sensitize peripheral afferent nerves. There is immune dysfunction, for example, stimulated lymphocyte expression of interleukin (IL)-5 and IL-13.82 There is also increased mucosal mast cells in patients with esophageal hypersensitivity and specifically those with FCP.83 The presence of esophageal hypersensitivity can be subsequently demonstrated long after the original stimulus is no longer present and the esophageal mucosa has healed. However, it is still unclear what factors are pivotal for the persistence of esophageal hypersensitivity. Studies have demonstrated that patients with non–GERD-related NCCP have lower perception thresholds for pain. Richter et al.84 used balloon distension protocol in the distal esophagus and found that 50% of patients with NCCP developed pain at volumes of 8 mL or less in comparison with 9 mL or more in healthy subjects who developed pain (Fig. 62.5). The authors found no difference in the pressure–volume curve of the two groups as well as no difference in esophageal motility. When the balloon was inflated to 10 mL, patients with a history of NCCP were more likely to experience pain (18/30) than the control subjects (6/30). Barish et al.81 evaluated 50 patients with NCCP and 30 healthy volunteers using graded balloon distension protocol. Of the patients with NCCP, 56% (28/50) experienced their “typical” chest pain during balloon distension as compared with 20% (6/30) of the normal controls. Of those with NCCP who experienced pain, 85% reported pain at values below the usual sensory threshold (20 cm H2O). There was no difference in esophageal tone between the two groups.

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FIGURE 62.5 Pain thresholds in noncardiac chest pain patients versus normal controls using a balloon distension protocol. (Redrawn after Richter JE, Barish CF, Castell DO. Abnormal sensory perception in patients with esophageal chest pain. Gastroenterology 1986;91[4]:845–852. Copyright © 1986 Elsevier. With permission.)

Rao et al.85 used impedance planimetry to evaluate 24 patients with NCCP and 12 healthy controls. Using balloon distention, they demonstrated that those with NCCP had lower perception thresholds for first sensation and moderate discomfort and pain in comparison to the healthy controls. Typical chest pain was reproduced in 83% of the NCCP patients. In addition, the reactivity of the esophagus to balloon distension was increased in those with NCCP, as was the pressure elastic modulus. Rao et al.86 also performed graded balloon distensions of the esophagus using impedance planimetry in 16 consecutive patients with NCCP (normal esophageal evaluation) and 13 healthy control subjects. Patients who experienced chest pain during balloon distension were subsequently restudied after receiving intravenous atropine (Fig. 62.6). Balloon distensions reproduced chest pain at lower sensory thresholds in most NCCP patients as compared with controls. Similar findings were documented after atropine administration despite relaxed and more deformable esophageal wall. Thus, the investigators concluded that esophageal hypersensitivity, rather than motor dysfunction, is the predominant mechanism for FCP.

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FIGURE 62.6 Mean pressure thresholds in controls and in patients with noncardiac chest pain (NCCP) before and after atropine was given. (Reprinted by permission from Nature: Rao S, Hayek B, Summers RW. Functional chest pain of esophageal origin: hyperalgesia or motor dysfunction. Am J Gastroenterol 2001;96[9]:2584–2589. Copyright © 2001 Springer Nature.)

As noted earlier, it was demonstrated the development of secondary allodynia in the proximal esophagus by repeated acid exposure of the distal esophagus.56 The patients with NCCP demonstrated both visceral hypersensitivity and amplified secondary allodynia in the esophagus. However, it is unclear from the study what mechanism is responsible for the exaggerated secondary allodynia and what initiates central sensitization in patients with NCCP. It is interesting to note that other studies in NCCP, using a similar human model of acute tissue irritation by acid infusion, showed no significant effect on pain thresholds.87 Börjesson et al.87 also demonstrated that patients with NCCP have reduced sensitivity to esophageal balloon distension during simultaneous transcutaneous electrical nerve stimulation (TENS) as compared with healthy controls. This further supports the role of visceral hypersensitivity in NCCP and suggests that the phenomenon is probably due to central sensitization.88 Mehta et al.88 also demonstrated that acid infusion into the distal esophagus reduces esophageal pain thresholds for balloon distension in patients with NCCP not previously sensitive to balloon distension or acid infusion. In another study that was noted earlier,55 the authors demonstrated short-term sensitization of mechanosensitive afferent pathways by transient exposure to acid. Sarkar et al.89 also evaluated 14 patients with GERD-related NCCP and 8 healthy controls. All subjects underwent an esophageal electrical stimulation protocol in the proximal esophagus, and 3271

those with NCCP demonstrated lower perception thresholds for pain than normal controls. However, there was an increase in the perception thresholds for pain during electrical stimulation in the NCCP patients after a 6-week course of high-dose PPI (omeprazole 20 mg twice daily) (Fig. 62.7).89 This study demonstrated that patients with NCCP and evidence of GERD have a component of esophageal hypersensitivity that is responsive to high-dose PPI therapy.

FIGURE 62.7 Patients with chest pain and occult gastroesophageal reflux disease (GERD) demonstrate visceral hypersensitivity that may be partially responsive to acid suppression with a proton pump inhibitor (PPI). (Reprinted by permission from Nature: Sarkar S, Thompson DG, Woolf CJ, et al. Patients with chest pain and occult gastroesophageal reflux demonstrate visceral pain hypersensitivity which may be partially responsive to acid suppression. Am J Gastroenterol 2004;99[10]:1998–2006. Copyright © 2004 Springer Nature.)

In another small study that enrolled 22 NCCP patients with documented nutcracker esophagus, the authors demonstrated that stepwise balloon distensions reproduced pain symptoms at a lower threshold in 90% of NCCP patients as compared with 20% of healthy controls.90 It was concluded that patients with NCCP and nutcracker esophagus also exhibit visceral hypersensitivity. Additionally, visceral hypersensitivity is the likely main underlying mechanism for patients’ symptoms rather than the presence of the high amplitude contractions (nutcracker esophagus). Unfortunately, the presence of GERD in these patients was not determined 3272

in this study. In a recent study, 75% of patients with FCP who underwent impedance planimetry demonstrated esophageal hypersensitivity.91 These patients had larger cross-sectional areas, decreased esophageal wall strain, distensibility, and lower thresholds for perception, discomfort, and pain as compared with FCP patients without esophageal hypersensitivity or healthy controls. Another recent study showed that pain evoked by bag distention in FCP patients is dependent primarily on stress and to a lesser degree on strain.92 The pain does not appear to be related to mucosal perfusion.

ALTERED AUTONOMIC ACTIVITY Tougas et al.93 have performed several studies exploring autonomic nervous system function and its role in the pathogenesis of NCCP. In one study, the investigators assessed autonomic activity, using spectral analysis of heart rate variability, before and during distal esophageal acidification of patients with NCCP and matched healthy controls.93 Of those with NCCP, 68% developed angina-like symptoms during the esophageal acidification. These patients had a higher baseline heart rate and a lower baseline vagal activity than patients without acid sensitivity. During acid infusion, vagal cardiac outflow increased in acid-sensitive patients as compared with patients without acid sensitivity. Additionally, Tougas94 have also documented increased vagal activity in patients with NCCP during other intra-esophageal stimuli, both mechanical and electrical. These studies indicate that autonomic dysregulation may be present in at least a subset of patients with NCCP. The authors further hypothesized that increased perception of esophageal stimulation may also reflect an exaggerated brainstem response. However, Tougas94 has hypothesized that in most cases in which both central and autonomic factors are involved, central factors will likely lead to autonomic dysregulation.

PSYCHOLOGICAL COMORBIDITY Psychological comorbidity has been shown to be common in NCCP and affects up to 75% of patients. It has yet to be determined if the high level of psychological comorbidity may be related to referral bias to tertiary 3273

referral centers or if it is the result of long-term experience of pain. Regardless, studies reported a high prevalence (>50%) of panic disorder, anxiety, and major depression in NCCP patients.15,95–108 Other psychological abnormalities have also been reported including neuroticism, hypochondriac behavior, obsessive-compulsive disorder, phobic disorder, and somatization.15,100–103,109–113 In a small study of 36 subjects with NCCP, the authors found that 58% had some type of psychological abnormality.114 Of those, anxiety, depression, and panic disorder were the most common. In a large population-based study in Australia, the authors surveyed a random sample of 1,000 residents in the Sydney area.15 Among those with NCCP, the prevalence of anxiety was 23% and depression 7%. In a telephone survey from Hong Kong that included 2,209 subjects, the authors demonstrated that depression and anxiety were significantly more common in NCCP patients than those without NCCP.104 Among all esophageal symptoms, chest pain was shown to closely correlate with psychometric abnormalities. In some patients, chest pain is part of a host of symptoms that characterize panic attack. Panic attack is a common cause for emergency room visits due to chest pain. In a large study that encompassed 441 consecutive ambulatory patients presenting with chest pain to the emergency department of a heart center, 25% were diagnosed as suffering from a panic attack.110 Although the reason for the observed association between NCCP and panic disorder remains to be fully elucidated, hyperventilation was demonstrated to precipitate chest pain in 15% of patients with NCCP.115 Additionally, it was demonstrated that hyperventilation could provoke reversible esophageal manometric abnormalities such as esophageal spasm (4%) and a nonspecific esophageal motor disorder (22%).116 Furthermore, studies have demonstrated that hyperventilation may precipitate a panic attack. Anxiety and depression influence reports of pain and thus contribute to the pathophysiology of NCCP. Lantinga et al.117 found that patients with NCCP had higher levels of neuroticism and psychiatric comorbidity before and after cardiac catheterization than did patients with CAD. This finding appears to have prognostic significance because these patients display less improvement in pain, more frequent pain episodes, greater social 3274

maladjustment, and more anxiety at 1-year follow-up than individuals with relatively low initial levels of psychosocial disturbances. In a large epidemiologic study from England, a significant relationship between NCCP and psychiatric disorders was demonstrated in young adults.118 Two independent variables were associated with chest pain: parental illness and fatigue during childhood. Studies have been inconsistent when the frequency of panic disorder, anxiety, and depression were compared between NCCP patients and those with CAD. Some studies reported increased panic disorder, anxiety, and depression in NCCP patients, whereas others found no significant difference in the prevalence of psychological disorders between the two groups.9,111,119–122 In one study of 199 participants, panic disorder was more common in NCCP as compared with those with CAD (41% vs. 22%).119 However, other psychiatric disorders were highly prevalent (72%) but without any difference between the two groups. In contrast, Cormier et al.123 demonstrated that 98 NCCP patients scored higher on measures of anxiety and negative life events and had a significantly greater prevalence of Diagnostic and Statistical Manual of Mental Disorders (3rd ed.; DSM-III) panic disorder (47% vs. 6%), major depression (39% vs. 8%), and two or more simple phobias (43% vs. 12%) than did patients with CAD. In a recent multivariate analysis, the authors were able to develop a predictive model for distinguishing between NCCP and CAD that includes alexithymia (a condition in which patients are unable to express their feelings with words), quality of life, and coping based on religion and seeking medical help (85.4% sensitivity and 80.0% specificity).124 NCCP patients with psychological disorders show diminished quality of life, more frequent chest pain, and less treatment satisfaction than NCCP patients without psychological comorbidity.108 One study suggested that NCCP patients with more than one psychological disorder are more difficult to treat than those with a single psychological disorder.125 Cheng et al.126 demonstrated that patients with NCCP, when compared to patients with rheumatism and healthy controls, tended to monitor more, use more problem-focused coping, display a coping pattern with a poorer strategy–situation fit, and receive less emotional support in times of stress. 3275

Additionally, monitoring perceptual style and problem-focused coping were associated with higher levels of anxiety and depression. Jerlock et al.127 evaluated 231 NCCP patients and compared their psychosocial profile with 1,069 healthy subjects without NCCP. The authors found that NCCP patients had more sleep problems, mental strain at work, stress at home, and negative life events as compared with the healthy group. Gender differences related to psychological factors have also been observed in NCCP patients. Men reported less depression and trait anxiety than women.128

Diagnosis of Noncardiac Chest Pain CARDIOLOGY EVALUATION A cardiology evaluation is required in patients with angina-like pain. This recommendation is primarily driven by the recognition that the morbidity and mortality of CAD far exceeds that of esophageal-related causes of NCCP. Furthermore, a patient’s history and characteristics do not reliably distinguish between cardiac and esophageal causes of chest pain.1 NCCP patients may report squeezing or burning substernal chest pain, which may radiate to the back, neck, arms, and jaw and is indistinguishable from cardiac-related chest pain.129–131 The description of chest pain obtained during a careful history is categorized as typical angina (80% to 90% likelihood of obstructive CAD), atypical angina (40% to 80% likelihood), or as noncardiac (20% to 70% likelihood). Typical angina is characterized by the following three characteristics: • Retrosternal chest discomfort experienced as pressure or heaviness • Duration of 5 to 15 minutes • Induced by stress or exertion, a large meal, or exposure to cold and relieved by rest or nitroglycerin Atypical angina is diagnosed when two of these are present, and NCCP is likely if none or only one of these cardinal features exists.132 Therefore, a patient who describes the spontaneous onset of “an elephant sitting on my chest” for 1 minute, with left arm involvement, diaphoresis, and nausea, actually has NCCP.132 Although some of the patients may have a 3276

high probability of CAD for their chest pain and others low probability, the majority of the patients with chest pain fall into the intermediate range and thus require further testing to determine the presence of significant CAD. Diagnosis of NCCP is more likely in younger patients with chest pain, particularly females, and those without personal or strong family history of CAD. A unique relationship between the esophagus and the heart has been proposed because the two organs share similar sensory innervation, and several studies have demonstrated that acidification of the distal esophagus may influence the flow of the coronary circulation.62–64 Chauhan et al.65 have shown a reduction in coronary artery blood flow in response to acid perfusion into the distal esophagus in patients with syndrome X. Syndrome X is defined as typical chest pain and electrocardiographic changes suggestive of myocardial ischemia on stress test but patent coronary arteries on angiogram.65 The reduction in coronary blood flow was also associated with typical angina pain, suggesting the presence of an esophagocardial inhibitory reflex. These findings were later confirmed by Rosztoczy et al.66 who showed a decrease in coronary artery blood flow in 19 out of 42 (45%) patients undergoing acid perfusion of the esophagus. In a subset of patients, ischemic heart disease and GERD or esophageal dysmotility may coincide.133 It is the role of the cardiologist to determine if the chest pain is related to the underlying heart disease. Only after the cardiologist confirmed that symptoms are unrelated to the underlying ischemic heart disease, then further esophageal workup is warranted. In conclusion, patients presenting for the first time with chest pain should initially undergo an evaluation by a cardiologist to exclude a cardiac cause.

GERD-RELATED NCCP There is no gold standard for diagnosing GERD-related NCCP. The currently available diagnostic tests to detect GERD in patients with NCCP include barium swallow, upper endoscopy, the acid perfusion test, ambulatory 24-hour esophageal pH monitoring, and the PPI test.

BARIUM ESOPHAGRAM 3277

Barium esophagram has very little use in the diagnosis of GERD. Barium esophagram has a low sensitivity (20%) for diagnosing GERD in general due to lack of anatomical and mucosal abnormalities in most of the GERD patients.134 Furthermore, the significance of barium reflux during the procedure as a diagnostic for GERD is questionable. Johnston et al.134 found that the proportion of patients with an abnormal 24-hour esophageal pH study was similar to the proportion of patients with a normal 24-hour esophageal pH study who had spontaneous barium reflux during the test. Additionally, spontaneous barium reflux has been demonstrated in up to 20% of healthy subjects.135 The role of barium esophagram is unclear in patients with GERDrelated NCCP primarily due to the rare presence of esophageal mucosal abnormalities. However, one may consider performing a barium esophagram as the initial diagnostic test in patients who report dysphagia in addition to chest pain.

UPPER ENDOSCOPY Upper endoscopy is frequently used as a diagnostic tool in the evaluation of unexplained upper digestive complaints and specifically in patients with NCCP. In 1990, the American Gastroenterological Association guidelines for chest pain of esophageal origin recommended the routine use of endoscopy in the evaluation of NCCP.136 Since then, several studies have reported a variable rate of diagnostic yield in NCCP. In one of the earlier endoscopic studies, Hsia et al.50 evaluated 100 consecutive patients with NCCP (mean age 50 years). In this single-center study, the authors found that 38% of the patients had a normal test, 24% erosive esophagitis (grades II to IV), 18% gastritis and/or duodenitis, 14% a sliding hiatal hernia without evidence of erosive esophagitis, and 6% gastric or duodenal ulcer.50 Several studies from different countries have also evaluated the value of upper endoscopy in NCCP. In a study of a northern Mexican population, only 10% of the NCCP patients demonstrated mucosal abnormalities during endoscopy. The vast majority of those were acid peptic–related.137 A study from Denmark evaluated 49 patients with NCCP (28 women, mean age 51.6 years) who were referred to a tertiary cardiology center. 3278

The authors detected grade I erosive esophagitis in 15 patients (31%), grade II erosive esophagitis in 1 patient, and peptic ulcer in 3 patients (6%).51 A study from China reported that in 70 consecutive patients with NCCP (mean age 58.5 ± 10), only 11% had endoscopic abnormalities (three with duodenal ulcer, three with gastric ulcer, and two with erosive esophagitis).138 In a study from Italy, 61 consecutive patients with NCCP underwent endoscopy, and only 10% demonstrated mucosal findings (most erosive esophagitis).133 In the largest study thus far addressing the role of upper endoscopy in NCCP, Dickman et al.53 reported mucosal findings in 3,688 consecutive patients undergoing endoscopic evaluation for NCCP (mean age 55.1 years, range 18 to 99.6 years). Patients were seen in 76 community, university, and Veteran Health Administration Care Centers. The authors found that 44% of the NCCP patients had a normal upper endoscopy. Endoscopic findings in those with abnormal tests included hiatal hernia (28.6%), erosive esophagitis (19.4%), BE (4.4%), esophageal stricture or stenosis (3.6%), and peptic ulcer (2%) (Table 62.4).53 The authors concluded that the mucosal findings in NCCP patients were primarily GERD-related. An important finding of this study is that 4.4% of the patients with NCCP also had BE. This was significantly lower than the BE rate (9.1%) observed in GERD patients in the same study. Two other small studies have also reported the presence of BE in 5.2% and in 6.7% of NCCP patients undergoing endoscopy.137,139

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TABLE 62.4 The Value of Upper Endoscopy in Chest Pain Patients as Compared to Those with Reflux-Related Symptoms Using a Large Multicenter Consortium Findings Barrett esophagus Esophageal inflammation Hiatal hernia Normal Stricture/stenosis

Chest Pain Group N = 3,688 (%)

Reflux Group N = 32,981 (%)

P Value

163 (4.4%) 715 (19.4%) 1,053 (28.6%) 1,627 (44.1%) 132 (3.6%)

3,016 (9.1%) 9,153 (27.8%) 14,775 (44.8%) 12,801 (38.8%) 1,223 (3.7%)

50

Tumor, infection, trauma, or mechanical impingement on nerve; MS, often no cause found 30

60% female

75% female

90% female

Autonomic changes Local tenderness Causative factors

Common age at onset (years) Gender

Rarely triggered; trigger usually in area of pain

Not restricted to specific cranial nerve distribution Poorly localized Intraoral or facial Can extend to neck or nasolabial fold Starts unilateral May progress to bilateral Common hypesthesia Dysesthesia, paresthesias Not triggered

Variable

The revised classification system utilizes the terms classical and painful trigeminal neuropathy. The term classical refers to trigeminal neuralgia (TN) including both idiopathic cases and those related to vascular compression of trigeminal nerve. The term classical rather than primary has been applied to those patients with a typical history even though a 3481

vascular or other source of compression or demyelination may be discovered during its course. The term painful trigeminal neuropathy (PTN) can then be reserved for those patients in whom a neuroma, tumor, multiple sclerosis (MS), or other cause has been demonstrated. In the past, the term symptomatic trigeminal neuralgia represented these cases. The term persistent idiopathic facial pain has replaced atypical facial pain in the taxonomy. This change reflects a lack of known mechanisms, continued recognition of the potential contribution of multiple etiologic factors to this syndrome, and an emerging knowledge of the pathophysiology of diffuse pain syndromes previously not well understood.5–8 This chapter is organized around the current classification of neuralgias of the cranial nerves and associated disorders. We cover most of these with particular emphasis on TN as this single disorder is best studied among cranial neuralgias and offers the most reports of diverse clinical experiences. Emphasis is made on updates in classification, diagnosis, and treatment of cranial neuralgias. A narrative bridge from past literature and understanding is included to enhance the reader’s understanding of more recent research, insights, and therapeutic approaches.

Classical Trigeminal Neuralgia HISTORY TN was described as early as the first century AD in the writings of Aretaeus (Fig. 66.1). Treatments at that time included bloodletting and the application of bandages containing arsenic, mercury, hemlock, cobra, and bee venom as well as other poisons. Eleventh-century Arab physician Jurjani advanced the vascular compression theory as the causative factor of the severe pain and spasm of this syndrome.9 The first clinical descriptions of TN in the European literature have been ascribed to Johannes Bausch in 1672 and John Locke in 1677. French physician Nicolas André, who in 1756 described five cases of “unbearably painful twitch,” is credited with first recognizing this condition as a unique medical entity. It was André who coined the term tic douloureux (“painful spasm”). English physician John Fothergill similarly published a full account of the syndrome and 3482

presented the paper to the Medical Society of London in 1773 and thus the disorder has sometimes been referred to him.9–11 Other historical names for TN include prosopalgia and neuralgia of the fifth.

FIGURE 66.1 Distribution of the trigeminal nerve (cranial nerve V). The trigeminal nerve gives rise to three divisions: V1, the ophthalmic nerve; V2, the maxillary nerve; and V3, the mandibular nerve. Each division provides sensory innervations to the skin, subcutaneous tissue, and dura mater. The sensory fibers from each division pass through an autonomic ganglion and project the postsynaptic parasympathetic fibers from that ganglion (V1 for the ciliary ganglion, V2 for the pterygopalatine ganglion, and V3 for the submandibular and otic ganglia). V3 additionally supplies motor innervations to four pairs of muscles: temporal, masseter, lateral, and medial pterygoid muscles. (Reprinted with permission from Moore KL, Dalley AF. Clinically Oriented Anatomy. 6th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2009. Figure 9-9.)

In a treatise on neuralgia published by Massachusetts physician E. P. Hurd12 in 1890, the following description of the clinical presentation of TN is found: “Probably no more atrocious suffering is known . . . During the attack, the patients utter loud outcries, toss about on their beds and smite their heads. The muscles of the affected side of the face are often the seat of rapid contractions, convulsive shocks, which have given to this disease one of the names by which it is known, [tic douloureux]. These contractions may be limited to single groups of muscles, as the zygomaticus, or the frontal part of the occipito-frontales . . . then the

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paroxysmal shocks diminish in frequency and intensity, and all becomes calm; the storm has passed, to be renewed again under the same form in a time not far distant.” In the 19th century, susceptibility to this condition was thought to be secondary to hereditary factors (with “the ancestors of the neuralgic subject being either neuralgic or sufferers from hysteria, epilepsy, or other neurosis”), in combination with other factors such as disease, intemperance, or insufficient diet. Medical treatment was ineffective until the introduction of trichloroethylene inhalation in the 1920s. Prior to this, treatment in the late 1800s focused on advocating a nutritious diet, adequate sleep, hydrotherapy, vigorous exercise, and moderation in all things. Patients were advised to avoid strain, reading, and brainwork, which were felt to be instrumental in initiating an attack, as well as alcohol, tobacco, and other stimulants. Successful nonsurgical treatment for TN was reported by such notable 19th-century physicians as Wilhelm Erb and Duchenne de Boulogne. These included the use of electrotherapy in the form of interrupted current and galvanism.11,12 Although early attempts at surgical treatment of TN by Mareschal, surgeon to King Louis XIV of France, around 1750 and Veillard and Dussans in 1768 were unsuccessful, Bell and Magendie’s clarification of the anatomy and function of the trigeminal and facial nerves in the early 19th century is thought to have contributed to subsequent effective surgical treatments for facial pain. Successful neurectomy of the inferior maxillary nerve was reported by Dr. Joseph Pancoast of Philadelphia in 1840 and in 1851. Dr. J. M. Carnochan described successful resection of the maxillary nerve and removal of Meckel’s ganglion from the foramen rotundum to the infraorbital foramen. Subsequent surgical advances in technique were made by Horsley, Taylor, and Coleman in 1891 (middle fossa approach) and Hartley and Krause in 1892 (subtemporal approach). Cushing’s modification to this approach, reported in 1900, involved approaching the trigeminal ganglion from below the middle meningeal artery. His contribution was credited with decreasing the mortality rate of the surgery to 5%. In 1921, Frazier suggested electrical stimulation to clearly define and spare the motor root, and in 1928, Stookey recommended differential sectioning of the sensory fibers of only the affected divisions of the 3484

trigeminal nerve. In 1925, Dandy reported a novel lateral suboccipital or cerebellar approach that preserved the motor root and was associated with little blood loss. Because of his posterior fossa approach, he was able to observe vascular loops impinging on the root entry zone (REZ) in many patients and inferred that this was the cause of TN.11,12 In 1967, Peter Jannetta reported use of the posterior fossa approach with the aid of an operating microscope.13,14 He was able to confirm Dandy’s observations of vascular loops compressing the REZ and subsequently performed a large series of successful surgical treatment of patients with TN using a technique that became known as microvascular decompression (MVD). MVD involves decompression of the nerve by moving the offending vascular loop(s), which are then restrained with nonabsorbent Teflon felt. Due to its low complication and high success rates, MVD has become the surgical procedure of choice for the treatment of intractable TN. The history of the medical and surgical treatments for TN has been thoroughly reviewed by Cole et al.1,11,12

EPIDEMIOLOGY Several epidemiologic studies have collected data on the incidence of TN. Although there is some variation in the reported incidence, in all cases, it continues to be reported as a rare neurologic disorder. A UK study by Brewis et al.15 published in 1966 reported an incidence of 2 per 100,000. This number was thought to be low due to lack of inclusion of patients seen by otolaryngologists. US studies by Kurtzke16 in 1982 and Katusic et al.17 in 1990 reported an incidence of 4 and 4.8, respectively (age and sex adjusted per 100,000 per year). A prospective UK study by MacDonald et al.18 reported an incidence of 8 per 100,000 per year. An epidemiologic study that was also performed in the United Kingdom reported an incidence of 26 per 100,000 per year between January 1992 and April 2002.19 This study reviewed patients diagnosed with TN by general practitioners rather than those referred to specialists. The incidence of TN has consistently been found to be higher in females with a 1.74:1 female/male ratio. Incidence increased with age, usually after age 40 years with peak occurrence between ages 50 and 80 years. Occurrence in patients younger than age 40 years should raise suspicion of 3485

secondary causes such as tumor or MS. TN occurs rarely in children.20,21

ETIOLOGY AND PATHOPHYSIOLOGY The various pathologic findings reported and complex theories advanced in the TN literature attempt to explain the combination of unique clinical features of TN such as the following: • Stereotyped paroxysms of lancinating pain which occur in a limited part of the trigeminal territory • Separation of the trigger area from the painful region • Nonnoxious triggers • Absence of sensory or motor deficit • Characteristic response of TN to antiepileptic medications New diagnostic techniques are now challenging theories that were previously advanced to resolve the many questions which remain regarding the etiology and pathophysiology of TN. Observation of surgical findings led to the 20th-century vascular compression theory of TN. This theory was proposed when Dandy, Gardner, and Miklos recognized the presence of a groove or distortion of the trigeminal nerve root by vessels, or rarely tumors. Jannetta produced convincing evidence that this was the cause of TN by his large series of effective MVD surgeries using the operating microscope. He also demonstrated the absence of trigeminal nerve compression in patients undergoing suboccipital craniotomy for other reasons and in a series of fresh cadaver studies.11,13,14 Jannetta’s review of 4,400 operative procedures from 1969 to 1999 revealed a rostroventral superior cerebellar artery loop compressing the trigeminal nerve either at the brainstem or distally to be the most common cause of vascular compression.22 Compression by the posterior inferior cerebellar, vertebral, and anterior inferior cerebellar arteries has been also been found. Other reported causes of compression of the trigeminal nerve have included meningiomas, epidermoid cysts, arachnoid cysts, and schwannomas arising from the nerve root itself.23 Malis24 proposed petrous ridge and fibrous dural band compression as a cause of TN and demonstrated successful alleviation of TN in a case series of 43 patients undergoing decompression of these fibrous bands. 3486

Kerr25 and King further argued a peripheral versus a central mechanism for TN. Kerr’s25 peripheral hypothesis, based on epidemiology, surgical resections, and cadaver and animal studies, suggested that the paroxysmal neuralgic pain of TN with associated trigger zones is consistent with minor mechanical or pulsatile compression superimposed on predisposing axonal degenerative changes due to hypertension, atherosclerosis, or disease such as MS. He also noted that with aging, replacement of the bony roof of the carotid canal with connective tissue is known to occur. He argued that these degenerative bony changes would permit pulsatile contact with areas of the ventral ganglion which correlate with the anatomic area in which most trigger zones are known to occur.14,25 King argued a central etiology for TN based on injections of alumina gel into the spinal nucleus of the fifth nerve in cats which resulted in a syndrome of dysesthesia of the face with overreaction to tactile stimulation.21,25 Calvin et al.26 proposed electrophysiologic mechanisms which required both peripheral and central events to produce the symptoms of TN. Fromm and colleagues27 published studies which implicated an initial peripheral injury followed by failure of central inhibitory mechanisms as causative factors leading to the onset of TN. The compression theory of TN, described by the findings of Dandy, Gardner, Miklos, Jannetta, and others, postulates a mechanism for production of the complex of TN symptoms that involves degenerative changes to the central peripheral myelin transitional zone of the trigeminal nerve due to either direct or indirect effects of compression along the course of the nerve from the pons to its entry into Meckel’s cave.28 Ultrastructure analysis of trigeminal root biopsy specimens of patients with TN obtained during surgery for MVD support this theory. They reveal axonopathy, axonal loss, demyelination, and axon apposition without intervening glial processes consistent with the “ignition hypothesis” of TN. This model correlates the mentioned pathophysiologic changes with the paroxysmal symptoms of TN based on similar foci of nerve root demyelination and juxtaposition of axons which have been demonstrated in patients with MS and TN together with experimental studies which indicate that this anatomic arrangement favors the ectopic generation of spontaneous nerve impulses and their ephaptic conduction to 3487

adjacent fibers. These studies also demonstrate that spontaneous nerve activity is likely to be increased by deformity of the nerve and frequently associated pulsatile vasculature.29–32 More conclusive evidence supporting both peripheral and central etiologies of TN can be found in electrophysiologic studies. One such study has revealed evidence of peripheral damage to small Aδ fibers of the trigeminal nerve near the REZ in the brainstem. Findings revealed demyelination and axonal degeneration or isolated advanced axonal damage on the symptomatic side in patients with classic TN (CTN). In patients with TN and concomitant chronic facial pain, facilitation of central trigeminal processing at the supraspinal level was found. This is consistent with divergent results of MVD in these two groups of patients. Outcome data from MVD in patients with TN shows excellent or good pain relief in 97% immediately postoperatively and in 80% of those with 5-year follow-up. In patients with TN and concomitant persistent facial pain, previously defined as “atypical,” only 51% show good or excellent pain relief at 5 years.33,34 Pre- and postoperative electrophysiologic recording sessions revealed that relief of pain correlates with normalization of previously prolonged trigeminal reflex responses. Electrophysiologic testing has also been able to differentiate TN from symptomatic TN with a high degree of sensitivity and specificity (94% and 98%).35 Although not practical for routine patient diagnostic purposes, this research is helpful in understanding the decreased response rates in these distinct groups of patients.

SYMPTOMS AND SIGNS Clear and concise criteria are essential in establishing a diagnosis and conducting research for TN. This is particularly true for a condition such as TN where there is no objective laboratory test to confirm the clinical diagnosis. White and Sweet36,37 helped to achieve these goals by publishing precise and succinct criteria which facilitated early and accurate clinical recognition of TN and facilitated subsequent research (Table 66.2). The International Headache Society recently established new clinical diagnostic criteria for TN as part of the ICHD-III, which have gained wide acceptance and reflect a significant advance that should further promote 3488

communication and stimulate research regarding TN. TABLE 66.2 The International Classification of Headache Disorders, 3rd Edition (ICHD-III) (Beta Version), Diagnostic Criteria for Classical Trigeminal Neuralgia ICHD-III Beta Diagnostic Criteria for Classical Trigeminal Neuralgia Description: Trigeminal neuralgia developing without apparent cause other than neurovascular compression Diagnostic criteria: A. At least three attacks of unilateral facial pain fulfilling criteria B and C B. Occurring in one or more divisions of the trigeminal nerve, with no radiation beyond the trigeminal distribution C. Pain has at least three of the following four characteristics: 1. Recurring in paroxysmal attacks lasting from a fraction of a second to 2 min 2. Severe intensity 3. Electric shock-like, shooting, stabbing, or sharp in quality 4. Precipitated by innocuous stimuli to the affected side of the face D. No clinically evident neurologic deficit E. Not better accounted for by another ICHD-III diagnosis Classical Trigeminal Neuralgia, Purely Paroxysmal Description: Trigeminal neuralgia without persistent background facial pain Diagnostic criteria: A. Recurrent attacks of unilateral facial pain fulfilling criteria for classical trigeminal neuralgia B. No persistent facial pain between attacks C. Not better accounted for by another ICHD-III diagnosis Comment: Classical trigeminal neuralgia, purely paroxysmal, is usually responsive, at least initially, to pharmacotherapy (especially carbamazepine or oxcarbazepine). Classical Trigeminal Neuralgia with Concomitant Persistent Facial Pain Previously used terms: Atypical trigeminal neuralgia; trigeminal neuralgia type 2 Description: Trigeminal neuralgia with persistent background facial pain Diagnostic criteria: A. Recurrent attacks of unilateral facial pain fulfilling criteria for classical trigeminal neuralgia B. Persistent facial pain of moderate intensity in the affected area C. Not better accounted for by another ICHD-III diagnosis

TN has well-described pathognomonic features which differentiate it from other types of facial pain. It is characterized by intense paroxysmal, electrical pain which may be accompanied by muscular spasms on the affected side of the face. The attacks generally last from fractions of a 3489

second to 2 minutes and are followed by a refractory period during which no pain can be triggered. Pain is abrupt in onset and termination. Between paroxysms, “The patient is in dreaded fear of the next flash of pain.”38 Occurrence of spontaneous remission of pain for weeks, months, or years is another feature of TN which may complicate accurate assessment of therapies.39 The pain of TN is limited to the distribution of one or more divisions of the trigeminal nerve and occurs most frequently in V2, V3, or a combination of V2 and V3. First division pain is rare in TN.40 The pain of TN occurs on the right side of the face more often than the left with predominance ranging from 59% to 66%. Reviews have reported a 3% to 5% occurrence of bilateral pain. Pain rarely occurs on both sides simultaneously. Rather, the painful spasms occur on one side for weeks or months and then, following a period of remission, occur on the opposite side.38,41–43 Pain occurring on both sides simultaneously or the presence of an abnormal neurologic exam should raise concerns of a secondary etiology such as tumor or MS.44,45 Trigger zones, or areas of the face or head that upon nonnoxious stimulation elicit a TN episode, are also a characteristic feature of TN. In two large series of patients with TN, trigger zones were reported to be present in 91%.36,46 Trigger zones may be found in more than one division of the trigeminal nerve. The pain can also be triggered in a different zone from the trigger. The central part of the face near the nose and lips is the area in which triggers most often occur (Fig. 66.2). Touch and vibration have been found to be the most effective stimuli.47 Attacks are reported to be set off by washing the face, shaving, talking, chewing, brushing of the hair and scalp, or a light breeze on the face of a patient. This can lead to poor hygiene, weight loss, dehydration, and social withdrawal. The ICHDIII criteria also list precipitation of pain paroxysms by “trigger areas” or “trigger factors.” These triggers may include stimuli outside of the trigeminal distribution, such as a limb movement, and may include other sensory stimulation such as bright lights, loud noises, or tastes.2

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FIGURE 66.2 The most likely sites of triggering for tic douloureux are in the anterior face.

Pre-TN is an additional syndrome reported initially in 1949 by Symonds.48 In these patients, a dull aching or burning pain involving a part of the upper or lower jaw develops for hours, days, or weeks and may be triggered by jaw movements or liquids. They may have several bouts of this pain with remissions for weeks, months, or years followed by sudden onset of the paroxysmal pain of TN. Carbamazepine (CBZ) and/or baclofen have been effective in most cases. Unfortunately, some patients undergo multiple dental procedures before the syndrome is recognized as an early sign of TN.48–50

DIFFERENTIAL DIAGNOSIS The diagnosis of TN is made essentially on clinical information. Differentiating TN from PTN and other causes of facial pain is of great relevance in treating underlying disease or lesions and for instituting effective medical or surgical therapy. This requires a thorough history to obtain the patient’s detailed description of defining characteristics, frequency and duration of pain, exacerbating factors, presence or absence of triggers, and associated symptoms. A complete physical exam is necessary to confirm the presence or absence of neurologic deficits. Appropriate tests, such as magnetic resonance imaging/angiography (MRI/MRA) with fast imaging employing steady-state acquisition 3491

(FIESTA) is often indicated to confirm the suspected diagnosis and exclude secondary causes. Development of time-of-flight (TOF) MRA, 3T MRI and 3D T2-weighted driven equilibrium (DRIVE) MRI provide excellent multidimensional images of brain structures, neighboring blood vessels, nerves, and cerebrospinal fluid. These technologic advancements help to locate exactly the site of neurovascular conflict (NVC) loop or any other secondary cause such as plaque and/or space occupying lesions. Because TN is itself a rare disease, rare presentations of other disease processes fulfilling the diagnostic criteria of TN may require close examination. Rare cases of sinusitis presenting as TN involving first and second division of the trigeminal nerve have been reported with one report of fatal progression in a diabetic patient.51,52 Because involvement of the ophthalmic branch occurs in less than 5% of TN patients, a high degree of suspicion is indicated in such cases. As the example earlier illustrates, it is important to differentiate TN and PTN because PTN may be secondary to a progressive lesion or disease process. Expedient treatment of the underlying disease process or lesion in these cases may limit patient morbidity and mortality and improve overall patient outcome. Although most patients with malignant and benign tumors present with sensory deficit or persistent idiopathic facial pain, the literature does contain reports of patients with tumors initially presenting with TN and no neurologic deficits.53,54 MS is a common cause of secondary TN which should be considered in any person under 50 years who presents with TN. Brainstem auditory evoked potential and blink reflex testing are sensitive methods for examining patients with TN. When the patient’s neurologic exam is abnormal or if the patient does not respond to standard medical therapy, increasingly sensitive methods of CT or MRI/MRA result in accurate diagnosis in almost all cases.34,55–58 The cranial neuralgias covered in greater depth later in this chapter must also be differentiated from TN. Glossopharyngeal neuralgia presents with paroxysmal, electrical pain, spontaneous remissions, and triggers associated with swallowing, chewing, coughing, and talking in some patients. Pain occurs most frequently in the ear, tonsils, larynx, and tongue and may radiate to the neck, shoulder, or face. In less than 10% of cases, 3492

there is an association with TN. Glossopharyngeal neuralgia is also rarely found in patients with MS.59 Intense and stabbing pain localized in the depth of the ear canal is also described in by patients with geniculate ganglion or nervus intermedius neuralgia, a rare disorder affecting the sensory branch of the facial nerve. Other cranial neuralgias which may be confused with TN include “tic convulsif” and hemifacial spasm. Patients with tic convulsif present with severe otalgia combined with unilateral facial spasm. This rare neuralgic disease is thought to be due to vascular compression of the sensory and motor components of the facial nerve at their junction with the brainstem. Hemifacial spasm is a neuralgia involving the facial nerve which is characterized by intermittent, involuntary, irregular, unilateral contractions of muscles supplied by the ipsilateral facial nerve.60–62 Cluster headache pain is unilateral and usually occurs in the ocular, frontal, and temporal areas (although it may occur in the infraorbital and maxillary regions). It usually presents initially in men who are between 18 and 40 years old. Pain is severe, constant, stabbing, burning, and throbbing with associated ipsilateral ptosis, miosis, tearing, and rhinorrhea. Bouts often occur for several weeks to months with one to three attacks in a 24hour period. Patients will not infrequently be woken from sleep with an attack. Pain-free intervals of several months may occur between bouts of attacks. These headaches tend to respond to ergot preparations, prednisone, and methysergide.63 Pain arising from a group of disorders known as trigeminal autonomic cephalgias may also be confused with TN. These include cluster headaches, chronic paroxysmal hemicranias, and short-lasting unilateral neuralgiform headaches with conjunctival injection and tearing (SUNCT). Knowledge of their epidemiology and a careful history will assist with accurate diagnosis.64 Chronic paroxysmal hemicrania usually occurs in women. It generally involves the ocular, frontal, and temporal areas. Occasionally, it may involve the occipital, infraorbital, aural, mastoid, and nuchal areas on the same side. Attacks vary in frequency in duration but may last 5 to 45 minutes. Pain is excruciating and is associated with ipsilateral conjunctival 3493

injection, lacrimation, nasal stuffiness, and rhinorrhea. These headaches respond well to indomethacin.65 SUNCT is a rare syndrome which typically affects males between age 23 and 77 years of age. It is characterized by unilateral burning, stabbing, or electric pain which is usually near the eye. Episodes generally last from 15 to 120 seconds, and multiple episodes can occur daily. Patients present with cutaneously triggered attacks in up to 75% of cases. These attacks are differentiated from TN by lack of a refractory period and presence of associated conjunctival injection, tearing, rhinorrhea, and facial sweating or flushing. As in TN, primary and secondary forms occur. Secondary forms may be due to cerebellopontine angle arteriovenous malformation, infection, and pituitary tumors.64,66,67 Painful ophthalmoplegia such as seen in Tolosa-Hunt syndrome, ocular diabetic neuropathy, ophthalmic herpes zoster (HZ), and ophthalmoplegic migraine must also be differentiated from TN. Tolosa-Hunt syndrome is a painful ophthalmoplegia caused by granulomatous inflammation in the cavernous sinus. It is characterized by episodic unilateral or bilateral orbital pain associated with paralysis of one or more of the third, fourth, or sixth cranial nerves. Involvement of the V2 and V3 divisions of the trigeminal nerve, the optic nerve, and the facial nerve has been reported. The pain is typically described as steady gnawing or boring. Spontaneous resolution may be followed by remissions and relapses of symptoms. Involvement of the optic, facial, acoustic, or trigeminal nerves has been reported. Treatment with corticosteroids results in resolution of pain and paresis in most cases within 72 hours. Failure of response to steroids or recurrence of symptoms should prompt further workup.2 Ocular diabetic neuropathy may present as eye and forehead pain associated with ocular cranial nerve paresis (usually cranial nerve III). As in other diabetic neuropathies, pain improves with glucose control, treatment with tricyclics, and anticonvulsant medications.2 HZ involving the trigeminal ganglion affects the ophthalmic division in the majority of cases. Ophthalmic herpes may be accompanied by palsies of the third, fourth, and/or sixth cranial nerves or with facial palsy. Burning pain, sometimes accompanied by neuralgic pain, is typically 3494

followed by vesicular eruption within 7 days. Pain may resolve or persist as postherpetic neuralgia.2 Ophthalmoplegic migraine is a rare clinical entity presenting as recurrent migraine-like headaches accompanied by paresis of one or more of the ocular cranial nerves in the absence or other intracranial lesion. There may be a latent period of up to 4 days from onset of headache to onset of ocular cranial nerve paresis. Demonstration on MRI of thickening and enhancement of the cisternal part of the occulomotor nerve in these patients suggests the etiology of recurrent demyelinating neuropathy.2 Other common causes of facial pain include pain caused by sinusitis or other inflammatory conditions involving the eyes, tumors of the nose or sinuses, disorders of the teeth, jaws, or related structures such as temporomandibular joint (TMJ) pain and posttraumatic pain of the peripheral branches of the trigeminal nerve. Sinusitis presents with pain involving the periocular, frontal, nasal, and maxillary areas. It is generally described as deep and constant and is associated with purulent discharge, fever, and fullness of the nose and ears. CT reveals opacification of the sinuses. In older patients or immunocompromised individuals, tumors or mycoses should be ruled out.68 Pain related to the teeth is often triggered by chewing or by hot, cold, sweet, and sour substances. It may have occasional sharp and shooting characteristics but usually will also have a diffuse, continuous aching, throbbing, or burning component which is difficult to localize. This type of pain is also differentiated from TN by lack of trigger zones or periods of spontaneous remissions. TMJ pain and myofascial pain related to the jaw is described as aching, burning, or cramping pain associated with use of the jaw or muscles of mastication. Clicking and other signs of joint dysfunction are associated features.69,70 These topics are discussed in further detail in Chapter 67 on facial pain within this text. Trauma to peripheral branches of the trigeminal nerve after surgery, blunt or penetrating trauma, or dental procedures generally presents as constant pain with burning, tingling, or stabbing components as well as a dull background pain. One study comparing patients with facial pain after nerve injury to patients with pain of spontaneous origin found decreased 3495

temperature and tactile thresholds and abnormal temporal summation of pain in patients with nerve injury but not in patients with spontaneous pain.71 Persistent idiopathic facial pain is typically described as a continuous, dull ache that is poorly localized. It fluctuates in intensity and is generally unresponsive to analgesics. It occurs most frequently in women with a mean age of 44.6 years and range of 17 to 87 years. Most of these patients have multiple diagnoses including depression, headache, neck and back pain, and irritable bowel disease. Neurologic and radiologic exams are normal by definition. These patients often have undergone multiple dental procedures.72

TREATMENT Treatment—Medical Management The use of the antiepileptic medications for the treatment of TN was first suggested by Bergougan73 in 1942. His trial of phenytoin in these patients was based on Trousseau’s theory that the paroxysmal pain of TN was similar to the paroxysmal brain activity occurring in patients with epilepsy.74 Medical therapy of TN is largely based on the efficacy of drugs that have undergone double-blind evaluation. This is particularly important in light of the need to obtain expedient relief of the excruciating pain of the paroxysms suffered by these patients with proven therapies. The occurrence of unpredictable periods of prolonged spontaneous remission in patients with TN creates a greater likelihood of attributing successful treatment of this disease to ineffective agents. Surgical consultation should be sought early for patients with structural lesions and in patients refractory to medical treatment. For patients unresponsive to medical therapy who are not surgical candidates due to coexisting medical conditions, treatment with radiation or percutaneous therapies, as described in the following paragraphs, may be effective. Of the medications studied in the treatment of TN, CBZ is considered the drug of choice according to the European Federation of Neurological Societies and the Quality Standards Subcommittee of the American Academy of Neurology.75 Current evidence suggests that oxcarbazepine 3496

(OXC) should be the first-line agent in patients with intolerable side effects or inadequate pain control with CBZ.76 The combination of CBZ with baclofen or lamotrigine has been shown to be effective in cases where patients do not respond to CBZ alone or in whom it loses efficacy.76 CBZ is an anticonvulsant, structurally similar to a tricyclic antidepressant, imipramine. It is metabolized primarily by cytochrome P450 isoenzyme CYP3A4. It slows the recovery rate of voltage-gated sodium channels, modulates activated calcium channel activity, and activates the descending inhibitory modulation system. Although it is one of the oldest antiepileptic drugs and many new drugs in this class exist with fewer side effects and fewer drug–drug interactions, four placebocontrolled studies and a systematic review have established its effectiveness in reducing the intensity and frequency of attacks and the number of triggers with a combined number needed to treat of 1.7.77–81 In a cumulative analysis, CBZ showed a 58% to 100% success in achieving pain control, whereas in comparison, a placebo showed a mere 0% to 40% response.35 CBZ is the only U.S. Food and Drug Administration (FDA)-approved drug for TN. Although CBZ has been shown to have an initial response rate of over 70% in TN patients, one long-term study which evaluated its efficacy over a 16-year period reported that by 5 to 16 years, only 22% of participants continued to have effective relief with 44% requiring additional or alternative treatment.82 The recommended starting dose is 100 to 200 mg twice daily with gradual increase by 200 mg until pain relief or intolerable side effects occur. The typical maintenance dose of CBZ is 600 to 1,200 mg daily in divided doses. Therapeutic level is 4 to 12 µg/mL. Side effects occur in up to 40% of patients initially but generally subside in most patients after a few weeks. The HLA-B*15:02 allele is a genetic susceptibility marker in Asians that is associated with an increased risk of developing Stevens-Johnson syndrome and/or toxic epidermal necrolysis. Screening for this allele in patients with Asian ancestry is recommended before to starting CBZ. If genetic testing results are positive for the presence of at least one copy of the HLA-B*15:02 allele, CBZ should be avoided. The biologic half-life of CBZ is 30 to 35 hours when first administered. This decreases to 12 hours with autoinduction of liver 3497

enzymes which occurs after a few weeks. Because pain relief appears to be closely related to serum level, slow-release formulations may be effective in maintaining serum drug concentration.83 The efficacy of CBZ is limited by side effects that include drowsiness, dizziness, constipation, nausea, and ataxia. More severe adverse effects include rashes, leukopenia, abnormal liver function, and, rarely, aplastic anemia and hyponatremia due to inappropriate secretion of antidiuretic hormone. Compared with placebo, it has a number needed to harm of 3 for minor side effects and 24 for major side effects. Monitoring of complete blood count, liver function, and sodium is recommended.84–86 OXC is the 10-keto analogue of CBZ. Due to its better tolerability, fewer drug–drug interaction, and proven efficacy, OXC is often considered as an initial medication for the treatment of TN. In three head-to-head randomized controlled trials (RCTs), CBZ and OXC both proved to be equally effective in 88% of patients who experienced greater than a 50% reduction in pain attacks.76 Tolerability was reported as “good” to “excellent” by 62% of patients receiving OXC compared with 48% of patients receiving CBZ. In comparison to CBZ, OXC only needs the monitoring of serum sodium levels. Lamotrigine also decreases repetitive firing of sodium channels by slowing the recovery rate of voltage-gated channels. In a small, doubleblind, crossover, RCT evaluating patients on CBZ or phenytoin who were refractory to treatment with these medications, lamotrigine (400 mg) versus placebo increased the number of patients who improved after 4 weeks of treatment.87 A case series also suggests its efficacy as monotherapy for TN. Side effects include dizziness, constipation, nausea, and drowsiness. Stevens-Johnson syndrome has been reported to occur in 1 in 10,000 patients taking lamotrigine. Its utility as a single agent may be limited by its long titration schedule.88,89 Phenytoin is one of our oldest anticonvulsants with a molecular structure similar to the barbiturates. It acts by blocking sodium channels in rapidly discharging neurons and by inhibiting presynaptic glutamate release. Although it is has been used longer than any other antiepileptic drug in the treatment of TN, there are no controlled trials supporting its efficacy. Uncontrolled observations report that it is effective in relieving 3498

symptoms in 23 of 30 patients when 3 to 5 mg/kg was given intravenously for acute therapy.90–92 Phenytoin interacts with many drugs including digoxin and warfarin. Severe rashes can occur in 1 of 10 to 20 patients. There is also a possibility of hyperglycemia, hepatotoxicity, gingival hyperplasia, and megaloblastic anemia. Fosphenytoin, a prodrug of phenytoin that is better tolerated intravenously, also appears to be effective in acutely ill patients.93 Baclofen is an analog of the neurotransmitter γ-aminobutyric acid. Its effectiveness in the treatment of TN may be due to depression of excitatory synaptic transmission in the spinal trigeminal nucleus.94 In three small RCTs, baclofen was shown to be effective as both monotherapy and add-on therapy to CBZ in the treatment of patients with TN. The starting dose is 5 to 10 mg three times a day, with gradual titration to a maintenance dose of 50 to 60 mg per day. Sedation, dizziness, and dyspepsia can occur with treatment. The dose should be adjusted in patients with decreased renal function because baclofen is excreted primarily by the kidneys. Baclofen has central nervous system and cardiovascular depressant effects, and thus, careful titration should occur in patients on other sedating medications and on antihypertensive agents. Antidiabetic medications may need to be adjusted secondary to increases in blood glucose. Baclofen should be discontinued slowly because seizures and hallucinations have been reported upon withdrawal.95–97 Intranasal lidocaine has shown some efficacy in trials. Intranasal 8% lidocaine spray was examined in 25 patients with V2 division TN in an RCT crossover study resulting in moderate or better pain relief in 23 of 25 subjects receiving lidocaine spray and 1 subject receiving placebo. Relief lasted from 0.5 to 24 hours.98 In a small open-label perspective study, 53 patients with TN received pregabalin 150 to 600 mg daily and were followed for 1 year. After 8 weeks of treatment, a quarter of the patients were pain-free and almost half of them had significant pain reduction with an overall response rate of 74%.99 In a small open-label pilot study, 4 out of 10 subjects taking levetiracetam for TN responded with 50% to 90% improvement in pain intensity.100 In another small open-label study, 23 patients who took levetiracetam for TN reported a 62% decrease in daily episodes of pain.101 3499

Uncontrolled observations and case studies have shown efficacy in the treatment of TN with valproic acid, clonazepam, and pimozide.102–105 The efficacy of pimozide is severely limited by its significant side effects which include Parkinsonism, mental retardation, and memory impairment. The anticonvulsant drugs gabapentin and topiramate have been shown to be effective in the treatment of neuropathic pain; however, there are no controlled studies of their effectiveness in the treatment of TN. Small case series report their effectiveness in the treatment of symptomatic TN secondary to MS.106–108 In a meta-analysis of effectiveness in TN, overall topiramate results did not differ from CBZ after 2 months of treatment.109 A small prospective randomized study and a case report demonstrated relief of TN symptoms with injection of botulinum toxin (16 to 100 units).110,111 A six-patient retrospective analysis and an eight-patient prospective trial of intravenous lidocaine, in doses ranging from 2 to 5 mg/kg/hour, resulted in partial or complete relief of TN pain paroxysms provoked by vibratory symptoms.47,112 In summary, the current literature supports CBZ as first-line therapy for TN, although data also supports use of OXC as first-line therapy, particularly in patients refractory to CBZ monotherapy or who have intolerable side effects. Those patients who do not respond to monotherapy of CBZ or OXC may benefit from combination therapy with gabapentin, lamotrigine, levetiracetam, pregabalin, topiramate, or baclofen. Intravenous phenytoin, fosphenytoin, or lidocaine or botulinum toxin injections may be effective in refractory cases of TN for treatment of severe, frequent attacks which may affect the patient’s ability to eat or drink. Infusions should be conducted in a carefully monitored setting with appropriate medical attention and emergency equipment available. Due to reports of spontaneous intermittent or permanent remissions of TN, periodic withdrawal of medications is warranted in patients who have prolonged pain-free periods on oral medications.

Treatment—Nerve and Neurolytic Blockade Local anesthetic injection or infusion has been used for diagnostic purposes and for temporizing treatment in patients with unbearable pain refractory to medical therapy and/or awaiting MVD.113 No controlled 3500

studies of nerve blockade for relief of TN have been reported, and controlled studies are needed to validate this approach. Small case series include significant reduction of pain and triggers in five elderly patients for a median of 2 months subsequent to injection of the infraorbital nerve in patients with second division TN using a combination of 4% tetracaine dissolved in 0.5% bupivacaine. Another study looking at relief of pain following injection of the infraorbital nerve reported greater than 3 months of relief with 4% tetracaine and 0.5% bupivacaine (compared to 3 days or less with 0.5% bupivacaine or 1% mepivacaine alone).114,115 A combination of ketamine, morphine, and bupivacaine produced similar pain relief and duration as reported following a series of injections of symptomatic peripheral trigeminal nerve branches in patients with TN.116 A case report of stimulator-guided mandibular and maxillary division nerve blockade using a combination of lidocaine, bupivacaine, clonidine, and fentanyl at monthly intervals for 1 year in two patients describes prolongation of relief after 3 months and pain-free status with no recurrence at 9-month follow-up. No sensory or motor disturbances were reported.117 Peripheral injections are of value in elderly patients who have not responded to medical or other surgical therapies. Standard precautions to avoid intravascular injection of drugs should be taken, and care should be taken when performing V2 and V3 blockade as total brainstem anesthesia with respiratory arrest following extraoral trigeminal V2 to V3 blocks has been reported.118 Careful aspiration, fluoroscopic guidance when available, utilizing contrast (when no contraindication exists), and digital subtraction can decrease the risk of intravascular or intrathecal injection. As with intravenous infusions, injections should be performed in a monitored setting with appropriate medical attention and readily available emergency equipment. Alcohol, phenol, or glycerol injection has long been reported in the treatment of TN. Percutaneous gangliolysis using glycerol is discussed under surgical techniques. A retrospective case audit of patients who received peripheral alcohol injections for TN from 1994 to 1999 found a mean duration of effect of 11 months.119 In a retrospective review of 100 patients with TN who were treated with 1 to 1.5 mL of absolute alcohol 3501

injection, 86% reported pain control. The duration of analgesia varied widely from a period of 2 to 56 months.120 In a prospective study from South Korea, 98 patients who received mandibular nerve blocks with alcohol had pain relief. At 1 year, 90.4%, at 2 years 69%, at 3 years 53.5%, and at 7 years 33% remained pain-free.121 Glycerol injections provided a mean of 7 months of pain relief.122 A retrospective analysis of 157 cases of intractable idiopathic TN treated with peripheral glycerol injections reported an initial 98% success rate with 60 patients having recurrent pain between 25 and 36 months. The study reports complete or near-complete pain relief in 154 patients at 4 years (with inclusion of patients with recurrent pain who were reinjected).123 Postinjection facial swelling, discomfort, and numbness are reported complications of alcohol injections. More serious complications occurred in 3 of 413 injections over a 20-year period.124 A small case series of 60 peripheral injections in 18 patients of the infraorbital, supraorbital, and mandibular nerves using 10% phenol in glycerol reported 87% initial marked or total pain relief and a median of 9 months of continued relief. Most patients with recurrent pain requested a repeated procedure rather than surgery or a ganglion nerve block. No serious complications or dysesthetic pain were reported. In patients with facial sensory loss, sensation was recovered within 6 months and was well tolerated.125 In a randomized control trial of 42 patients with TN, 68% of the subjects who received botulinum toxin type A (BTX-A) in comparison to only 15% of the placebo group subjects, showed significant improvement in pain intensity and frequency after 2 weeks.126 In an RCT, both 25 and 75 units of BTX-A were better (70.4% and 86.2%) than placebo (32.1%) in the treatment of TN at 8 weeks follow-up. There was no significant difference between two doses of BTX-A.127

Treatment—Surgical Surgical therapies are aimed at either damaging or destroying pain transmitting nerve fibers or relieving pressure on the nerve from vascular loops, fibrous bands, or mass lesions. Radiation therapy may relieve pain in patients who are not surgical candidates and who are refractory to medical management of TN.

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Microvascular Decompression MVD is performed under general anesthesia using a microscope to visualize the trigeminal nerve as it leaves the pons via a suboccipital craniectomy. Compression of the nerve by a vein or artery is relieved by repositioning the artery or coagulating the vein. Although MVD is invasive, it is associated with the best long-term outcome and overall mortality and complication rates are low. An analysis of long-term followup data of 1,324 patients with TN who underwent MVD between 1976 and 2000 revealed an increase in the postoperative cure rate from 92.9% to 96.7% in patients operated on after 1986. Recurrence rate decreased from 10.2% to 6.5% in the patients operated on between 1986 and 2000 compared to the patients who underwent MVD between 1976 and 1986.128 Barker et al.129 reported results of 1,185 patients who underwent MVD over a 20-year period. It was noted that the rate of complications was significantly reduced, and no deaths occurred after 1980 when intraoperative monitoring of brainstem evoked response was used. Female gender, symptoms lasting more than 8 years, venous compression of the terminal REZ, and the lack of immediate postoperative cessation of pain were significant predictors of eventual recurrence.129 Endoscopic microvascular decompression (E-MVD) was used in 47 patients with TN. In the follow-up period of 15 ± 8 months after the surgery, patients reported overall excellent pain control. One patient had permanent hearing loss as a complication of the surgery. E-MVD was deemed to be safe and effective in the treatment of TN.130 In a comparative study of endoscopic versus traditional microscopic microvascular decompression (M-MVD) for TN, 167 subjects were followed up from 2006 to 2013. Out of 167 patients, 93 patients underwent M-MVD and 74 underwent E-MVD. Overall outcome and complications rates were comparable.131 In a retrospective comparative analysis of 225 patients who underwent MVD and 206 having undergone percutaneous trigeminal radiofrequency rhizotomy, 64% of patients who underwent MVD remained completely pain-free 20 years postoperatively versus 50% risk of recurrence of pain 2 years after radiofrequency rhizotomy.132 Hospital and surgeon volume was found to be a significant factor affecting morbidity in a study conducted from 1996 to 2000 by Kalkanis and associates.133 The overall mortality 3503

rate was 0.3% with volume and mortality not statistically related. The rate of discharge other than to home was 3.8%, with hospitals and/or surgeons who performed the surgeries at low volumes being 5.1% as compared to 1.6% for high volume.133 Percutaneous rhizotomy or gangliolysis is useful in treating the elderly or debilitated patient who is refractory or intolerant to medical therapy and for whom surgery is not warranted due to risk factors. Gangliolysis is performed under fluoroscopic guidance by placing a needle percutaneously through the foramen oval and advancing it to the trigeminal cistern. The three techniques currently used for gangliolysis include percutaneous radiofrequency ablation/thermocoagulation, trigeminal ganglion compression, and retrogasserian glycerol rhizolysis. Percutaneous radiofrequency trigeminal gangliolysis involves the use of radiofrequency to create anatomically distinct lesions in cycles of 45 to 90 seconds at 60° to 90° C. Percutaneous trigeminal ganglion compression is performed under general anesthesia utilizing a Fogarty catheter that is inserted via a 14G catheter into the trigeminal cistern and inflated with radiocontrast to compress the gasserian ganglion. Careful observation of heart rate and blood pressure is required due to the possibility of severe bradycardia and hypotension which may require treatment with atropine and vasopressors. Percutaneous glycerol rhizolysis is performed in a sitting position. After confirmation of needle location with radiocontrast, 0.1 to 0.4 mL of anhydrous glycerol is injected into the cistern of Meckel’s cave. In a prospective longitudinal study of 48 patients with TN, 31 had pure TN and the remainder presented with atypical facial pain and mixed TN. They were treated with radiofrequency thermocoagulation of the gasserian ganglion with overall favorable outcomes after the treatment. The mean time for reoccurrence of pain was 40 months for the CTN cohort and 36 months for TN patients with atypical facial pain.134 An analysis of 100 subjects who underwent percutaneous balloon compression (PBC) of the trigeminal rootlets showed initial pain relief in 90% of patients. Twenty months was the median time to be symptom-free without the help of any medications.135 A systematic review of radiofrequency ablation/thermocoagulation techniques for the treatment of TN demonstrated complete pain relief without medication in a median of 88% 3504

in patients undergoing radiofrequency thermocoagulation at 6-month follow-up.136 This dropped to 61% at the 3-year follow-up. Retrospective analysis of patients undergoing percutaneous glycerol rhizolysis showed complete pain relief in 84% of patients with or without medication at 6 months following treatment. This dropped to a median of 54% at 3-year follow-up. Complications with any of the ablative techniques described earlier have been noted to include dysesthetic disturbances in 4% to 10% of patients treated. Up to 30% of patients treated with radiofrequency thermocoagulation experienced significant permanent sensory loss. Other complications included corneal numbness and keratitis, anesthesia dolorosa, transient masseter weakness, cranial nerve deficits, and vascular injuries. The complication rate was highest in patients undergoing radiofrequency thermocoagulation, although most complications were transient.136 Ablative procedures are less invasive than MVD and are generally associated with a high initial response rate. Recurrence is common, however, and the incidence of facial numbness is higher than with MVD. Patients who have a recurrence of TN after an ablative procedure can successfully undergo MVD.129 Stereotactic Radiosurgery The first radiosurgical device was developed in the 1950s by Professor Lars Leksell at the Karolinska Institute in Stockholm. This work resulted in the development of the gamma knife which is able to precisely irradiate small intracranial targets with gamma ray photons. Of 149 patients who received gamma knife stereotactic radiosurgery (GKS) for TN, 76%, 69%, and 60% reported pain control at 1, 2, and 3year follow-up, respectively. Twenty-seven patients were treated with repeat GKS; 70% and 62% reported freedom from pain at 1 and 2 years.137 Pain relief with GKS occurs after a lag time of about 1 month.3,138 A systematic review of these data found that approximately 75% of patients report complete relief within 3 months, and 50% of patients can permanently stop drug therapy after surgery. Sensory disturbances (e.g., numbness, paresthesias, and dysesthesias) are the most frequent 3505

complications.138 CyberKnife radiosurgery is a more recently developed system to incorporate a miniature linear accelerator mounted on a flexible, robotic arm. This system offers targeting accuracy without the need for the invasive head frame and is able to treat tumors anywhere in the body. Although GKS has the advantage of over 30 years of clinical use, observational studies using the CyberKnife system for the treatment of TN report a 92.7% initial success for pain relief at a median latency to pain relief of 7 days. Long-term response rate at 11 months was 78%.139 Larger study groups and longer follow-up is needed to further evaluate long-term pain relief and complications. In an analysis of outcomes in 27 patients who had refractory TN who received CyberKnife radiosurgery, 42.9% were pain-free within 1 month after the procedure. The time for reoccurrence of pain widely varied.140 Although radiosurgery is less effective than MVD, it is an effective, minimally invasive treatment option for patient’s refractory to medical therapy who are not surgical candidates or in whom the risks of surgery are not acceptable. Patients who fail to respond to radiosurgery or who have recurrence of symptoms may respond to repeat treatment.141,142 In a retrospective analysis, 870 patients who received stereotactic radiosurgery for TN (95% CTN), based on treatment dose, were divided into three groups: 352 patients received the dose of ≤82 Gy, 85 patients received 83 to 86 Gy, and 433 patients ≥90 Gy. In a 4-year follow-up, pain control was 79%, 82%, and 92%, respectively.143 In a recent analysis, the stereotactic radiosurgery outcome of 112 patients who had type 1 (TN1) or 2 (TN2) TN (old classification) and treated between 1994 and 2016 was reviewed. At 5, 10, and 15 months, symptom relief was 75%, 90%, and 90% for TN1 and 47%, 77%, and 87% for TN2. In a long-term follow-up at 24 and 36 months, 67% and 52% for TN1 and 32% and 32% for TN2 reported symptom relief.144 Peripheral Neurectomy Surgical destruction of the peripheral branches of the trigeminal nerve is indicated for patients who have failed medical therapy, who have failed gangliolysis, or who have severe cardiopulmonary disease and are unable 3506

to tolerate a suboccipital craniectomy and MVD. Duration of good to excellent relief varies from less than 1 year to a range of 2 to 5 years in reported series. In one series, the median pain-free period among 88 patients was 41 months with a mean of 52.5 months. Analysis of 40 patients found excellent to good results in all patients for a period of time ranging from 2 to 5 years.145,146 The procedure can be repeated; however, the risk of neuroma is increased as is diminished success. Following neurectomy, dense numbness in the distribution of the eradicated nerve can occur. Cryoablation of the peripheral branches of the trigeminal nerve can be performed using a 1.4- to 2-mm probe which incorporates a nerve stimulator to test both sensory and motor function as well as a thermistor to identify temperature at the tip of the probe. A 3.5- to 5.5-mm ice ball is produced which results in disruption of the nerve structure with wallerian degeneration while leaving the myelin sheath and endoneurium intact (axonotmesis).147 The use of cryotherapy to successfully treat patients with TN has been reported by several authors to provide analgesia for periods ranging from 6 to 13 months. No permanent sensory loss was reported; however, in one review, up to one-third of patients developed atypical facial pain following the procedure.148–150

Painful Trigeminal Neuropathy PTN is differentiated from TN through demonstration of a causative lesion other than vascular compression. Sensory impairment and bilaterality may be present as well as lack of a refractory period after a paroxysm.2 MS and benign or malignant neoplasms are the most common cause of PTN, although fungal infection and bacterial sinusitis with intracranial extension, scrub typhus, hardened felt from previous MVD surgery, and TN as the first manifestations of mixed connective tissue disorder have also been reported.139,151–155

MULTIPLE SCLEROSIS MS is an inflammatory autoimmune systemic disease which is characterized by demyelinating lesions and plaques within the central 3507

nervous system. Widespread neuronal loss with periods of remyelination may be associated with periods of remission. MS affects women more than men with a cumulative ratio of females to males of 1.77 to 1.0. Median and mean age of onset of MS is 23.5 and 30 years of age, respectively.156 TN occurs in up to 2% of patients with MS, although this represents only about 0.5% of patients presenting with TN.157,158 These patients can present with symptoms which mimic CTN but often present with bilateral symptoms and persistent background facial pain.158 The pathophysiology of TN in MS continues to be debated. Although demyelinating lesions affecting the trigeminal REZ have been found on autopsy and on MRI, 24 MS patients out of a series of 851 studied at one institution were found to have entry zone lesions which were clinically silent.159,160 Although MVD was once thought to be contraindicated in MS patients with PTN, a report of MVD performed in 35 MS patients with severe neurovascular compression at the REZ resulted in a 39% excellent and 22% fair to good long-term pain relief. Seventy-four percent of these patients had demyelinating lesions affecting the brainstem trigeminal pathway on the painful side in addition to neurovascular compression.161 In a series of five patients with TN and MS who were refractory to medical treatment and had undergone multiple unsuccessful percutaneous procedures, those patients undergoing MVD combined with partial sectioning of the nerve did better than those undergoing MVD alone.162 A study reported 43 patients with MS related TN who were treated with GKS, 91% reported initial symptom relief. The actuarial probability to live pain-free was 87.2%, 71.8%, 43.1%, 38.3%, and 20.5%, at 6 months, 1, 3, 5, and 10 years, respectively.163 In general, patients with PTN secondary to MS respond less favorably to medical and interventional therapies and may require significantly more treatment than their cohorts with CTN.164

NEOPLASM The presentation of TN does not rule out the presence of a tumor. Some authors advocate advanced imaging of all patients presenting with TN due 3508

to delayed neurologic symptoms in patients with space-occupying lesions.154 Among 2,972 patients diagnosed with TN at the Mayo Clinic between 1976 and 1990, tumors were the cause of facial pain in approximately 10% (296 patients). Sex and pain distributions paralleled those in TN; however, patients presenting with tumors were younger than those with TN. Delay in tumor diagnosis averaged 6.3 years. The development of neurologic deficits prompted further imaging and diagnosis of tumor in 47% of these patients. These patients were often successfully treated medically for many years prior to onset of neurologic symptoms.53,165 Meningioma and epidermoid and acoustic neuroma are the most frequent posterior fossa tumors associated with PTN. In a review of 161 and 80 consecutive posterior fossa tumors from 1993 to 1999 and 1979 to 2003 at separate institutions, cranial nerve dysfunction was the most common neurologic sign on admission. Intracranial hypertension and disturbance of gait also presented in up to 44% of these patients.166,167 Twenty cases of TN caused by contralateral tumors of the posterior fossa have been reported. Only 4 of these cases symptomatically conformed to CTN. The mechanism of contralateral tumor causing TN is thought to be distortion and displacement of the brainstem and compression of the contralateral Meckel’s cave.168,169 Pain in all three divisions of the trigeminal nerve is the first symptom of a tumor in Meckel’s cave in over 65% of cases. The most common cavernous sinus tumors are trigeminal schwannomas and meningiomas. Tumors in this location make up only 0.5% of all intracranial tumors.170 Case reports of metastatic disease to Meckel’s cave presenting as TN include colorectal cancer, esophageal cancer, breast cancer, renal cell carcinoma, and lymphoma.170–174 Primary melanoma, adenocarcinoma, and lymphoma involving Meckel’s cave and associated with TN have also been reported.175–178 TN with subacute onset of numbness in one or more divisions of the trigeminal nerve is thought to be associated with rapidly expanding tumor in this region.174 Other reported causes of symptomatic TN include platybasia (a skull base deformity),179 sarcoid granuloma of the trigeminal nerve, and infarction of the REZ of the trigeminal nerve in the pons.180,181 TN has 3509

also been seen in adults and children as the only manifestation of Chiari type I malformations.182–184 Patients with hydrocephalus from remote causes such as a lumbar myxopapillary ependymoma and a quadrigeminal arachnoid cyst have also presented with TN.185,186 Shunting and relief of hydrocephalus resulted in resolution of symptoms in these cases. Five percent to 10% of TN has been reported to be PTN secondary to brain tumors.187 Although persistent pain, numbness, palsies, and gait disturbances along with other neurologic signs often differentiate these patients from those with TN, delay in the presentation of neurologic deficits is not infrequent. Expedient workup including advanced imaging is indicated in cases of TN with new onset of neurologic signs such as numbness or palsies.

HERPES ZOSTER AND POSTHERPETIC NEURALGIA HZ and postherpetic neuralgia is classified by ICHD-III as a subgroup of TN under subclassification of PTN caused by HZ infection, whereas the International Association for the Study of Pain (IASP) categorizes it as postherpetic neuralgia.

Etiology Acute HZ results from the reactivation of the varicella zoster virus which is referred to as “chickenpox” in children or “shingles” in adults. The virus remains dormant in the dorsal root ganglia of cranial or spinal nerves after resolution of the original infection. As cellular immunity wanes with disease, chemotherapy, or age, the virus is reactivated and is transported along peripheral nerves producing an acute neuritis. Viral replication results in direct nerve sheath and neuronal injury. Destruction of tissue and inflammation result in excitation of nociceptors and dorsal horn sensitization. The dorsal horns of patients who do not develop postherpetic neuralgia show less tissue damage and more rapid resolution of inflammatory changes.188

Epidemiology The rate of HZ and the rate of HZ-associated complications increase with age, with 68% of cases occurring in those aged 50 years and older. 3510

Postherpetic neuralgia occurs in 18% of adult patients with HZ and in 33% of those aged 79 years and older.189 In HZ involving the trigeminal nerve, neuronal spread of the virus occurs along the ophthalmic (first) and less frequently the maxillary (second) division of the fifth cranial nerve. Vesicular eruptions usually occur at the terminal points of sensory innervation, causing extreme pain. HZ involving the ophthalmic ganglion of the trigeminal nerve, or zoster ophthalmicus, accounts for as many as 10% to 25% of HZ cases. Nasociliary involvement will most likely cause ocular inflammation. Inflammation of the eye can lead to impairment of vision and in some cases temporary blindness. Such cases are considered emergent, and prompt treatment is required to prevent chronic inflammation or long-term vision loss. Contiguous spread of the virus may lead to the involvement of other cranial nerves, resulting in optic neuropathy (cranial nerve II) or isolated cranial nerve palsies (cranial nerve III, IV, or VI).

Symptoms and Signs Acute HZ typically presents with a prodrome consisting of hyperesthesia, paresthesias, burning dysesthesias, or pruritus along the affected dermatome(s). This prodrome is usually accompanied by fever and general malaise. It generally lasts 1 to 2 days but may precede the appearance of skin lesions by up to 3 weeks. Manifestation of prodromal symptoms without development of the characteristic rash may occur in some patients. This presentation is known as “zoster sine herpete” and may delay correct diagnosis and treatment. Following the prodromal period, a vesicular skin rash appears along the affected nerve. Involvement of the trigeminal nerves characteristically respects the vertical midline. The vesicles will discharge fluid and begin to scab over after about 1 week. The pain is extreme during the inflammatory stage. Vesicles at the tip of the nose are known as Hutchinson sign and signal a 75% likelihood of ocular sequelae which may include follicular conjunctivitis; epithelial and/or interstitial keratitis; dendritic keratitis; uveitis; scleritis chorioretinitis; optic neuropathy; and palsies of the third, fourth, or sixth cranial nerves. 3511

Pain that persists beyond healing of the rash but which resolves within 4 months of onset is referred to as subacute herpetic neuralgia. Postherpetic neuralgia refers to pain persisting longer than 4 months from initial onset of rash.190 Affected patients usually report constant, severe, burning, lancinating pain in the distribution of the affected nerve(s). Patients may also complain of pain in response to nonnoxious stimuli (allodynia). Even the slightest pressure from clothing, bedsheets, or a slight breeze may elicit severe pain.

Diagnosis The diagnosis of acute HZ is essentially clinical, based on the characteristic unilateral appearance of a vesicular rash limited to the distribution of a specific nerve or nerve root. As discussed in the “Symptoms and Signs” section earlier, this is preceded most commonly by a painful prodrome characterized by burning dysesthesias or paresthesias along the affected dermatome. The criterion standard of laboratory diagnosis is polymerase chain reaction testing together with direct identification of varicella zoster virus in culture. Immunocompromised patients may benefit from immunoglobulin (Ig) G- and IgA anti-varicella zoster virus antibodies.191,192

Treatment The goals of treatment of acute HZ include treatment of the acute viral infection, treatment of the severe acute pain associated with HZ infection, and prevention of postherpetic neuralgia. Acute HZ infection should be treated with antiviral medication within 72 hours of vesicular eruption to reduce the duration and severity of pain associated with the infection. The use of antivirals may produce a moderate reduction in the risk of development of postherpetic neuralgia. Oral steroids may also be beneficial in reducing the severe pain of acute HZ.193 Acute treatment of acute HZ with neuropathic analgesics (i.e., anticonvulsants or tricyclic antidepressants) starting within 48 hours of onset of rash may also reduce acute pain and incidence of postherpetic neuralgia.194–197 Patients with ocular involvement should have immediate 3512

evaluation and treatment of ophthalmic complications by a specialist. The varicella zoster vaccine was approved by the FDA in May 2006 and was found to reduce the incidence of shingles by 51% in a randomized double-blind study. Pain was reduced by 61% in those who received the vaccine but still developed the infection, and postherpetic neuralgia was reduced by two-thirds compared with placebo.198 The FDA recently approved a new shingles vaccine called Shingrix for adults age 50 years and older.199 Nutritional counseling may also be indicated in populations at risk for HZ. In a review of 243 HZ cases, it was determined that individuals, particularly those over age 60 years, who ate less than one serving of fruit or vegetables weekly had a threefold greater risk of HZ compared to those who ate more than three servings daily independent of vitamin supplement intake.200 An association between deficiency of vitamin A (a key immune modulator involved in the synthesis of lymphocytes, neutrophils, cytokines, and immunoglobulins) and increased risk of HZ has also been observed.201 Systematic reviews of the literature have concluded that pharmacologic therapies shown to be more effective than placebo for postherpetic neuralgia include tricyclic antidepressants, opioids, gabapentin, pregabalin, tramadol, capsaicin, and lidocaine 5% patch. Intrathecal methylprednisolone was shown to be of benefit in patients refractory to pharmacologic therapies.202,203 Safety and tolerability should be considered when selecting pharmacologic treatments. Older patients may have more intolerable side effects at standard doses and thus may require smaller doses and more gradual titration. They may also be on multiple medications for coexisting medical conditions with potential for drug–drug reactions. In a 13-week RCT for the treatment of 370 patients with postherpetic neuralgia, pregabalin showed efficacy from week 1 and continued for 13 weeks. Most common side effects were dizziness (5.8%), somnolence (2.9%), and ataxia (2.5%).204 Sympathetic blockade, including stellate ganglion block, has commonly been used to provide pain relief of variable duration in both acute HZ and in postherpetic neuralgia. Although a review of sympathetic blocks in the treatment of acute HZ and postherpetic neuralgia found the evidence to be 3513

inconclusive due to lack of properly controlled studies, it found available data to suggest that sympathetic blocks may provide considerable pain relief during acute HZ but appear to provide only short-term relief in postherpetic neuralgia.188

Nervus Intermedius Neuralgia Nervus intermedius neuralgia is an uncommon disorder affecting the sensory branch of the facial nerve (cranial nerve VII) (Fig. 66.3). It is located between the motor component of the facial nerve and the vestibulocochlear nerve (cranial nerve VIII). Sensory fibers contained in the nervus intermedius nerve carry afferent sensory input from the skin of the external auditory meatus; mucous membranes of the nasopharynx and nose; and taste from the anterior two-thirds of the tongue, floor of the mouth, and the palate. The geniculate ganglion contains the cell bodies of the sensory fibers of the nervus intermedius. Compression of the geniculate ganglion therefore can also result in nervus intermedius neuralgia.

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FIGURE 66.3 A,B: Distribution of the facial nerve (cranial nerve VII). The facial nerve emanates from the brainstem between the pons and the medulla. The motor part of the facial nerve arises from the facial nerve nucleus in the pons and divides into five branches after coursing through the petrous temporal bone, the internal auditory meatus, the facial canal, the stylomastoid foramen, and the parotid gland. It is responsible for muscles of facial expression and supplies preganglionic parasympathetic fibers to ganglia of the head and neck. It also supplies taste sensation to the anterior two-thirds of the tongue, partial afferent innervations of the oropharynx, as well as some cutaneous sensation around the auricle. (Reprinted with permission from Moore KL, Dalley AF. Clinically Oriented Anatomy. 6th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2009. Figure 9-10.)

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The cell bodies of parasympathetic axons within the nervus intermedius are contained within the superior salivatory nucleus. These axons synapse with neurons which supply parasympathetic innervations to the lachrymal gland as well as the submandibular and sublingual glands. Nervus intermedius neuralgia involves severe pain deep in the ear which may radiate to the outer ear, mastoid, or eye region. The syndrome was reported as “tic douloureux of the sensory filaments of the facial nerve” by Clark and Taylor in 1909.205 Rare cases continue to be reported.

ETIOLOGY Vascular compression is suggested as the cause of many cases of nervus intermedius neuralgia. Jannetta206 described relief of nervus intermedius and other cranial neuralgias following MVD in 1976. He reviewed 14 cases of nervus intermedius neuralgia, which, after failed conservative treatment, went on to MVD. Over 71% experienced an excellent outcome, over 21% experienced partial relief, and 7% had no relief following MVD. Good long-term results were seen in 90% of patients. In a 1991 review of 18 cases of “primary otalgia” seen over a 15-year period, vascular loops, adhesions, thickened arachnoid, and benign osteoma were among abnormalities involving the nervus intermedius. The authors reported decompression of cranial nerves V, IX, X, the tympanic nerve and the chorda tympani in addition to the nervus intermedius in many of these cases.207,208 Nonetheless, the existence of nervus intermedius as a unique entity has been questioned due to the similarity of its presentation to that of glossopharyngeal neuralgia.

SYMPTOMS AND SIGNS The pain of nervus intermedius neuralgia is sharp, lancinating, and paroxysmal. Painful attacks are unilateral and can be triggered by cold, noise, swallowing, or touch. Patients may also experience symptoms such as increased salivation, bitter taste, tinnitus, and vertigo during paroxysms. Patients with nervus intermedius neuralgia may also rarely have pain in the trigeminal distribution. This may be due to cross compression of cranial nerve V in addition to the nervus intermedius (as has been seen on surgical exploration).209 3516

DIAGNOSIS Sensation is supplied to the area of the ear by the cranial nerves V, VII, VIII, IX, and X and the second and third cervical nerves. A thorough history should be taken to ascertain the exact distribution and character of the pain as well as any triggers or precipitating factors. A comprehensive examination should rule out other causes of otalgia before the diagnosis of geniculate ganglion neuralgia can be made. This should include examinations of the nose, paranasal sinuses, mouth, teeth, nasopharynx, pharynx, and larynx to rule out other causes of pain, audiogram, auditory evoked response potentials, and vestibular tests. MRI with gadolinium enhancement of the brain, cerebellopontine angle, and facial nerve and MRA should be performed. As described earlier, vascular compression or other pathology may involve more than one of the cranial nerves in the middle fossa. As described in the previous section, nervus intermedius neuralgia can be caused by HZ infection. The pain from acute HZ involving the geniculate ganglion is usually constant and burning as opposed to the lancinating paroxysmal pain of nervus intermedius neuralgia. Onset of the pain from acute HZ is generally followed by a vesicular eruption involving the eardrum and external auditory canal.

TREATMENT Pharmacologic treatment of nervus intermedius neuralgia is similar to that of TN. When conservative management fails, a thorough workup to exclude other causes of pain should be investigated. The nervus intermedius or geniculate ganglion cannot be injected with local anesthetic or other solution; however, blockade of other nerves supplying the area of the ear can be anesthetized to exclude them as causes of the otalgia. Surgical management consists of MVD or section of the nervus intermedius. Excision of the nervus intermedius and geniculate ganglion has also been advocated along with selective retrolabyrinthine V nerve section in extreme cases.208

Glossopharyngeal Neuralgia 3517

Glossopharyngeal neuralgia is a rare neuralgia with a reported relative frequency of 0.75% to 1% compared to TN.210,211 It is defined as paroxysmal pain in the areas supplied by cranial nerves IX and X. The glossopharyngeal or ninth cranial nerve exits the upper medulla just rostral to the vagus nerve. Sensory fibers carried in the glossopharyngeal nerve supply the posterior one-third of the tongue, the tonsils, pharynx, the middle ear, and the carotid body. The glossopharyngeal nerve also supplies parasympathetic fibers to the parotid gland via the otic ganglion, motor fibers to the stylopharyngeus muscle, and contributes to the pharyngeal plexus. The symptoms associated with glossopharyngeal neuralgia can be better understood upon review of its branches, which include the tympanic nerve, stylopharyngeal nerve, tonsillar nerve, nerve to the carotid sinus, branches to the posterior third of the tongue, lingual branches, and a communicating branch to the vagus nerve (Fig. 66.4).

FIGURE 66.4 Distribution of the glossopharyngeal nerve. A: The glossopharyngeal nerve exits the skull via the jugular foramen between the internal jugular vein and internal carotid artery, lateral

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and ventral to the vagus and accessory nerves. It receives general sensory fibers via the tympanic nerve, the nerve to the palatine tonsils, and pharyngeal nerve branches. It receives special sensory fibers (taste) from the posterior one-third of the tongue and visceral sensory fibers from the carotid bodies and carotid sinus. B: The parasympathetic component of the glossopharyngeal nerve supplies the postsynaptic innervations to the parotid gland via the otic ganglion. The glossopharyngeal nerve is responsible for the afferent limb of the gag reflex, and thus, the gag reflex is absent in patients with damage to the glossopharyngeal nerve. The efferent limb of the gag reflex is supplied by the vagus nerve. (Reprinted with permission from Moore KL, Dalley AF. Clinically Oriented Anatomy. 6th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2009. Figure 9-13.)

ETIOLOGY Similar to TN nomenclature, classical or idiopathic and secondary or symptomatic forms of glossopharyngeal neuralgia exist. Idiopathic glossopharyngeal neuralgia occurs most commonly from vascular compression of cranial nerve IX (often in association with cranial nerve X). Symptomatic causes include tumors, peritonsillar abscess, carotid aneurysm, Chiari type I malformations, and Eagle syndrome (in which cranial nerve IX is compressed against an ossified stylohyoid ligament).212–214 The vertebral artery or posterior inferior cerebellar arteries are most often implicated on surgical exploration.

SYMPTOMS AND SIGNS The character of pain in the patient with glossopharyngeal neuralgia is similar to that of TN. The unbearable, electrical, lancinating pain is located unilaterally in the ear, larynx, tonsillar fossa, or base of the tongue. It is rarely bilateral. It may radiate toward the ear, the angle of the jaw, or the upper and lateral aspect of the neck. Paroxysms of pain are often triggered by swallowing, yawning, coughing, or talking.

DIAGNOSIS A careful history and physical exam is essential in the evaluation of a patient suspected of suffering from glossopharyngeal neuralgia. MRI/MRA should be performed to rule out a mass lesion or vascular pathology. An ossified stylohyoid ligament (consistent with Eagle syndrome) may be identified on roentgenogram. As in TN, the paroxysms of glossopharyngeal neuralgia may last from seconds to minutes. Dozens of attacks may occur daily with episodes lasting from weeks to months 3519

followed by periods of remission. The patient is generally free from pain between attacks, although dull background pain may persist. Investigation should also exclude MS in younger patients with bilateral symptoms or neurologic deficits. The branch of the glossopharyngeal nerve to the carotid sinus is involved in maintenance of blood pressure and is thought to play a role in some profound cardiac arrhythmias or even asystole which occur in some patients in association with pain paroxysms. The differential diagnosis includes geniculate or nervus intermedius neuralgia. Rare glossopharyngeal zoster has been reported.215

TREATMENT The pharmacologic treatment of glossopharyngeal neuralgia is similar to TN. When conservative therapy has failed, surgical exploration and vascular decompression has been shown to be highly effective on longterm follow-up with a low complication rate.216,217 When a source of neurovascular compression is not found, successful relief of symptoms has been obtained with section of the glossopharyngeal nerve together with the upper fibers of the vagus nerve.218,219

Vagal Neuralgia The two sensory branches of the vagus nerve, the auricular branch and the superior laryngeal nerve, are involved in this rare neuralgia (Fig. 66.5). The auricular branch of the vagus nerve, or Alderman’s nerve, divides into two branches: the posterior auricular nerve and the nerve supplying the auricula and posterior part of the external acoustic meatus. The superior laryngeal nerve descends behind the internal carotid artery and divides into the internal and external laryngeal nerves. The internal laryngeal nerve supplies sensation to the base of the tongue, epiglottis, and the larynx to above the vocal cords. The external laryngeal nerve supplies the cricothyroid muscle and the inferior pharyngeal constrictor and communicates with the superior cardiac nerve behind the common carotid artery.

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FIGURE 66.5 Distribution of the vagus nerve (cranial nerve X). The vagus nerve originates in the brainstem and courses through the jugular foramen to extend into the head, neck, thorax, and abdomen where it provides efferent motor parasympathetic innervation to viscera as well as afferent innervation that delivers information about the state of organs to the brain. (Reprinted with permission from Moore KL, Dalley AF. Clinically Oriented Anatomy. 6th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2009. Figure 10-16.)

ETIOLOGY Idiopathic or classic vagal neuralgia is characterized by lack of a known precipitating lesion or by vascular compression of the upper fibers of the vagus nerve as they leave the brainstem. Secondary or symptomatic vagal neuralgia involving the superior laryngeal branch has been reported to be secondary to multiple causes including deviation of the hyoid bone, lateral pharyngeal diverticulum, and as a complication following carotid endarterectomy.220–222

SYMPTOMS AND SIGNS 3521

Vagal neuralgia is characterized by severe pain paroxysms in the submandibular region, throat, and/or under the ear. Attacks are triggered by swallowing, talking, yawning, coughing, or straining and turning the head. A trigger zone is generally present in the larynx or lateral aspect of the throat overlying the hyoid bone. Compression of the vagus nerve has also reported to be associated with intractable hiccups, coughing, spontaneous gagging, and dysphagia.223,224

DIAGNOSIS The diagnosis of vagal neuralgia is based on a thorough history to define the distinct characteristics and precipitating factors of the patient’s pain. A careful exam of the head and neck should be performed to rule out other pathology. MRI/MRA should be performed to rule out compressive mass lesions or neurovascular compression. Hoarseness of speech and a trigger point superolateral to the thyroid cartilage may be noted on exam of the patient. Differential diagnosis includes glossopharyngeal neuralgia, geniculate neuralgia, and carotidynia.

TREATMENT Pharmacologic therapy of vagal neuralgia is identical to that of TN. Successful treatment of superior laryngeal neuralgia with high concentration lidocaine injections after CBZ treatment failure has been reported.225 Surgical treatment following pharmacologic therapy failure warrants consideration. MVD has been successful when neurovascular compression of the vagus is identified. When no compressive lesion is identified, relief of pain can be obtained following section of the glossopharyngeal nerve and the upper rootlets of the vagus nerves. The medial aspect of the descending trigeminal tract has also been sectioned in refractory cases to produce loss of pain and temperature sensation in the pharynx.226 Kandan et al.227 reported that 21 patients with glossopharyngeal and vagus nerves neuralgias underwent surgery over 19 years, with MVD being the most common procedure. Treatment outcomes were reported as similar to surgical treatments of TN.

Other Terminal Branch Neuralgias 3522

Rare neuralgias involving branches of the trigeminal nerve have been reported. These include supraorbital neuralgia, nasociliary neuralgia, infraorbital neuralgia, and nummular headache. Injury or entrapment of other peripheral branches of the trigeminal nerve such as the lingual, alveolar, or mental nerves may result in pain in the area supplied by that branch. Supraorbital neuralgia is characterized by paroxysmal or constant pain in the region of the supraorbital notch. It is unilateral and radiates to the medial aspect of the forehead in the area supplied by the supraorbital nerve. It can be caused by injury or entrapment of the supraorbital nerve at its outlet. The pain is transiently relieved by injection of a small volume of local anesthetic at the supraorbital notch. Medical treatment is often unsuccessful when entrapment of the nerve is present. Successful treatment with cryoablation and surgical release of the nerve at its outlet has been reported.228,229 Nasociliary neuralgia, or Charlin’s neuralgia, is a rare condition characterized by stabbing pain lasting seconds to hours in one side of the nose. The pain radiates to the medial frontal region and is triggered by touching the lateral aspect of the ipsilateral nostril. Temporary relief from pain following local anesthetic blockade of the nasociliary nerve is diagnostic. Inflammatory cutaneous lesions and chronic sinusitis have been implicated as secondary causes of nasociliary neuralgia.230,231 Relief following surgical section of the nasociliary nerve, turbinectomy, and septoplasty has been described.232 Infraorbital neuralgia has been reported most frequently in association with posttraumatic entrapment syndromes.233 If pain is not successfully alleviated by reduction of zygomatic fracture and mobilization of surrounding soft tissue and bone, pharmacologic therapy with antiepileptic agents alone or combined with antidepressants such as the tricyclics or serotonin norepinephrine reuptake inhibitors may be effective. Nummular headache is thought to be neuralgia related to a terminal cutaneous branch of the trigeminal nerve. It has been described as a primary disorder characterized by head pain felt exclusively in a small round area generally 2 to 6 cm in diameter. The pain is not attributed to another disorder, and neurologic and neuroimaging exams are normal by 3523

definition. A constant background pain may be described as well as exacerbations which are spontaneous or triggered by combing the hair or touch in the affected area. A 2013 review found that gabapentin was effective in 60% of subjects, TCAs in about 45% and peripheral nerve block in 42% of the cases.234 In patients refractory to pharmacologic therapy, nerve blocks are also effective. Despite small sample size, onabotulinum toxin A was reported to reduce pain for an average of 14 weeks after initial and repeat injections.235 In all cases of idiopathic neuralgia of the terminal branches of the trigeminal nerve, a careful history and physical exam to rule out other causes of facial pain the is imperative. Age less than 40 years and presence of neurologic deficit should prompt further diagnostic radiologic exams to rule out compressive lesions.

Other Cranial Neuralgia–Related Causes of Pain: Anesthesia Dolorosa Anesthesia dolorosa is also known as painful posttraumatic trigeminal neuropathy.

ETIOLOGY Anesthesia dolorosa is defined as perception of pain in an area that is anesthetic. It is a dreaded complication of trigeminal nerve surgery, including partial nerve sections, MVD, percutaneous gangliolysis, neurolytic injections, and stereotactic radiosurgery. It has also been reported after penetrating cranial injury.236 The area of persistent and painful anesthesia is in the distribution of the injured nerve.

SYMPTOMS AND SIGNS The patient with anesthesia dolorosa complains of burning, pulling, or stabbing pain which can also include a sharp, stinging, shooting, or electrical component. The pain often increases with cold or with rapid temperature changes.

DIAGNOSIS 3524

As it pertains to the head and face, anesthesia dolorosa typically involves the territory of a specific branch or branches of the trigeminal nerve or the occipital nerve. Quantitative sensory testing may be used to confirm lack of sensation.

TREATMENT There are no controlled trials evaluating pharmacologic therapy for anesthesia dolorosa. Empiric treatment of pain by clinical characteristics has led to use of anticonvulsants in patients with lancinating and electrical pain; tricyclic antidepressants, and serotonin norepinephrine reuptake inhibitors in patients with burning pain; and intravenous lidocaine and ketamine infusions in patients unresponsive to other pharmacologic therapy.237,238 Motor cortex stimulation was the recommended surgical treatment of choice for facial anesthesia dolorosa according to authors of a review of the literature on central and neuropathic pain over the last 15 years. Motor cortex stimulation may act by replacing nociceptive with nonnociceptive sensory input at the cortical, thalamic, brainstem, and spinal level. It may also interfere with the emotional component of nociceptive perception.239 In a prospective study of 10 patients undergoing trial and treatment with motor cortex stimulation, patients with facial weakness and sensory loss regained both strength and discriminative sensation during stimulation.240 Raslan et al.241 reported positive results of motor cortex stimulation for trigeminal neuropathic or deafferentation pain. Anesthesia dolorosa did not appear to respond to deep brain stimulation according to one 15-year series of 141 patients.242

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171. Mastronardi L, Lunardi P, Osman FJ, et al. Metastatic involvement of the Meckel’s cave and trigeminal nerve. A case report. J Neurooncol 1997;32(1):87–90. 172. Nakano I, Iwwsuki K, Kondo A. Solitary metastatic breast carcinoma in a trigeminal nerve mimicking a trigeminal neuroma. Case report. J Neurosurg 1996;85(4):677–680. 173. Hirota N, Fujimoto T, Takahashi M, et al. Isolated trigeminal nerve metastases from breast cancer: an unusual cause of trigeminal mononeuropathy. Surg Neurol 1998;49(5):558–561. 174. Kuntzer T, Bogousslavsky J, Rilliet B, et al. Herald facial numbness. Eur Neurol 1992;32(5):297–301. 175. Inatomi Y, Inoue T, Nagata S, et al. Trigeminal neuralgia caused by the metastasis of malignant lymphoma to the trigeminal nerve: a case report. No Shinkei Geka 1998;26(5):401– 405. 176. Falavigna A, Borba LA, Ferraz FA, et al. Primary melanoma of Meckel’s cave: case report. Arq Neuropsiquiatr 2004;62(2A):353–356. 177. Tacconi L, Arulampalam T, Johnston F, et al. Adenocarcinoma of Meckel’s cave: case report. Surg Neurol 1995;44(6):553–555. 178. Abdel Aziz KM, van Loveren HR. Primary lymphoma of Meckel’s cave mimicking trigeminal schwannoma: case report. Neurosurgery 1999;44(4):859–862. 179. Kanpolat Y, Tatli M, Ugur HC, et al. Evaluation of platybasia in patients with idiopathic trigeminal neuralgia. Surg Neurol 2007;67(1):78–81. 180. Quinones-Hinojosa A, Chang EF, Khan SA, et al. Isolated trigeminal nerve sarcoid granuloma mimicking trigeminal schwannoma: case report. Neurosurgery 2003;52(3):700–705. 181. Golby AJ, Norbash A, Silverberg GD. Trigeminal neuralgia resulting from infarction of the root entry zone of the trigeminal nerve: case report. Neurosurgery 1998;43(3):620–622. 182. Ivánez V, Moreno M. Trigeminal neuralgia in children as the only manifestation of Chiari I malformation. Rev Neuro 1999;28(5):485–487. 183. Rosetti P, Ben Taib NO, Brotchi J, et al. Arnold Chiari Type I malformation presenting as a trigeminal neuralgia: case report. Neurosurgery 1999;44(5):1122–1123. 184. Teo C, Nakaji P, Serisier D, et al. Resolution of trigeminal neuralgia following third ventriculostomy for hydrocephalus associated with Chiari I malformation: case report. Minim Invasive Neurosurg 2005;48(5):302–305. 185. Schwartz NE, Rosenberg S, So YT. Action at a distance: a lumbar spine tumor presenting as trigeminal neuralgia. Clin Neurol Neurosurg 2006;108(8):806–808. 186. Ohnishi YI, Fujimoto Y, Taniguchi M, et al. Neuroendoscopically assisted cyst-cisternal shunting for a quadrigeminal arachnoid cyst causing typical trigeminal neuralgia. Minim Invasive Neurosurg 2007;50(2):124–127. 187. Uzumi N, Hasegawa J, Kaoru K, et al. Pain relief by stellate ganglion block in a case with trigeminal neuralgia caused by a cerebellopontine angle tumor. Anesth Prog 2002;49:88–91. 188. Wu CL, March A, Dworkin RH. The role of sympathetic nerve blocks in acute herpes zoster and postherpetic neuralgia. Pain 2007;87:121–129. 189. Wollan PC, St Sauver JL, Kurland MJ, et al. A population-based study of the incidence and complication rates of herpes zoster before zoster vaccine introduction. Mayo Clin Proc 2007;82(11):1341–1349. 190. Dworkin RH, Portenoy RK. Pain and its persistence in herpes zoster. Pain 1996;67:241. 191. Sampathkumar P, Drage LA, Martin DP. Herpes zoster(shingles) and post herpetic neuralgia. Mayo Clin Proc 2009;84(3):274–280. 192. Gross G, Schöfer H, Wassilew S, et al. Herpes zoster guideline of the German Dermatology Society (DDG). J Clin Virol 2003;26(3):277–289. 193. Schmader K. Management of herpes zoster in elderly patients. Infect Dis Clin Pract 1995;4:293–299.

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194. Crooks RJ, Jones DA, Fiddian AP. Zoster associated chronic pain: an overview of clinical trials with acyclovir. Scand J Infect Dis Suppl 1991;80:62–68. 195. Whitley RJ, Weiss H, Gnann J, et al. Acyclovir with and without prednisone for treatment of herpes zoster. A randomized, placebo-controlled trial. Ann Intern Med 1996;125:376–383. 196. Bowsher D. The effects of pre-emptive treatment of postherpetic neuralgia with amitriptyline: a randomized, double-blind, placebo controlled trial. J Pain Symptom Manage 1997;13:327– 331. 197. Kuraishi Y, Takasaki I, Nojima H, et al. Effects of the suppression of acute herpetic pain by gabapentin and amitriptyline on the incidence of delayed postherpetic pain in mice. Life Sci 2004;74:2619–2626. 198. Oxman MN, Levin MJ, Johnson GR, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 2005;352(22):2271–2284. 199. Bharucha T, Ming D, Breuer J. A critical appraisal of “Shingrix,” a novel herpes zoster subunit vaccine (HZ/Su or GSK1437173A) for varicella zoster virus. Hum Vaccin Immunother 2017;13(8):1789–1797. doi:10.1080/21645515.2017.1317410. 200. Thomas SL, Wheeler JG, Hall AJ. Micronutrient intake and the risk of herpes zoster: a casecontrol study. Int J Edidemiol 2006;35:307–314. 201. High KP, Legault C, Sinclair JA, et al. Low plasma concentrations of retinol and alphatocopherol in hematopoietic stem cell transplant recipients: the effect of mucositis and the risk of infection. Am J Clin Nutr 2002;76:1358–1366. 202. Alper BS, Lewis PR. Treatment of postherpetic neuralgia: a systematic review of the literature. J Fam Pract 2002;51:121–128. 203. Hempenstal K, Nurmikko TJ, Johnson RW, et al. Analgesic therapy in postherpetic neuralgia: a quantitative systematic review. PLoS Med 2005;2:e164. 204. van Seventer R, Feister HA, Young JP, et al. Efficacy and tolerability of twice-daily pregabalin for treating pain and related sleep interference in postherpetic neuralgia: a 13week, randomized trial. Curr Med Res Opin 2006;22(2):375–384. 205. Clark LP, Taylor AS. True tic douloureux of the fibers of the sensory filaments of the facial nerve. JAMA 1909;53:2144–2146. 206. Jannetta PJ. Microsurgical approach to the trigeminal nerve for tic douloureux. Prog Neurosurg 1976;7:180–200. 207. Lovely TJ, Jannetta PJ. Surgical management of geniculate neuralgia. Am J Otol 1997;18(4):512–517. 208. Rupa V, Sauders RL, Weider DJ. Geniculate neuralgia: the surgical management of primary otalgia. J Neurosurg 1991;75(4):505–511. 209. Pulek JL. Geniculate neuralgia: long-term results of surgical treatment. Ear Nose Throat J 2002;81(1):30–33. 210. Bohm E, Strann RR. Glossopharyngeal neuralgia. Brain 1962;85:371–388. 211. Chawla JC, Falconer MA. Glossopharyngeal and vagal neuralgia. BMJ 1967;3:529–531. 212. Bryun GW. Glossopharyngeal neuralgia. In: Vinkin PJ, Gruyn GW, Klawans HL, eds. Handbook of Clinical Neurology. Amsterdam, The Netherlands: Elsevier; 1985:459–473. 213. Fini G, Gasparini G, Filippini F, et al. The long styloid process syndrome or Eagle’s syndrome. J Craniomaxillofac Surg 2000;28:123–127. 214. Soh KB. The glossopharyngeal nerve, glossopharyngeal neuralgia and the Eagle’s syndromecurrent concepts and management. Singapore Med J 1999;40:659–665. 215. Nakagawa H, Nagasao M, Kusuyama T, et al. A case of glossopharyngeal zoster diagnosed by detecting viral antigen in the pharyngeal mucous membrane. J Laryngol Otol 2007;121(2):163–165. 216. Sampson JH, Grossi PM, Asaoka K, et al. Microvascular decompression for glossopharyngeal

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neuralgia: long-term effectiveness and complication avoidance. Neurosurgery 2004;54(4):884–889. Zhao K, Zuo H, Zhang L, et al. Long-term follow-up results of microsurgical treatment for glossopharyngeal neuralgia. Zhonghua Wai Ke Za Zhi 2000;38(8):598–600. Resnick DK, Jannetta PJ, Bissonnette D, et al. Microvascular decompression for glossopharyngeal neuralgia. Neurosurgery 1995;36:64–68. Patel A, Kassam A, Horowitz M, et al. Microvascular decompression in the management of glossopharyngeal neuralgia: analysis of 217 cases. Neurosurgery 2002;50:705–710. Kodama S, Oribe K, Suzuki M. Superior laryngeal neuralgia associated with deviation of the hyoid bone. Auris Nasus Larynx 2007;35(3):429–431. Bagatzounis A, Geyer G. Lateral pharyngeal diverticulum as a cause of superior laryngeal nerve neuralgia. Laryngorhinootologie 1994;73(4):219–221. O’Neill BP, Aronson AE, Pearson BW, et al. Superior laryngeal neuralgia: carotidynia or just another pain in the neck? Headache 1982;22(1):6–9. Johnson DL. Intractable hiccups: treatment by microvascular decompression of the vagus nerve. Case report. J Neurosurg 1993;78(5):813–816. Resnick DK, Jannetta PJ. Hyperactive rhizopathy of the vagus nerve and microvascular decompression. Case report. J Neurosurg 1999;90(3):580–582. Takahashi SK, Suzuki M, Izuha A, et al. Two cases of idiopathic superior laryngeal neuralgia treated by superior laryngeal nerve block with a high concentration of lidocaine. J Clin Anesth 2007;19(3):237–238. Kunc Z. Treatment of essential neuralgia of the ninth nerve with selective tractotomy. J Neurosurg 1965;23:494–500. Kandan SR, Khan S, Jeyaretna DS, et al. Neuralgia of the glossopharyngeal and vagal nerves: long-term outcome following surgical treatment and literature review. Br J Neurosurg 2010;24(4):441–446. doi:10.3109/02688697.2010.487131. Trescott AM. Headache management in an interventional pain practice. Pain Physician 2000;3(2):197–200. Sjaastad O, Stolt-Nielsen A, Pareja JA, et al. Supraorbital neuralgia. On the clinical manifestation and a possible therapeutic approach. Headache 1999;39(3):204–212. Lambert WC, Okorodudu AO, Schwartz RA. Cutaneous nasociliary neuralgia. Acta Derm Venereol 1985;65(3):257–258. Spokoinaia VA. Neuralgia of the trigeminal nerve and pterygopalatine ganglion as a complication of paranasal sinusitis [in Russian]. Vestn Otorinolaringol 1989;4:49–53. Zhao Y, Li H, Cai Q, et al. Partial middle turbinatectomy and folded for nasociliary neuralgia by transnasal endoscopic surgery [in Chinese]. Lin Chauang Er Bi yan Hou Ke Za Zhi 2004;18(2):91–92. Rath EM. Surgical treatment of maxillary nerve injuries. The infraorbital nerve. Atlas Oral Maxillofac Surg Clin North Am 2001;9(2):31–41. Schwartz DP, Robbins MS, Grosberg BM. Nummular headache update. Curr Pain Headache Rep 2013;17(6):340. doi:10.1007/s11916-013-0340-0. Mathew NT, Kailasam J, Meadors L. Botulinum toxin type A for the treatment of nummular headache: four case studies. Headache 2007;48(3):442–447. Tatli M, Keklikci U, Aluclu U, et al. Anesthesia dolorosa caused by penetrating cranial injury. Eur Neurol 2006;56(3):162–165. Stillman M. Clinical approach to patients with neuropathic pain. Cleve Clin J Med 2006;73(8):726–739. Wallace MS. Pharmacologic treatment of neuropathic pain. Curr Pain Headache Rep 2001;5:138–150.

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239. Lazorthes Y, Sol JC, Fowo S, et al. Motor cortex stimulation for neuropathic pain. Acta Neurochir Suppl 2007;97(pt 2):37–44. 240. Brown JA, Pilitsis JG. Motor cortex stimulation for central and neuropathic facial pain: a prospective study of 10 patients and observations of enhanced sensory and motor function during stimulation. Neurosurgery 2005;56(2):290–297. 241. Raslan AM, Nasseri M, Bahgat D, et al. Motor cortex stimulation for trigeminal neuropathic or deafferentation pain: an institutional case series experience. Stereotact Funct Neurosurg 2011;89(2):83–88. 242. Levy RM, Lamb S, Adams JE. Treatment of chronic pain by deep brain stimulation: long term follow-up and review of the literature. Neurosurgery 1987;21(6):885–893.

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CHAPTER 67 Facial Pain ALAA ABD-ELSAYED, PAMELA J. HUGHES, and AHMED M.T. RASLAN Facial pain syndromes are common in clinical practice. Many of these syndromes are also unique, given the complex anatomy and specialized sensory innervation of the head, face, and neck. The complexity of the anatomy can pose diagnostic challenges when endeavoring to treat facial pain syndromes. The common descriptive terms for facial pain complaints are frequently misleading. To avoid confusion, clinicians should be familiar with the International Headache Society’s Diagnostic Classification for Head, Face, and Neck Pain Disorders (Table 67.1). TABLE 67.1 International Headache Society International Classification of Headache Disorders1 Primary headaches

Secondary headaches

Headache or facial pain attributed to disorders of cranium, neck, eyes, ears, nose, sinuses, teeth, mouth, or other facial or cranial

Migraine without aura, with aura Tension-type headache Cluster headache and other trigeminal autonomic cephalalgias Other primary headaches Attributed to head and/or neck trauma Attributed to cranial or cervical vascular disorder Attributed to nonvascular intracranial disorder Attributed to a substance or its withdrawal Attributed to infection Attributed to disorder of homeostasis Headache or facial pain attributed to disorder of cranium, neck, eyes, ears, nose, sinuses, teeth, mouth, or other facial or cranial structures Attributed to psychiatric disorder Cranial bones Neck Eyes Ears Rhinosinusitis (sinus disorders)

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structures

Cranial neuralgias, central and primary facial pain, and other headaches

Teeth, jaws, or related structures TMJ disorders (TMD) Other Trigeminal neuralgia Glossopharyngeal neuralgia Occipital neuralgia Constant pain caused by compression, irritation, or distortion of cranial nerves or upper cervical roots by structural lesions Head or facial pain attributed to herpes zoster Postherpetic neuralgia Central causes of facial pain Anesthesia dolorosa Central poststroke pain Facial pain attributed to multiple sclerosis Persistent idiopathic facial pain Burning mouth syndrome

TMD,temporomandibular disorder; TMJ, temporomandibular joint.

The aforementioned grouping of diagnose(s) is a rather exhaustive differential diagnosis of facial pain. This includes acute and subacute conditions that affect a vast majority of the structures of the human head. This would include ocular, nasal, sinus, dental, oral, muscular, mucosal, and any other causes specific to the region of the head and face. Although such a list is good for an all-encompassing reference, it is not necessarily helpful for pain practitioners who deal mostly with chronic pain conditions. In this chapter, the focus is on chronic pain conditions that would present as facial pain. Because the primary differential diagnosis of facial pain is trigeminal neuralgia and the nociceptive pain pathway responsible for facial pain, conditions that present in a similar fashion to trigeminal neuralgia or could be misdiagnosed as such are discussed in detail here.

Trigeminal and Other Cranial Nerve Neuropathic Conditions TRIGEMINAL NEUROPATHY Trigeminal neuropathy is a spectrum, the earliest of which is classically called trigeminal neuralgia. Because the most classic description of trigeminal neuralgia is episodic, sharp shooting pain without any

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detectable sensory or motor deficit, there are also other forms of trigeminal neuropathic pain that signify a higher degree of neuropathy. The best description of the spectral nature of trigeminal facial pain is found in the classification offered by Burchiel et al.2,3 in 2003 and 2005. In that classification, pain is classified based on the understanding of the pathophysiology of neuralgia (Table 67.2). TABLE 67.2 Classifications and Pathophysiology of Neuralgia Type 1 Neuralgia

Type 2 Neuralgia

Sharp stabbing episodic pain for >50% of the time Constitute the typical TN

Sharp stabbing pain 10 times per month for >3 months 3. Lasts 15 minutes and up to 4 hours after waking 4. No cranial autonomic symptoms or restlessness Not accounted for by any other condition Although pathophysiology remains unclear, several mechanisms have been proposed as posterior hypothalamic condition and central sensitization of trigeminal processing but with conflicting results.59 Several medications were studied for treatment of acute attacks, but results have been controversial. Caffeine-containing analgesics seem to be the most effective.60 Preventive medications including lithium, caffeine, indomethacin, and topiramate have been proposed for treatment of chronic hypnic headaches.

Secondary Headache Conditions MEDICATION OVERUSE HEADACHE Medication-overuse headache (MOH) is a headache condition that occurs in patients with previously existing primary headache that occurs on more than or equal to 15 days per month for more than 3 months. It is a headache condition that is caused by overuse of medications used for 3559

treating headache. MOH is diagnosed by fulfilling the following criteria1: headache on ≥15 days per month, preexisting headache disorder, overuse of acute and/or symptomatic headache drugs for >3months, and no other condition can explain those symptoms. The pathophysiology of MOH is not fully understood, and several theories have been proposed including angiotensin-converting enzyme polymorphism, brain-derived neurotrophic factor polymorphism, catecholO-methyltransferase polymorphism, and serotonin transporter polymorphism. Additionally, it has been postulated that headache may result from interactions with various neurotransmitter systems, neuronal hyperexcitability, and drug dependence.61–66 Treatment of MOH can be challenging, as medication used for treating the primary headache condition is the cause of the headache. It is important to start the treatment with educating the patient on MOH. Reducing the doses of medications used for treating the primary headache condition should follow dedicated education. Sometimes, detoxification with abrupt withdrawal may be necessary with reinstating the preventive therapy later at lower doses.67,68 Prevention is the best option to avoid MOH. Patients and providers need to work on avoiding very high doses of medications for treating primary headache with close follow-up and monitoring for early detection and treatment.

SINUS HEADACHES Sinus headache, although commonly used, specialists consider it an inaccurate term. It refers to headache or facial pain associated with sinus disease. A more accurate term proposed by specialists is rhinogenic headache.69 The HIS diagnostic criteria for headache attributed to rhinosinusitis include the following70: Frontal headache associated with pain in one or more regions of the face and fulfilling criteria 2 and 3 1. Presence of clinical, nasal endoscopic, CT and/or MRI, and/or laboratory evidence of acute or acute on top of chronic rhinosinusitis 2. Headache and facial pain that develops simultaneously with onset of 3560

rhinosinusitis 3. Headache and/or facial pain that resolves within 7 days after remission or treatment of acute rhinosinusitis Management includes treatment of sinusitis, which is essential, migraine-directed therapy,71 and nasal surgery for mucosal contact point.72

HEAD INJURY HEADACHES Posttraumatic headache (PTHA) is a form of secondary headache that develops within 7 days after a head trauma.73 There is no specific pattern for PTHA, as it can share criteria of migraine and tension headaches, but the most important factor is its association with a trauma or traumatic brain injury (TBI). The pathophysiology has been proposed to possibly be related to peripheral or central sensitization mechanisms. Treatment strategies should match the type of headache associated with the trauma. A multidisciplinary approach is highly recommended.74

SHORT-LASTING, UNILATERAL, NEURALGIFORM HEADACHE ATTACKS WITH CONJUNCTIVAL INJECTION AND TEARING Short-lasting, unilateral, neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) syndrome is a unilateral headache/facial pain characterized by brief paroxysmal attacks accompanied by ipsilateral local autonomic signs, usually conjunctival injection and lacrimation.75 Diagnostic features include the following76–78: Unilateral, mostly described as ocular-related pain but can involve larger area of the head Typically does not change sides or cross midline Moderate to severe Usually stabbing or pulsating in nature Pain lasts from 5 to 240 seconds Three patterns of attacks are described as follows: Classical single attacks Groups of a number of attacks “Sawtooth” pattern with numerous attacks lasting minutes 3561

The frequency of attacks is from 3 to 200 daily. Additional features include the following: It is accompanied by marked ipsilateral conjunctival injection and lacrimation that appear rapidly with onset of an attack. Whereas nasal stuffiness and rhinorrhea are common, sweating is rare to accompany the attack. Pathophysiology: The mechanism of SUNCT is still unclear, but studies suggested the presence of a relationship between the hypothalamus and the condition. MRI has allowed for recognition of activation within the hypothalamus during an attack. There is a direct connection between the trigeminal nucleus caudalis within the brainstem and the posterior hypothalamus. It is possible that stimulation of the peripheral trigeminal nerve activates the hypothalamus, and the hypothalamus in turn communicates with the trigeminal nucleus caudalis via the release of neurotransmitters. In support of this possible hypothalamic mechanism, elevated levels of prolactin has been associated with SUNCT.79–81 SUNCT is refractory to most treatment modalities except for the antiepileptic drug group. Lamotrigine is proposed to be the first-line medication.82,83 However, intravenously delivered lidocaine and phenytoin have shown some efficacy.

SHORT-LASTING, UNILATERAL, NEURALGIFORM HEADACHE ATTACKS WITH CRANIAL AUTONOMIC FEATURES Short-lasting, unilateral, neuralgiform headache attack with cranial autonomic features (SUNA) is a novel type of headache. It can be difficult to differentiate from SUNCT. One of the main differences is that the attack duration can be extended to 10 minutes with a similar treatment paradigm as SUNCT.

PAROXYSMAL HEMICRANIAS This type of chronic headache is usually continuous with a small percentage of patients who suffer with episodic paroxysmal hemicrania.84 Clinically, it is usually unilateral; severe orbital or periorbital pain; rarely becomes bilateral; may extend to a larger area in the head; can refer to the shoulder, neck, and arm; lasts 2 to 30 minutes; and sharp in nature. 3562

Additionally, it is accompanied by at least one of these ipsilateral autonomic phenomena/signs: conjunctival injection/lacrimation, nasal congestion, eyelid edema, facial sweating, and miosis/ptosis. Attacks may occur more than five times daily, might be seasonal temporal, periauricular, maxillary, and rarely the occipital region. Referral to the shoulder, neck, and arm is also quite common, and strong pain may cross the midline; the vast majority of attacks do not change sides. The response to indomethacin is absolute, but the mechanism is not well understood. Other alternatives include calcium channel blockers, naproxen, and carbamazepine.84–87

CONTACT POINT HEADACHE Another headache responsible for facial pain features is the contact point headache. The contact point headache is also called anterior ethmoidal neuralgia, Sluder’s neuralgia, sphenopalatine ganglion neuralgia, and pterygopalatine ganglion neuralgia. It presents as a persistent stabbing or sharp pain in a single localized area/spot on the face.88 It is thought to develop due to nerve compression related to a structural abnormality usually inside the nose, such as a septal spur or a deviated septum. The nerve affected is usually the anterior ethmoid nerve, a nerve that branches off sphenopalatine ganglion (pterygopalatine ganglion). Clinically, it presents with a pain syndrome that usually starts after the patient has had an upper respiratory infection and presents as localized pain on one spot and one side of the face; it can be localized to the roof of the mouth and upper teeth. Pain is commonly localized to an area between the eye and cheek but can radiate to other parts of the face. The only single medication that had shown effectiveness in providing relief of contact point headache is an over-the-counter decongestant. Surgery is the main treatment to cure the condition and relieve the pressure on the nerve.89 References 1. Headache Classification Committee of the International Headache Society. The International Classification of Headache Disorders, 3rd edition (Beta version). Cephalalgia 2013;33:629– 808. 2. Burchiel KJ. A new classification for facial pain. Neurosurgery 2003;53:1164–1167.

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3. Eller JL, Raslan AM, Burchiel KJ. Trigeminal neuralgia: definition and classification. Neurosurg Focus 2005;18(5):E3. 4. Devor M, Amir R, Rappaport H. Pathophysiology of trigeminal neuralgia: the ignition hypothesis. Clin J Pain 2002;18:4–13. 5. Devor M, Govrin-Lippmann R, Rappaport ZH. Mechanism of trigeminal neuralgia: an ultrastructural analysis of trigeminal root specimens obtained during microvascular decompression surgery. J Neurosurg 2002;96:532–543. 6. Burchiel KJ, Slavin KV. On the natural history of trigeminal neuralgia. Neurosurgery 2000;46:152–154. 7. Peñarrocha M, Alfaro A, Bagán JV, et al. Idiopathic trigeminal sensory neuropathy. J Oral Maxillofac Surg 1992;50:472–476. 8. Reddy GD, Viswanathan A. Trigeminal and glossopharyngeal neuralgia. Neurol Clin 2014;32(2):539–552. 9. Rey-Dios R, Cohen-Gadol AA. Current neurosurgical management of glossopharyngeal neuralgia and technical nuances for microvascular decompression surgery. Neurosurg Focus 2013;34(3):E8. 10. Haller S, Etienne L, Kövari E, et al. Imaging of neurovascular compression syndromes: trigeminal neuralgia, hemifacial spasm, vestibular paroxysmia, and glossopharyngeal neuralgia. AJNR Am J Neuroradiol 2016;37(8):1384–1392. 11. Chen J, Sindou M. Vago-glossopharyngeal neuralgia: a literature review of neurosurgical experience. Acta Neurochir (Wien) 2015;157(2):311–321. 12. Ma Y, Li YF, Wang QC, et al. Neurosurgical treatment of glossopharyngeal neuralgia: analysis of 103 cases. J Neurosurg 2016;124(4):1088–1092. 13. Rupta V, Saunders RL, Wieder DJ. Geniculate neuralgia: the surgical management of primary otalgia. J Neurosurg 1991;75:505–511. 14. Tubbs RS, Steck DT, Mortazavi MM, et al. The nervus intermedius: a review of its anatomy, function, pathology and role in neurosurgery. World Neurosurg 2013;79(5):763–767. 15. Tang IP, Freeman SR, Kontorinis G, et al. Geniculate neuralgia: a systemic review. J Laryngol Otol 2014;128:394–399. 16. Dym H, Israel H. Diagnosis and treatment of temporomandibular disorders. Dent Clin North Am 2012;56:149–161. 17. Israel H. Internal derangement of the temporomandibular joint: new perspectives on an old problem. Oral Maxillofac Surg Clin North Am 2016;28:313–333. 18. Fricton J. Myofascial pain: mechanisms to management. Oral Maxillofac Surg Clin North Am 2016;28:289–311. 19. Scrivani S, Spierings E. Classification and differential diagnosis of oral and maxillofacial pain. Oral Maxillofac Surg Clin North Am 2016;28:233–246. 20. Blau JN. Migraine: theories of pathogenesis. Lancet 1992;339:1202–1207. 21. Lance JW, Goadsby PJ. Mechanism and Management of Headache. London: ButterworthHeinemann; 1998. 22. Silberstein SD, Lipton RB, Goadsby PJ. Headache in Clinical Practice. 2nd ed. London: Martin Dunitz; 2002. 23. Olesen J, Tfelt-Hansen P, Welch KMA. The Headaches. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 2000. 24. Lipton RB, Silberstein SD, Saper JR, et al. Why headache treatment fails. Neurology 2003;60(7):1064–1070. 25. Lipton R, Dodick D, Silberstein S, et al. Single-pulse transcranial magnetic stimulation for acute treatment of migraine with aura: a randomised, double-blind, parallel-group, shamcontrolled trial. Lancet Neurol 2010;9:373–380.

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26. Goadsby P, Grosberg B, Mauskop A, et al. Effect of noninvasive vagus nerve stimulation on acute migraine: an open-label pilot study. Cephalalgia 2014;34:986–993. 27. Dodick D, Freitag F, Banks J, et al. Topiramate versus amitriptyline in migraine prevention: a 26-week, multicentre, randomized, double-blind, double-dummy, parallel-group noninferiority trial in adult migraineurs. Clin Ther 2009;31:542–549. 28. Linde K, Rossnagel K. Propranolol for migraine prophylaxis. Cochrane Database Syst Rev 2004;(2):CD003225. 29. Magis D, Schoenen J. Advances and challenges in neurostimulation for headaches. Lancet Neurol 2012;11:708–719. 30. Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia 2004;24(suppl 1):9–160. 31. Ashina M. Neurobiology of chronic tension-type headache. Cephalalgia 2004;24:161–172. 32. Bendtsen L. Central sensitization in tension-type headache—possible pathophysiological mechanisms. Cephalalgia 2000;20:486–508. 33. Jensen R. Pathophysiological mechanisms of tension-type headache: A review of epidemiological and experimental studies. Cephalalgia 1999;19:602–621. 34. Ulrich V, Russell MB, Jensen R, et al. A comparison of tension-type headache in migraineurs and non-migraineurs: a population-based study. Pain 1996;67:501–506. 35. Steiner TJ, Lange R, Voelker M. Aspirin in episodic tension-type headache: placebocontrolled dose-ranging comparison with paracetamol. Cephalalgia 2003;23:59–66. 36. Ashina S, Ashina M. Current and potential future drug therapies for tension-type headache. Curr Pain Headache Rep 2003;7:466–474. 37. Bendtsen L, Mathew NT. Prophylactic pharmacotherapy of tension-type headache. In: Olesen J, Goadsby PJ, Ramadan N, et al. The Headaches. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2005:735–741. 38. Bendtsen L, Jensen R, Olesen J. A non-selective (amitriptyline), but not a selective (citalopram), serotonin reuptake inhibitor is effective in the prophylactic treatment of chronic tension-type headache. J Neurol Neurosurg Psychiatry 1996;61:285–290. 39. Singh NN, Mishra S. Sertaline in chronic tension-type headache. J Assoc Physicians India 2002;50:873–878. 40. Manna V, Bolino F, Di Cicco L. Chronic tension-type headache, mood depression and serotonin: therapeutic effects of fluvoxamine and mianserine. Headache 1994;34:44–49. 41. Langemark M, Olesen J. Sulpiride and paroxetine in the treatment of chronic tension-type headache. An explanatory double-blind trial. Headache 1994;34:20–24. 42. Zissis N, Harmoussi S, Vlaikidis N, et al. A randomized, double-blind, placebo-controlled study of venlafaxine XR in out-patients with tension-type headache. Cephalalgia 2007;27:315–324. 43. Bendtsen L, Jensen R. Mirtazapine is effective in the prophylactic treatment of chronic tension-type headache. Neurology 2004;62:1706–1711. 44. Shimmomura T, Awaki E, Kowa H, et al. Treatment of tension type headache with tizanidine hydrochloride, its efficacy and relationship with plasma MHPG concentration. Headache 1991;31:601–604. 45. Holroyd KA, Martin PR, Nash JM. Psychological treatments of tension-type headache. In: Olesen J, Goadsby PJ, Ramadan N, et al, eds. The Headaches. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2005:711–719. 46. May A, Bahra A, Büchel C, et al. Hypothalamic activation in cluster headache attacks. Lancet 1998;352:275–278. 47. Cohen AS, Burns B, Goadsby PJ. High-flow oxygen for treatment of cluster headache: a

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randomized trial. JAMA 2009;302:2451–2457. May A, Leone M, Afra J, et al. EFNS guidelines on the treatment of cluster headache and other trigeminal-autonomic cephalalgias. Eur J Neurol 2006;13:1066–1077. Rasche D, Klase D, Tronnier VM. Neuromodulation in cluster headache. Clinical follow-up after deep brain stimulation in the posterior hypothalamus for chronic cluster headache, case report—part II [in German]. Schmerz 2008;22(suppl 1):37–40. Ansarinia M, Rezai A, Tepper SJ, et al. Sphenopalatine ganglion (SPG) stimulation during acute migraine and cluster headaches. Headache 2010;50:1164–1174. May A, Leone M, Boecker H, et al. Hypothalamic deep brain stimulation in positron emission tomography. J Neurosci 2006;26:3589–3593. Broggi G, Messina G, Franzini A. Cluster headache and TACs: rationale for central and peripheral neuromodulation. Neurol Sci 2009;30(suppl 1):S75–S79. Rooke D. Benign exertional headache. Med Clin North Am 1968;52:801–808. McCrory P. Recognizing exercise-related headache. Phys Sports Med 1997;25:33–43. Paulson GW. Weightlifters headache. Headache 1983;23:193–194. MacDougall JD, Tuxen D, Sale DG, et al. Arterial blood pressure response to heavy resistance exercise. J Appl Physiol 1985;58:785–790. Liang JF, Wang SJ. Hypnic headache: a review of clinical features, therapeutic options and outcomes. Cephalalgia 2014;34(10):795–805. Dodick D. Patient perceptions and treatment preferences in migraine management. CNS Drugs 2002;16 (suppl 1):19–24. de Tommaso M, Valeriani M, Guido M, et al. Abnormal brain processing of cutaneous pain in patients with chronic migraine. Pain 2003;101:25–32. Holle D, Naegel S, Krebs S, et al. Clinical characteristics and therapeutic options in hypnic headache. Cephalalgia 2010;30:1435–1442. Phillips MI. Functions of angiotensin in the central nervous system. Annu Rev Physiol 1987;49:413–435. Binder DK, Scharfman HE. Brain-derived neurotrophic factor. Growth Factors 2004;22:123– 131. Cargnin S, Viana M, Ghiotto N, et al. Functional polymorphisms in COMT and SLC6A4 genes influence the prognosis of patients with medication overuse headache after withdrawal therapy. Eur J Neurol 2014;21:989–995. Srikiatkhachorn A, Tarasub N, Govitrapong P. Effect of chronic analgesic exposure on the central serotonin system: a possible mechanism of analgesic abuse headache. Headache 2000;40:343–350. Ayzenberg I, Obermann M, Nyuis P, et al. Central sensitization of the trigeminal and somatic nociceptive systems in medication overuse headache mainly involves cerebral supraspinal structures. Cephalalgia 2006;26:1106–1114. Fuh JL, Wang SJ, Lu SR, et al. Does medication overuse headache represent a behavior of dependence? Pain 2005;119:49–55. Rossi P, Di Lorenzo C, Faroni J, et al. Advice alone vs. structured detoxification programmes for medication overuse headache: a prospective, randomized, open-label trial in transformed migraine patients with low medical needs. Cephalalgia 2006;26:1097–1105. Rossi P, Faroni JV, Tassorelli C, et al. Advice alone versus structured detoxification programmes for complicated medication overuse headache (MOH): a prospective, randomized, open-label trial. J Headache Pain 2013;14:10. Cady RK, Dodick DW, Levine HL, et al. Sinus headache: a neurology, otolaryngology, allergy, and primary care consensus on diagnosis and treatment. Mayo Clin Proc 2005;80(7):908–916.

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70. Levine HL, Setzen M, Cady RK, et al. An otolaryngology, neurology, allergy, and primary care consensus on diagnosis and treatment of sinus headache. Otolaryngol Head Neck Surg 2006;134:516–523. 71. Ishkanian G, Blumenthal H, Webster CJ, et al. Efficacy of sumatriptan tablets in migraineurs self-described or physician-diagnosed as having sinus headache: a randomized, double-blind, placebo-controlled study. Clin Ther 2007;29:99–109. 72. Welge-Luessen A, Hauser R, Schmid N, et al. Endonasal surgery for contact point headaches: a 10-year longitudinal study. Laryngoscope 2003;113:2151–2156. 73. Walker WC, Seel RT, Curtiss G, et al. Headache after moderate and severe traumatic brain injury: a longitudinal analysis. Arch Phys Med Rehabil 2005;86(9):1793–1800. 74. Ivanhoe CB, Hartman ET. Clinical caveats on medical assessment and treatment of pain after TBI. J Head Trauma Rehabil 2004;19:29–39. 75. Sjaastad O, Saunte C, Salvesen R, et al. Shortlasting unilateral neuralgiform headache attacks with conjunctival injection, tearing, sweating, and rhinorrhea. Cephalalgia 1989;9(2):147– 156. 76. Cohen AS, Matharu MS, Goadsby PJ. Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) or cranial autonomic features (SUNA): a prospective clinical study of SUNCT and SUNA. Brain 2006;129(pt 10):2746–2760. 77. Sjaastad O, Kruszewski P. Trigeminal neuralgia and “SUNCT” syndrome: similarities and differences in the clinical pictures. An overview. Funct Neurol 1992;7(2):103–107. 78. Pareja JA, Cuadrado ML. SUNCT syndrome: an update. Expert Opin Pharmacother 2005;6(4):591–599. 79. Auer T, Janszky J, Schwarcz A, et al. Attack-related brainstem activation in a patient with SUNCT syndrome: an ictal fMRI study. Headache 2009;49(6):909–912. 80. Goadsby PJ, Lipton RB. A review of paroxysmal hemicranias, SUNCT syndrome and other short-lasting headaches with autonomic feature, including new cases. Brain 1997;120(pt 1):193–209. 81. Bosco D, Labate A, Mungari P, et al. SUNCT and high nocturnal prolactin levels: some new unusual characteristics. J Headache Pain 2007;8(2):114–118. 82. Cohen AS. Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing. Cephalalgia 2007;27:824–832. 83. Cohen AS, Matharu MS, Goadsby PJ. Trigeminal autonomic cephalalgias: current and future treatments. Headache 2007;47:969–980. 84. Boes CJ, Dodick DW. Refining the clinical spectrum of chronic paroxysmal hemicrania: a review of 74 patients. Headache 2002;42(8):699–708. 85. Antonaci F, Sjaastad O. Chronic paroxysmal hemicrania (CPH): a review of the clinical manifestations. Headache 1989;29(10):648–656. 86. Matharu MS, Goadsby PJ. Bilateral paroxysmal hemicrania or bilateral paroxysmal cephalalgia, another novel indomethacin-responsive primary headache syndrome? Cephalalgia 2005;25(2):79–81. 87. Boes CJ, Vincent M, Russell D. Chronic paroxysmal hemicrania. In: Olesen J, Goadsby PJ, Ramadan NM, et al, eds. The Headaches. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2006:815–822. 88. Ahamed SH, Jones NS. What is Sluder’s neuralgia? J Laryngol Otol 2003;117(6):437–443. 89. Karlov VA, Tebloev IK, Savitskaia ON, et al. Facial autonomic and trophic disorders [in Russian]. Zh Nevropatol Psikhiatr Im S S Korsakova 1979;79(4):416–420.

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CHAPTER 68 Neck and Arm Pain ANITA H. HICKEY and ZAHID H. BAJWA The unique anatomy of the cervical spine and upper extremity balances the attributes of strength and stability with those of flexibility and range of motion. The biomechanical properties associated with these combined properties allow for a high incidence of degenerative changes. These increase with aging and are often associated with episodic or chronic pain. Although the origin of pain in the neck is often categorized as axial pain versus radicular pain and musculoskeletal pain versus neuropathic pain, the patient presenting for treatment in the clinical setting may not always be representative of these categorical descriptions. An understanding of the normal anatomy of the neck and upper extremity, pathophysiology of common disorders of the cervical spine, diversity of clinical presentations of neck and arm pain, and the potential contribution of systemic and psychological factors is critical in forming a differential diagnosis, referring the patient for appropriate diagnostic tests and evaluations and instituting timely and appropriate treatment. This chapter focuses on the anatomy of the cervical spine and upper extremity; recent data regarding the epidemiology of neck and arm pain; the critical role of the clinician in performing a thorough and targeted history and physical examination; and finally, a discussion of the etiology and treatment of neck and arm pain. The common causes of mechanical neck and arm pain, including cervical spondylosis and myelopathy, cervical radiculopathy, cervicogenic headache (CEH), brachial plexopathy, peripheral nerve entrapment syndromes of the upper extremity, and thoracic outlet syndrome (TOS), are discussed in this chapter. Myofascial pain syndromes, fibromyalgia, and acute musculoskeletal disorders can involve the neck and upper extremities and are covered in detail elsewhere in this text. Neck and arm pain may also be secondary to primary or metastatic disease. Cancer pain 3568

is discussed more thoroughly elsewhere as well. Therapeutic modalities are covered more extensively in Part V: Methods for Symptomatic Control.

Anatomy of the Neck and Arm CERVICAL SPINE The anatomy of the cervical spine is complex in order to allow for support of the weight of the cranium, to provide protection and support of the neurovascular elements of the cervical spine, and to simultaneously permit functional mobility in relation to the surrounding structures. It is composed of 7 vertebrae, 5 intervertebral disks, 12 joints of Luschka, and 14 zygapophyseal joints, uniquely bound and connected to numerous ligaments and muscles which both limit and permit varying degrees of motion of the cervical spine.1 With the exception of the first two cervical vertebrae, which have unique characteristics, each of the seven cervical vertebrae is composed of a segmental unit, which includes a vertebral body, an intervertebral disk, four uncovertebral joints of Luschka, two pedicles, two lamina, two inferior, and two superior zygapophyseal (articular facet) joints. Between each vertebral segment, a spinal nerve, radicular blood vessels, and the sinuvertebral (recurrent meningeal) nerves pass through neural openings or foramina on each side of the cervical spine (Fig. 68.1).1

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FIGURE 68.1 Anatomy of the cervical spine. A: Lateral view, showing landmarks of the spine, including the hyoid bone, thyroid and cricoid cartilages, and transverse and spinous processes. B: View of the skeletal portion of the lower skull and cervical spine. The skull and spinous processes are shown in sagittal section, whereas the vertebral bodies are shown as normal. C: Sagittal view of the cervical spine showing the relationship of the brainstem, medulla oblongata, foramen magnum, and spinal canal, containing the spinal cord. Normally, the lower portion of the medulla is outside and below the foramen magnum so that subluxation of the atlas on the axis and compression of the lower brainstem can occur by compression from the odontoid process, which moves posteriorly against the neuraxis. (Modified from Bland JH. Disorders of the Cervical Spine: Diagnosis and Medical Management. Philadelphia, PA: Saunders; 1987. Copyright © 1987 Elsevier. With permission.)

The upper two segments of the cervical spine have unique anatomic and biomechanical characteristics when compared with the lower five segments of the cervical spine. The atlas, or C1 vertebra, is a ring-shaped vertebra with paired lateral pillars, which function as articulating joints or 3570

facets. The upper ellipsoid facets articulate superiorly with the occipital condyles to form the atlantooccipital joints, whereas the round and concave inferior facets articulate inferiorly with the axis to form the atlantoaxial joints. The anterior arch of the atlas incorporates an articular surface which contacts the anterior surface of the dens or odontoid process of the axis. The atlas is the widest of the cervical vertebrae, allowing for the spinal cord, dens, and a surrounding cushion of spinal fluid. It has a mean internal, anteroposterior dimension of approximately 31.7 mm and an internal width of 32.2 mm. The atlas is the only cervical vertebra not associated with an intervertebral disk. Its transverse process is longer than the other cervical vertebrae to support the attachments of the muscles that rotate the head, and its transverse foramen contains the vertebral artery, veins, and sympathetic nerves (Fig. 68.2).

FIGURE 68.2 Anatomy of the atlas and axis. A: Superior view of the atlas. B: The axis viewed from a superior and posteroanterior aspect. C: Lateral view of the axis.

The axis, or C2 vertebra, has a small body anteriorly from which the odontoid process arises and projects upward. Its oval-shaped anterior face articulates with that on the anterior arch of the atlas. The posterior surface of the odontoid process articulates with the transverse ligament. The facets on the upper and lower surfaces of the lateral masses of the axis articulate with the atlas above and the C3 facet joints below. The atlas also has a large palpable bifid spinous process and small transverse processes with transverse openings or foramina through which the vertebral artery, veins, and the vertebral sympathetic plexuses pass. Because both the atlas and the axis lack pedicles and intervertebral foramen, the nerve roots of the first and second spinal nerves pass above and posterior to the articulating lateral masses of each vertebrae. The hypoglossal nerves traverse the 3571

occipital condyles anterolaterally through the hypoglossal foramen a mean of 12.2 mm from the posterior margin of the occipital condyle (see Fig. 68.2).1 The five lower cervical vertebrae share common characteristics in that they are composed of a vertebral body, an intervening intervertebral disk, two pedicles, two laminae, two vertebral arches, and a spinous process. The upper and lower surfaces of the pedicles form the articulating facets of the cervical zygapophyseal joints. The transverse processes are situated anterolaterally to the facet joints. Their trough-shaped surfaces contain the roots of the cervical spinal nerves and a foramen through which the vertebral artery, veins, and vertebral sympathetic nerve pass.1 The anterior portions of the C2 through C7 vertebral bodies, like those of the thoracic and lumbar spine, are connected at their upper and lower surfaces by intervertebral disks, which make up the main joints of the spinal column. Each disk is made up of a central nucleus pulposus surrounded by a thick ring of fibrous cartilage called the annulus fibrosis. The disk is connected to the vertebral body above and below by a hyaline cartilage endplate whose fibers interface with the disk and the vertebral body.1 The nucleus pulposus contains collagen and elastin fibers embedded in a colloidal proteoglycan gel which is osmotically active in healthy disks with an approximately 80% water content. The annulus is made up of 15 to 25 concentric rings or lamellae made up of collagen fibers oriented in an alternating criss-cross oblique fashion with elastin fibers layered between the lamellae. The annulus attaches around the entire circumference of the upper and lower endplates and, together with the nucleus pulposus, forms a fluid elastic system. These properties allow the disk to absorb and more evenly distribute the mechanical stress of high-impact activity. By the third decade of life, the disk has become avascular and must rely on diffusion of nutrients and water through the endplates and lymph. The properties of the healthy disk permit disk hydration by way of compression and relaxation of the viscoelastic system, similar to the action of squeezing a sponge. With aging, atherosclerosis, and trauma, degenerative changes occur within the disk. A decrease in protein polysaccharide content and thus its water composition leads to loss of its viscoelastic properties. 3572

Degeneration of the disk increases the axial load and shear on the zygapophyseal joints and contributes to simultaneous degenerative changes of these posterior spinal elements (Fig. 68.3).1

FIGURE 68.3 Schematic depiction of the hydraulic mechanism of the intervertebral disk. A: Normal disk at rest. The internal pressure is exerted in all directions, and the fibers of the annulus are taut. B: When the disk is compressed, the fluid within the nucleus pulposus cannot compress, so the annulus must bulge. C: With flexion of the spine, the fluid shifts within the intervertebral disk; the cubic contents remain the same, but the fluid shift causes fibers of the anterior annulus to shorten and those of the posterior annulus to elongate. W, weight. (From Cailliet R. Neck and Arm Pain. 2nd ed. Philadelphia: FA Davis; 1981. Reproduced with permission of F.A. Davis Co., in the format Republish in a book via Copyright Clearance Center.)

The posterior elements of the lower segments of the cervical spine consist of two vertebral arches, a central posterior spinous process, two transverse processes, and a paired articulation. The transverse processes and posterior spinous processes serve as sites for attachment of supporting ligaments and neck muscles. The zygapophyseal facet joints are true joints with cartilaginous surfaces lined with synovium, containing synovial fluid and surrounded with a ligamentous joint capsule. As such, they are subject to the same inflammatory and degenerative diseases found in other synovial joints. The cervical zygapophyseal joints provide a guiding and gliding movement between the adjacent cervical vertebrae. The movements allowed at the atlantooccipital and atlantoaxial joint are much different from those allowed at the C2–C3 through C7–T1 joints. Differences between the cervical and lumbar spine are summarized in Table 68.1 and Figure 68.4.1 3573

TABLE 68.1 Differences between the Cervical and Lumbar Spine Characteristic

Cervical

Lumbar

Disk to vertebral body height ratio Vertical height of disk

1:2

1:3

Anterior height 2× that of posterior height/wedge shaped Convex and concave, nucleus in anterior portion of disk False joints or pseudoarthrosis, appear at 10–20 years of age Double layered between vertebrae Broad, thick, and complete across postvertebra Forward and backward gliding motion

Anterior height slightly greater anterior

Vertebral endplates Joints of von Luschka

Posterior longitudinal ligament

Movement between vertebrae

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Flat and parallel, nucleus centrally located Not present in lumbar or thoracic spine Incomplete posteriorly from L3 to S1

Rocking movement

FIGURE 68.4 Comparative views of the cervical and lumbar functional units. A: Cross-section of the five joints of the cervical spine, which include an intervertebral disk, the paired uncovertebral (Luschka) joints, and the paired posterior articulations. B: Cross-section of the three joints of the lumbar spine, which include an intervertebral disk and the paired posterior articulations. C,D: Lateral views of the same vertebrae shown in A and B. The dashed lines divide the anterior supporting portion from the posterior gliding portion of each functional unit. E,F: Lateral views of the bodies of the vertebrae of the cervical and lumbar spines, depicting particularly the shapes of the intervertebral disks. Note that in the cervical region, the anterior portion of the disk is larger (higher) than the posterior portion, whereas in the lumbar region, the difference between the anterior and posterior portions is much less. (Modified from Cailliet R. Neck and Arm Pain. 2nd ed. Philadelphia: FA Davis; 1981. Reproduced with permission of F.A. Davis Co., in the format Republish in a book via Copyright Clearance Center.)

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Ligaments of the Cervical Spine The ligaments of the cervical spine provide essential protection to the spinal cord and nerves during various stresses which occur owing to a topheavy and eccentrically balanced head atop a relatively narrow elastic cervical spine. The greatest range and amplitude of movement in the cervical spine occurs between the occiput and the C3 vertebra, whereas nodding in an up and down movement in the sagittal plane occurs between the atlas and the axis.1 Atlantooccipital Unit Flexion and extension at the occiput to C1 level is limited to 23 to 24.5 degrees by impingement of the tip of the dens on the foramen magnum in flexion and the tectorial membrane in extension. The tectorial membrane is a fan-shaped continuation of the posterior longitudinal ligament to the base of the occiput where its fibers connect with the dura mater. Lateral bending is resisted by the anatomy of the occipital-C1 articulation and the alar ligaments and averages 3.4 to 5.5 degrees per side. The alar ligaments are enclosed in a synovial membrane and extend to the margin of the foramen magnum from each side of the odontoid process. Axial rotation is also limited by the atlantooccipital joint and the alar ligament, 2.4 to 7.2 degrees per side. Lateral translation, stretch and compression, and sagittal plane translation are restricted by the tectorial membrane, the alar, and the apical ligaments as well as the occipital-C1 articulation. The apical ligament is a vestigial remnant of the notochord and attaches from the peak of the odontoid process to the anterior foramen magnum. Other ligaments at this level include the posterior atlantooccipital membrane, which forms the connection between the anterior margin of the foramen magnum and the anterior arch of the atlas, and the posterior atlantooccipital membrane, which extends posteriorly over the vertebral artery.1 Atlantoaxial Unit Axial rotation is the primary movement of the C1–C2 segment. The average 23.3 to 38.9 degree per side rotation is limited by the atlantoaxial joints, the transverse ligament of the ipsilateral side, the alar ligaments of the contralateral side, and capsular ligaments. Flexion rotation is 10.1 to 22.4 degrees and is resisted by the transverse ligament during flexion, the 3576

tectorial membrane and joint anatomy. Lateral bending is limited to 6.7 degrees mostly by the alar ligament. Posterior movement or translation at this level is resisted by abutment of the dens on the arch of C1. The transverse ligament extends posteriorly to the odontoid process between the lateral pillars of the atlas. The destabilizing effect of a tear of the transverse ligament is equal to that of a fracture of the odontoid process.1,2 Other Cervical Ligaments The posterior longitudinal ligament and the anterior longitudinal ligaments limit the degree of flexion, extension, and transverse sliding of the C2 to C7 vertebrae. The anterior longitudinal ligament blends with the annulus as it crosses the disk spaces and adheres to the front of the vertebral bodies. The posterior longitudinal ligament is a double-layered structure which is firmly bound to the posterior surface of the cervical disks and loosely bound to the posterior cervical vertebrae. It reinforces the capsular ligaments and the anterior border of the cervical spinal canal.1 The ligamentum flavum is a paired structure forming the posterior border of the epidural space. Collectively referred to as ligament flava, they extend between the anterior-inferior surface of the lamina above and to the posterior-superior surface of the lamina below. Posterior to the ligamentum flavum, the interspinous ligaments extend between and connect each spinous process. The ligamentum nuchae is the superior continuation of the supraspinous ligaments of the thoracic and lumbar vertebrae. It is a strong fibrous posterior ligament which extends from the base of the skull to the tips of the posterior cervical spinous process and vertebra (Fig. 68.5).1

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FIGURE 68.5 A–C: Ligaments of various parts of the cervical spine (see text for details).

MUSCULATURE OF THE NECK The capital movers are the muscles of the neck that flex and extend the head. The capital extensors include the posterior rectus capitis minor and major and the obliquus capitis superior and inferior. The groups of longer muscles that act as capital extensors while working together bilaterally include the longissimus capitis, semispinalis capitis, and splenius capitis. The capital flexors are the short recti and the longus capitis muscles. The most extension and extensor musculature is at the atlantoaxial and C6 through T1 joints. The cervical extensors include the splenius cervicis, longissimus cervicis, and semispinalis cervicis. Maximum flexion of the cervical spine and maximum cervical lordosis occur at C4–C5. The flexors of the cervical spine consist of the scalenus anterior, medius, and posterior. Unilateral rotators of the head include the splenius cervicis, splenius capitis, longissimus capitis, and sternocleidomastoid. The erector muscles of the vertebral column are also involved in movement of the neck (Fig. 68.6).1

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FIGURE 68.6 Musculature of the head and neck. A: The capital extensors attach on the skull and move the head on the neck. B: The cervical extensors originate from and attach on the cervical spine and alter the curvature of the spine. C: The capital flexors flex the head on the neck. D: The cervical flexors attach occlusively on the cervical vertebrae and have no significant functional attachment to the skull. (Modified from Clemente CD, ed. Gray’s Anatomy of the Human Body. 30th ed. Philadelphia: Lea & Febiger; 1985; and from Cailliet R. Neck and Arm Pain. 2nd ed. Philadelphia: FA Davis; 1981. Reproduced with permission of F.A. Davis Co., in the format Republish in a book via Copyright Clearance Center.)

THE VERTEBRAL CANAL A transverse cut through the cervical vertebral canal reveals its triangular shape with the base or anterior wall made of the vertebra, disk, posterior longitudinal ligament, pedicle, and neural foramina. The lateral and dorsolateral aspects of the other two sides of the triangle include the zygapophyseal joints, laminae, and ligament flava. The canal has its largest sagittal diameter, a range of 16 to 30 mm, at the C1–C2 level and its smallest sagittal diameter, a range of 14 to 23 mm, at the C5–C6 level. The cervical canal lengthens and the intervertebral foramina enlarge during flexion, whereas shortening of the cord and a decrease in the size of 3579

the foramen occurs with extension. Lateral flexion or rotation causes the ipsilateral foramina to decrease in size and the contralateral foramina to enlarge. These changes in size of the foramen become significant in the degenerative spine (Fig. 68.7).1

FIGURE 68.7 Changes in the size of the intervertebral foramina with movement of the neck. A: With lateral flexion and rotation of the head, the foramina become smaller on the side of the head to which the head flexes laterally or rotates, and they are open on the opposite side. B: With forward flexion, the intervertebral foramina become larger, whereas with extension they become smaller. (Modified from Cailliet R. Neck and Arm Pain. 2nd ed. Philadelphia: FA Davis; 1981. Reproduced with permission of F.A. Davis Co., in the format Republish in a book via Copyright Clearance Center.)

The spinal cord is covered by meninges which consist of the delicate pia matter attached to the cord, the web-like arachnoid membrane, and the strong outer dura mater. The dura mater is attached to the foramen magnum and the dorsal surfaces of the C2 and C3 vertebra. The spinal cord is suspended in and protected by surrounding cerebrospinal fluid and is attached laterally to the dural sheath by the dentate ligaments, which are 3580

thickenings of the pia mater between and anterior and posterior roots. The anterior and posterior rootlets join the anterior and posterior roots, respectively, at the inner aspect of the intervertebral foramina (Fig. 68.8). An enlargement of the cervical cord occurs from the C3–T1 levels. It is larger than the lumbar enlargement as it contains the ascending and descending long tracts for the trunk as well as the upper and lower limbs. The transverse diameter of the cervical spinal cord is greater than its sagittal diameter, and the cervical cord occupies approximately 40% of the canal. With neck extension, the dura relaxes to form a corrugated appearance and the vertebra above approximates the arch of the vertebra below causing encroachment into the cervical canal. These factors, together with shortening of the cord during extension, increase the risk of impingement of the cord during neck extension.1

FIGURE 68.8 Transverse sections of the cervical spine. A: The spinal cord and anterior and posterior rootlets join to form the spinal nerve. Note the relationship of the nerves to the Luschka and zygapophyseal joints and the two vertebral arteries, which pass through the transverse foramina and are located just anterior to the nerve. B: Cross-section of a cervical vertebra showing some details of the relationship of the posterior root to the lateral aspect of the ligamentum flavum, which covers the zygapophyseal joint just posterior to it. The anterior root and its dural covering are close to the lateral part of the posterior longitudinal ligaments and to the capsules of the joint of Luschka. The proximal portion of the dorsal root ganglion is in the outer portion of the intervertebral foramen, whereas the remainder is in the gutter of the transverse process. C: Detailed anatomy of a nerve root and its meningeal covering. Note the extent of the root pouch and root sleeve. Just distal to the joining of the anterior and posterior roots is the short spinal nerve covered by epineurium (the continuation of the dura), which promptly divides into the anterior primary division (APD) and posterior primary division (PPD) and gives off a white ramus communicantes (WRC). (A, Modified from Bland JH. Disorders of the Cervical Spine: Diagnosis and Medical Management. 2nd ed. Philadelphia, PA: Saunders; 1987. Copyright © 1987 Elsevier. With permission.; B and C,

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Modified from Cailliet R. Neck and Arm Pain. 2nd ed. Philadelphia: FA Davis; 1981. Reproduced with permission of F.A. Davis Co., in the format Republish in a book via Copyright Clearance Center.)

VERTEBRAL ARTERIES The vertebral arteries are the first branches from the subclavian trunk and pass cephalad as they course through the transverse foramina of C6–C2 anterior to the cervical nerves. They are accompanied by the vertebral venous plexus and the vertebral nerve and sympathetic plexus, whose fibers originate from neurons in the stellate and intermediate cervical sympathetic ganglia. Branches from the vertebral artery pass through the intervertebral foramina where they supply ligaments, dura, and bone and communicate with the posterior and anterior spinal arteries, which are also branches of the vertebral arteries. The vertebral arteries are supplied by fibers from the vertebral sympathetic plexus as are the basilar artery, circle of Willis, superior cerebellar, and posterior cerebellar artery (Fig. 68.9).1

FIGURE 68.9 A: Lateral view of the cervical vertebrae depicting the course of the vertebral artery from C6 to C1 through bony ridges of the foramina transversaria. Note the double U turn the artery makes from C2 to C1 in its posterior course around the lateral mass of the atlas. B: The two vertebral arteries join to form the basal arteries. Also shown is the circle of Willis. Note the origin

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of the anterior spinal artery and the two posterior spinal arteries from the two vertebral arteries.

CERVICAL NERVES A more detailed discussion of peripheral and spinal pain mechanisms and applied anatomy relevant to pain can be found in earlier chapters of this text. The spinal nerve roots are composed of a dorsal sensory root and a ventral motor root. The posterior root breaks into 12 or more rootlets which attach in series to the dorsolateral sulcus of the cord near Lissauer’s tract and then project into the dorsal and ventral horns. Peripherally, the sensory rootlets converge into the fascicule radiculae which unite to form the dorsal root ganglion. A smaller number of rootlets make up the anterior root which arises from the ventrolateral sulcus of the cord. Each rootlet is covered by pia mater, and as they coalesce to form dorsal and ventral roots, they become separately covered in arachnoid-dural sleeves which are attached to the bony margin of the intervertebral foramen. The anterior roots are in contact with Luschka’s joint, and the disk annulus and the dorsal root approximates the articular process and zygapophyseal joint capsule as they pass through the cervical intervertebral foramen. The dorsal and anterior roots join slightly beyond the dorsal root ganglion to form the composite spinal nerve.1 The figure eight-shaped intervertebral foramina are largest at the C2–C3 level and progressively narrow and shorten to the C6–C7 level with an average vertical diameter of 10 mm and transverse diameter of 5 mm. The first and second cervical nerves are unique in that they do not pass through an intervertebral foramen. The first cervical nerve passes between the occiput and C1 lateral to the occipital condyle and the second between C1 and C2 posterior to the lateral pillars.1 In addition to the nerve roots, the foramina contain the spinal radicular arteries, intervertebral veins, and venous plexuses together with loose areolar tissue and fat from the adjoining extension of the epidural space. These provide a protective cushion in the healthy spine. Each spinal nerve receives one or more gray rami communicantes from the cervical sympathetic ganglia after exiting the spinal canal. Spinal nerves 1 through 4 receive fibers from the superior cervical sympathetic ganglion, spinal nerves 5 and 6 from the intermediate ganglia, spinal nerves 7 and 8 from the inferior cervical ganglion, and spinal cervical nerve 8 and thoracic 1 3583

from the first thoracic ganglion. The meninges are supplied from a branch of the cervical spinal nerve at each level (Figs. 68.8 and 68.10).1

FIGURE 68.10 Lateral view showing the course and relation of the cervical nerves and the cervical sympathetic chain.

Lateral to the intervertebral foramen, posterior to the vertebral artery, the spinal nerves separate into posterior and anterior primary divisions with the anterior motor divisions being much larger than the posterior divisions, with the exception of C1. Each spinal nerve supplies muscles (myotomes) and skin (dermatomes) as well as ligamentous and bony structures (sclerotomes). The posterior primary division passes over the posterior portion of the transverse process around the articular pillar and divides into the medial sensory and lateral muscular branches, with the exception of the C1 nerve.1 The first cervical nerve or suboccipital nerve remains as one trunk and supplies the muscles of the suboccipital triangle. Sensory fibers from the C1 nerve supply the periosteum and body of the atlas and occiput, the atlantooccipital and atlantoaxial joints, and ligaments around these joints. It may occasionally supply skin of the scalp and communicate with the 3584

greater and lesser occipital nerves. The posterior primary divisions of the other cervical spinal nerves supply the muscles of the posterior neck (lateral branches) and skin of the neck (medial branches).1 The greater occipital nerve is the medial or sensory branch of the posterior division of the second cervical nerve. It communicates with the third cervical nerve to supply the scalp over the vertex and top of the head and gives muscular branches to the semispinalis capitis. The third or least occipital nerve arises from the medial sensory branch of the posterior division of the third cervical nerve (Figs. 68.11 and 68.12).1

FIGURE 68.11 Cross-section of the third cervical segment showing the course and distribution of the posterior primary division, with its medial branch passing posteriorly to supply the skin and subcutaneous structures and the lateral branch supplying the muscles. Also shown is a cross-section of the superior cervical ganglion and its connection to the nerve by the white ramus communicantes. Note the vertebral vessels just anterior to the nerve.

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FIGURE 68.12 Cutaneous nerves derived from the cervical plexus (see text for details).

THE CERVICAL AND BRACHIAL PLEXUS The cervical plexus is made up of the anterior primary divisions of the upper four cervical nerves. The brachial plexus is formed from the lower four cervical nerves, C5 through C8, together with T1 (Fig. 68.13).1

FIGURE 68.13 Anterior view showing the formation of the cervical and brachial plexuses.

The anterior trunks from cervical nerves two through four divide into 3586

ascending and descending branches which form a series of three loops. These are located lateral to the vertebrae, anterior to the levator scapulae and scalenus medius muscles, and beneath the sternocleidomastoid muscle. The deep branches of the cervical plexus lie beneath the sternocleidomastoid muscle and are divided into the lateral or external group and the medial or internal group. The lateral group of branches supplies muscular branches to the scalenus medius, sternocleidomastoid, trapezius, and levator scapulae. It also sends communicating branches to the spinal accessory nerve. The medial or internal branches send off communicating fibers which join the vagus, hypoglossal and descendens hypoglossi nerves, the superior cervical sympathetic ganglion, and, by means of the ansa hypoglossi, supply the thyrohyoid, geniohyoid, omohyoid, sternothyroid, and sternohyoid muscles. The medial branches also supply the rectus capitis, lateralis, and anticus, the longus capitis and longus colli muscles, as well as the diaphragm by way of the phrenic nerve.1 The superficial or cutaneous branches of the cervical plexus are often referred to as the superficial cervical plexus and include the lesser occipital nerve, the great auricular nerve, the anterior cutaneous nerve, and the supraclavicular nerve. The lesser occipital nerve joins with the greater occipital and greater auricular nerves to supply the posterior scalp. Its auricular branch supplies the upper and posterior auricula and communicates with the mastoid branch of the great auricular nerve. The great auricular nerve supplies the skin of the face over the parotid gland and communicates with the facial nerve via its anterior or facial branch. Another branch supplies the lobule and lower part of the concha of the ear and communicates with the lesser occipital nerve, the auricular branch of the vagus, and the posterior auricular branch of the facial nerve. The anterior cutaneous nerve supplies the cranial, ventral, and lateral aspects of the neck as far as the sternum.1 Finally, the supraclavicular nerve supplies the skin and superficial fascia of the clavicular region as well as the periosteum and bone of the clavicle. Via its medial or supraclavicular branches known also as the suprasternal nerves, it supplies the skin of the infraclavicular region medially as far as the midline and laterally to the junction of the medial and middle third of 3587

the clavicle. The intermediate supraclavicular nerve supplies the skin over the pectoralis major as far as the second or third rib and communicates with the cutaneous branches of the second and third intercostals nerves. The lateral supraclavicular nerves or supraacromial nerves supply the skin of the top and dorsal parts of the shoulder (Figs. 68.14 and 68.15).1

FIGURE 68.14 Origin and composition of the cervical plexus. m., muscle; n., nerve.

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FIGURE 68.15 Dermatomes of the neck and head derived from the upper four cervical nerves.

The brachial plexus is formed from the primary anterior divisions of the fifth through eighth cervical nerves and the first thoracic nerve with occasional contributing branches from the anterior primary divisions of the fourth cervical and second thoracic nerves. These combine to form three trunks which include (1) the upper trunk, formed from the primary divisions of the fifth and sixth cervical nerves; (2) the middle trunk, formed from the seventh primary division; and (3) the lower trunk, formed from the eighth cervical and first thoracic primary divisions.1 The upper trunk gives off the suprascapular nerve which supplies the shoulder joint, 3589

the supraspinatus and infraspinatus muscles, and the subclavius nerve, which supplies the subclavius muscle. The three trunks continue from the interscalenus space in an anterolateral and inferior direction toward the first rib. These further divide into anterior and posterior divisions which pass beneath the midclavicular region to enter the apex of the axilla. Within the axilla, the anterior and posterior divisions form the lateral, medial, and posterior cords. The anterior divisions of the upper and middle trunks, containing fibers from the fifth, sixth, and seventh cervical nerves, form the lateral cord. The anterior division of the lower trunk continues as the medial cord and contains fibers from the eighth cervical and first thoracic nerves. The union of all the posterior divisions makes up the posterior cord, which thus contains fibers from all nerves of the brachial plexus. The three cords divide to give rise to the peripheral nerves of the upper extremity at the lateral border of the pectoralis minor. The lateral aspect of the median nerve and the musculocutaneous nerves derive from the lateral cord. The medial cord divides into the medial head of the median nerve, the ulnar nerve, and the medial antebrachial and brachial cutaneous nerves as well as a branch to the intercostobrachial nerve. The axillary and radial nerves are terminating branches from the posterior cord.1 In addition to supplying terminal branches to the upper extremity, the brachial plexus carries postganglionic sympathetic fibers from the cervical and thoracic sympathetic chain to the upper limbs. The brachial plexus also supplies branches to the longus colli muscle and the scalene muscles. The fifth cervical nerve sends fibers to the phrenic nerve, the rhomboid muscles, and the levator scapulae muscles via the dorsal scapular nerve. Fibers from the anterior divisions of the fifth, sixth, and seventh cervical nerves supply the serratus anterior muscle via the long thoracic nerve (Table 68.2 and Figs. 68.16 and 68.17). The segmental and peripheral nerve supply of the neck and arm is summarized in Figures 68.18 and 68.19 as well as Tables 68.3, 68.4, and 68.5. Sympathetic nervous system contributions to the upper extremity from the cervical and thoracic preganglionic neurons are illustrated and described in Figure 68.20. Contributions from the anterolateral and posterolateral subclavian sympathetic nerves, which supply the subclavian artery and its branches 3590

distal to the scalene muscles, contain both sympathetic and sensory fibers.1 TABLE 68.2 Organization and Branches of the Brachial Plexus Structure

Neurotome

Branches of Cervical Nerves To phrenic nerve To longus colli and scaleni muscles

C5 C5–C7

Branches from Roots Dorsal scapular nerve Long thoracic nerve

C4, C5 C5–C7

Branches from Trunks (Superior Trunk) Nerve to subclavius Suprascapular nerve Posterior cord origin (from all trunks)

C5, C6 C5, C6 C5–C8, T1

Branches Superior subscapular nerve Inferior subscapular nerve Thoracodorsal nerve

C5, C6 C5, C6 C6–C8

Terminal Branches Axillary Radial Lateral cord origin (superior and middle trunk)

C5, C6 C5–C8, T1 C5–C7

Branches Anterior pectoral

C5–C7

Terminal Branches Musculocutaneous nerve Median nerve, lateral portion Medial cord origin (inferior trunk)

C5–C7 C6, C7 C8–T1

Branches Medial brachial cutaneous nerve Medial antebrachial cutaneous nerve

C8–T1 C8–T1

Terminal Branches Median nerve (medial portion) Ulnar nerve

C8–T1 C8–T1

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FIGURE 68.16 Anatomy of the brachial plexus. A: Schematic depiction of the brachial plexus. B: Relation of the roots of the brachial plexus to the scalene muscles showing the position of the plexus over the first rib and its course into the axilla.

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FIGURE 68.17 Anatomy of the median, ulnar, and radial nerves. Anterior view (A) and posterior view (B) of the upper limb showing the course of the three nerves and some of the muscles (m.) they supply.

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FIGURE 68.18 Segmental nerve supply to the upper limb showing the anterior view (above) and posterior view (below). A: Dermatomes. B: Myotomes. C: Sclerotomes.

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FIGURE 68.19 Peripheral nerve supply to the upper limb showing the anterior view (above) and posterior view (below). A: Various cutaneous nerves and their territories (B). C: Nerve supply to the bones and joints.

TABLE 68.3 Nerve Supply of Muscles of the Neck Muscle

Nerve Supply

Capital Flexors Rectus capitis anterior Rectus capitis lateralis Longus capitis

C1, C2 C1, C2 C1–C4

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Capital Extensors Rectus capitis posterior major Rectus capitis posterior minor Oblique capitis superior Oblique capitis inferior Longus capitis Splenius capitis Semispinalis capitis

C1 C1 C1 C1 C1–C4 C3–C5 C3–C5

Cervical Spine Flexors Scalenus anterior Scalenus medius Scalenus posterior Longus colli Sternocleidomastoid

C4–C7 C3–C8 C5–C8 C2–C8

Cervical Spine Extensors Splenius cervicis Longissimus cervicis

C2–C7

Cranial nerve XI; C2, C3b

Semispinalis cervicis

C1–C8a C1–C8a

Multifidus

C3–T1

Head Rotatorsa Sternocleidomastoid Splenius cervicis Semispinalis cervicis Longissimus cervicis

See above

Other Neck Muscles Geniohyoid Thyrohyoid Sternohyoid Sternothyroid Omohyoid

C1 C1 C1–C3 C1–C3 C1–C3

a

When the muscle of one side contracts. muscles of both sides contract.

bWhen

TABLE 68.4 Sclerotomal Distribution Pattern of the Cervical and First Thoracic Nerves Segment

Sclerotome

Joints

Ligaments

C1

Periosteum and body of atlas

Atlantoaxial, medial, atlantoaxial, lateral, atlantoaxial

Alar, cruciform, apical dental, accessory atlantoaxial, articular capsules, nuchal, anterior

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C2

Periosteum and body of axis

Medial atlantoaxial, lateral atlantoaxial, intervertebral

C3

Periosteum and body of C3 vertebra and clavicle Periosteum and body of C4 vertebra and clavicle

Intervertebral, Luschka, sternoclavicular, zygapophyseal Intervertebral, Luschka, sternoclavicular, zygapophyseal

C5

Periosteum and body of C5 vertebra and portions of humerus, scapula, and proximal ulna

C6

Periosteum and body of C6 vertebra and portions of humerus, radius, scapula, and first metacarpal bone Periosteum and body of C7 vertebra and portions of humerus, scapula, radius, and ulna Periosteum and body of C8 vertebra and portions of humerus, ulna, carpal bones, and bones of fourth and fifth fingers Periosteum and body of T1 vertebra

Acromioclavicular, glenohumeral Luschka, intervertebral, elbow, zygapophyseal, sternoclavicular Glenohumeral, intervertebral, Luschka, elbow, zygapophyseal

C4

C7

C8

T1

atlantooccipital membrane, posterior atlantooccipital membrane Anterior longitudinal, atlantoaxial membrane, atlantoaxial, capsular, cruciform, nuchal Anterior longitudinal, posterior longitudinal, capsular, nuchal Anterior longitudinal, posterior longitudinal, capsular, ligamentum flavum, nuchal Anterior longitudinal, posterior longitudinal, capsular, nuchal, ligamentum flavum

Anterior longitudinal, posterior longitudinal, capsular, nuchal, ligamentum flavum

Elbow, Luschka, intervertebral, zygapophyseal

Anterior longitudinal, posterior longitudinal, nuchal, ligamentum flavum

Intervertebral, Luschka, zygapophyseal, elbow, wrist, hand

Supraspinous, interspinous, anterior longitudinal, posterior longitudinal

Intervertebral, zygapophyseal, costovertebral, elbows, wrist, hand

Anterior longitudinal, posterior longitudinal, supraspinous, interspinous, ligamentum flavum

TABLE 68.5 Nerve Supply of the Muscles of the Upper Limbs Region/Muscle

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Group/Functiona Shoulder rotator cuff Supraspinatus Infraspinatus Subscapularis Teres minor Scapular motion Elevation Levator scapulae Rhomboideus Trapezius (superior fibers) Depression Trapezius (inferior fibers) Pectoralis major Subclavius Upward rotation Serratus anterior Trapezius (upper/lower fibers) Downward rotation Levator scapulae Rhomboideus Pectoralis major and minor Latissimus dorsi Abduction (protraction) Serratus anterior Pectoralis major Adduction (retraction) Trapezius (middle fibers) Rhomboideus Latissimus dorsi Arm motion Flexion Pectoralis major (clavicular head) Deltoid (anterior fibers) Coracobrachialis Biceps brachii Extension Latissimus dorsi Teres major Deltoid (posterior fibers) Triceps brachii Abduction

Peripheral Nerve Supply

Segmental Nerve Supplyb

Suprascapular Suprascapular Nerve to subscapularis Axillary

C5, C6 C5, C6 C5, C6 C5, C6

Dorsal scapular Dorsal scapular Spinal accessory

C4, C5 C4, C5 CN XI

Spinal accessory Medial/lateral pectorals Nerve to subclavius

CN XI C5, C6, C7, C8, T1 C5, C6

Long thoracic Spinal accessory

C5, C6, C7 CN XI

Dorsal scapular Dorsal scapular Lateral/medial pectorals Thoracodorsal

C4, C5 C4, C5 C5, C6, C7, C8, T1 C6, C7, C8

Long thoracic Medial/lateral pectorals

C5, C6, C7 C5, C6, C7, C8, T1

Spinal accessory Dorsal scapular Thoracodorsal

CN XI C4, C5 C6, C7, C8

Medial/lateral pectorals

C5, C6, C7, C8, T1u

Axillary Musculocutaneous Musculocutaneous

C5, C6 C6, C7 C5, C6

Thoracodorsal Subscapular Axillary Radical

C6, C7, C8 C5, C6 C5, C6 C7, C8

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Deltoid (middle fibers) Supraspinatus Infraspinatus Teres minor Adduction Pectoralis major and minor Latissimus dorsi Teres major Medial rotation Subscapularis Latissimus dorsi Pectoralis major and minor Lateral rotation Infraspinatus Teres minor Elbow/forearm motion Extension Triceps brachii Anconeus Flexion Biceps brachii Brachialis Brachioradialis Wrist motion Flexion Flexor carpi radialis Flexor carpi ulnaris Palmaris longus Extension Extensor carpi radialis longus/brevis Extensor carpi ulnaris Radial deviation Flexor carpi radialis Extensor carpi radialis longus/brevis Ulnar deviation Flexor carpi ulnaris Extensor carpi ulnaris Digits (2–5) Flexion Flexor digit superficialis Flexor digit profundus Extension

Axillary Suprascapular Suprascapular Axillary

C5, C6 C5, C6 C5, C6 C5, C6

Medial/lateral pectorals Thoracodorsal Subscapular

C5, C6, C7, C8, T1 C6, C7, C8 C5, C6

Nerve to subscapularis Thoracodorsal Medial/lateral pectorals

C5, C6 C6, C7, C8 C5, C6, C7, C8, T1

Suprascapular Axillary

C5, C6 C5, C6

Radial Radial

C6, C7, C8 C7, C8

Musculocutaneous Musculocutaneous Radial

C5, C6 C5, C6 C5, C6

Median Ulnar Median

C6, C7 C7, C8 C7, C8

Radial

C6, C7

Radial (posterior interosseus)

C7, C8

Median Radial

C6, C7 C6, C7

Ulnar Radial (posterior interosseus)

C7, C8 C7, C8

Median Median (anterior interosseus)

C7, C8, T1 C7, C8, T1

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Extensor digit communis Extensor digit minimi Extensor indicis Abduction Dorsal interossei Adduction Palmar interossei Motion of thumb Flexion Flexor pollicis longus Extension Extensor pollicis longus Extensor pollicis brevis Abductor pollicis longus Adduction Adductor pollicis Abduction Abduction pollicis brevis Opponens pollicis Opposition Opponens pollicis Hypothenar group (motion of fifth finger) Abduction digiti minimi Flexor digiti brevis Opponens digiti minimi

Radial (posterior interosseus) Radial (posterior interosseus) Radial (posterior interosseus)

C7, C8 C7, C8 C7, C8

Ulnar

C8, T1

Ulnar

C8, T1

Median (anterior interosseus)

C7, C8

Radial (posterior interosseus) Radial (posterior interosseus) Radial (posterior interosseus)

C7, C8 C7, C8 C7, C8

Ulnar

C8, T1

Median Median

C8, T1 C8, T1

Median

C8, T1

Ulnar Ulnar Ulnar

C8, T1 C8, T1 C8, T1

CN, cranial nerve. a Only the primary muscle nerves are included. bMain root is underlined.

3600

FIGURE 68.20 Schematic depiction of the origins and courses of preganglionic sympathetic neurons destined to supply the upper limbs. Note that the axons of the preganglionic neurons, which are located in spinal segments T2–T8 (and occasionally T9), pass through the anterior root as white rami communicantes and from there to the paravertebral sympathetic chain, where they ascend and synapse with postganglionic fibers primarily in the second thoracic, stellate, and intermediate and middle cervical ganglia, and occasionally in the third cervical ganglion (not shown). Some of the postganglionic fibers pass directly to the subclavian artery, but most pass as gray rami communicantes to the roots of the brachial plexus. ICG, inferior cervical ganglion; MG, middle cervical ganglion; SCG, superior cervical ganglion; SG, stellate ganglion.

PECTORAL GIRDLE AND SHOULDER ANATOMY The differential diagnosis of neck and arm pain includes many disorders of the pectoral girdle and shoulder which can result not only in shoulder pain but also in radiation of pain to the neck and/or arm. Common disorders involving the shoulder and pectoral girdle include rotator cuff tears, tendonitis, impingement syndromes, and arthritis (Figs. 68.21 and 68.22). An understanding of the complex anatomy and biomechanics of pectoral girdle and shoulder is thus essential for the diagnosis and treatment of pain in this region.1 3601

FIGURE 68.21 Anterior (A) and posterior (B) views of the shoulder identifying the various bones and joints and also the sites of pathologic processes that produce pain and tenderness. (1) Subacromial space, which can be involved with calcific tendinitis, rotator cuff tendinitis and impingement syndrome, and rotator cuff tear; (2) bicipital groove, which can be involved in bicipital tendinitis and biceps tendon subluxation and tear; (3) acromioclavicular joint, which can be involved with degenerative and infectious processes; (4) anterior glenohumeral joint, which can be the site of glenohumeral arthritis, osteonecrosis, glenoid labial tears, and adhesive capsulitis; (5) sternoclavicular joint, which can be the site of pain caused by infection, degenerative changes, or trauma; (6) posterior edge of the acromion, which can contribute to rotator cuff tendinitis, calcific tendinitis, and rotator cuff tear; (7) suprascapular notch, which can be the site of suprascapular nerve entrapment; and (8) quadrilateral space, which can be the site of axillary nerve entrapment. m., muscle.

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FIGURE 68.22 With progressive cuff fiber failure, the head moves upward against the coracoacromial arch. A: Normal relationships of the cuff and the coracoacromial arch. B: Upward displacement of the head, squeezing the cuff against the acromion and the coracoacromial ligament. C: Greater contact and abrasion, giving rise to a traction spur in the coracoacromial ligament. D: Still greater upward displacement, resulting in abrasion of the humeral articular cartilage and cuff tear arthropathy. (Reprinted from Matsen FA. Practical Evaluation and Management of the Shoulder. 1st ed. Philadelphia, PA: Saunders; 1994:123. Copyright © 1994 Elsevier. With permission.)

The pectoral girdle is made up of the scapula and clavicle, the sternoclavicular and acromioclavicular joints, and the scapulothoracic and humeroacromial interfaces. Unlike the lower limb, which is built for weight bearing as well as locomotion, the upper limb function is primarily to allow mobility and a wide range of motion for the arm and hand. The girdle does not articulate with the vertebral column, as does the pelvic girdle, but with the thoracic cage at the saddle-shaped sternoclavicular joint. The sternoclavicular joint is divided into two spaces by an articular disk and is surrounded by a strong, lax capsule. In addition to the capsule, the joint is stabilized by the interclavicular ligament superiorly, inferiorly 3603

by the costoclavicular ligament (which limits elevation and rotation of the clavicle and serves as the fulcrum of movements at the sternoclavicular joint), and the posterior sternoclavicular ligament. Dislocation of the costoclavicular joint is rare but tends to occur anteriorly where the joint is weakest when it does occur (Fig. 68.23).

FIGURE 68.23 Anatomy of the sternoclavicular joints viewed from the front. (Adapted with permission from Clement CD. Gray’s Anatomy of the Human Body. 30th ed. Philadelphia, PA: Lea & Febiger; 1985:366–367.)

The acromioclavicular joint of the pectoral girdle is surrounded by a weak and lax capsule. It is stabilized by the acromioclavicular ligament superiorly; the fan-shaped coracoclavicular ligament, which serves as a vertical axis for scapular rotation; and the trapezoid ligament, which serves as a hinge for scapular motion about the horizontal axis. A partial or complete disruption of the coracoclavicular ligament, resulting in separation of the acromioclavicular joint, may occur with a fall on the shoulder. The scapulothoracic interface allows a gliding movement between the ventral surface of the scapula and the thorax overlying the second through the seventh ribs. The scapula is held in close approximation to the thorax by the serratus anterior, the trapezius, and the rhomboid muscles. For full abduction and forward flexion of the shoulder to occur, the scapula must undergo upward rotation. Movements of the pectoral girdle consist of upward-downward rotation, protraction-retraction, and elevationdepression (Table 68.6 and Figs. 68.24 and 68.25). 3604

TABLE 68.6 Prime Movers of the Pectoral Girdle Movement

Muscles

Elevation

Trapezius (upper fibers) Rhomboids Levator scapulae Latissimus dorsi Pectoralis major (costal fibers) Trapezius (lower fibers) Serratus anterior Pectoralis minor Pectoralis major Trapezius Rhomboids Trapezius Serratus anterior Rhomboids

Depression

Protraction

Retraction Upward rotation Downward rotation

FIGURE 68.24 Anatomy of the shoulder joint. A: Anterior view of ligaments of the left shoulder. B: Coronal section through the head of the left humerus and shoulder joint, anterior half viewed from behind. C: Interior of the right shoulder viewed from its lateral aspect. (Adapted with permission from Clement CD. Gray’s Anatomy of the Human Body. 30th ed. Philadelphia, PA: Lea & Febiger; 1985368–372.)

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FIGURE 68.25 The muscles that rotate the scapula upward during abduction of the arm. Note that the upper part of the trapezius, which is attached to the outer part of the scapular spine, pulls upward and that the lower part of the serratus anterior, attached to the lower part of the scapula, pulls the inferior angle laterally, whereas the lower portion of the trapezius, attached to the medial part of the scapular spine, pulls downward. (Reprinted with permission from Rosse C, GaddumRosse P. Hollinshead’s Textbook of Anatomy. 5th ed. Philadelphia, PA: Lippincott–Raven; 1997:235.)

The glenohumeral joint is a synovial joint that consists of the interface of the head of the humerus with the pear-shaped glenoid cavity and ring of fibrocartilage known as the glenoid labrum. These deepen the socket of the scapula and assist with stability of the glenohumeral joint. The supraglenoid and infraglenoid tubercles above and below the glenoid cavity are attachment sites for the long head of the biceps and triceps, respectively. The joint capsule is strong but lax, to allow for mobility, and attaches to the scapula proximally and distally to the articular margins of the head of the humerus superiorly and the surgical neck of the humerus inferiorly. The ligaments of the glenohumeral joint consist of the superior, middle, and inferior glenohumeral ligaments (thickenings of the anterior capsule); the coracohumeral ligament (which attaches to the greater and lesser tuberosities and limits flexion and extension); and the coracoacromial ligament (which extends from the undersurface of the acromion to the coracoid process and acts as an articulating surface for the 3606

head of the humerus). The subacromial and subdeltoid bursae lie between the coracoacromial arch and the rotator cuff tendons and have been implicated in shoulder impingement (see Fig. 68.24). Movement at the shoulder requires the combined motion of the glenohumeral joint and the pectoral girdle for flexion or abduction greater than 90 degrees. For example, the abduction or elevation of the arm to 180 degrees requires 60 degrees of scapular rotation to alter the angle of the glenoid fossa during its articulation with the head of the humerus (Figs. 68.26 and 68.27). Prime movers of the pectoral girdle and glenohumeral joint are listed in Tables 68.6 and 68.7.1 TABLE 68.7 Prime Movers of the Glenohumeral Joint Flexion Extension Internal rotation

External rotation

Abduction Adduction

Pectoralis major (clavicular head) Deltoid (anterior fibers) Latissimus dorsi Deltoid (posterior fibers) Pectoralis major Latissimus dorsi Teres major Subscapularis Infraspinatus Teres minor Deltoid (posterior fibers) Deltoid Supraspinatus Pectoralis major Latissimus dorsi Teres major Subscapularis

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FIGURE 68.26 Biomechanics of the glenohumeral movements of arm abduction. A: Normal position of the head and shaft of the humerus. The circle in the head of the humerus indicates the center of rotation. B: Humerus (H) abducted 45 degrees and the scapula (S) beginning upward rotation. The upper panel shows that the incongruity of the articulating surface of the head of the humerus and the surface of the glenoid cavity causes the greater tuberosity of the humerus to impinge on the coracoacromial ligament. The upper panel in C shows that to allow the greater tuberosity to pass under the coracoacromial hood during arm abduction, the humeral head is depressed (depicted by downward movement of the center of rotation) and the humeral head rotated (thin arrow). The abduction movement of the arm is accomplished in a smooth coordinated movement during which for each 15 degrees of arm abduction, 10 degrees of motion occurs at the glenohumeral joint, and 5 degrees occurs because of scapular rotation on the thorax. Thus, as noted in C, abduction of the arm to 90 degrees is accomplished by 60 degrees rotation of the humerus and 30 degrees rotation of the scapula. Full abduction of the arm, as shown in D, is accomplished by 120 degrees of rotation at the glenohumeral joint and 60 degrees rotation of the scapula. (Modified from Cailliet R. Shoulder Pain. 2nd ed. Philadelphia: FA Davis; 1981. Reproduced with permission of F.A. Davis Co., in the format Republish in a book via Copyright Clearance Center.)

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FIGURE 68.27 Muscles that move the shoulder and arm: flexors (A), extensors (B), adductors (C), abductors (D), and rotators (E). (Adapted with permission from Hollinshead WH. Anatomy for Surgeons. Vol 3: The Back and Limbs. 3rd ed. New York: Harper & Row; 1982:325–330.)

Epidemiology of Neck and Arm Pain According to The Global Burden of Disease Study 2013, which evaluated the national disability-adjusted life years (DALYs) for 306 diseases and injuries and healthy life expectancy (HALE) for 188 countries from 1990 3609

to 2013, back and neck pain have risen from the seventh leading cause of disability in 1990 to the fourth leading cause of disability in 2013, following ischemic heart disease, cerebrovascular disease, and lower respiratory infections.3 The methodology and definition of neck pain varies significantly in epidemiologic studies of neck and arm pain. An average prevalence of 15% to 50% with a mean of 37.2% have been reported in most epidemiologic studies and a recent systematic review. Associated conditions identified with neck and arm pain include psychosocial factors such as anxiety, depression, kinesiophobia, poor coping skills as well as sedentary lifestyle, sleep disorders, smoking, and genetic risk factors. Associated poor health, as well as musculoskeletal and psychological health complaints, were prognostic for poor outcome. Prevalence was found to be overall higher in females with prevalence peaking in middle age.4 Controversy exists regarding the relationship between radiologic evidence of cervical spine degeneration and neck pain, with some finding no significant difference in the degree of neck pain in patients with or without radiographic evidence of cervical spine degenerative changes, with others correlating neck pain with increasing grade of disk degeneration.5 Zapletal et al.6 showed increasing evidence of neck pain with increasing prevalence of atlantoodontoid degenerative changes. Up to 78% of asymptomatic subjects have been found to have degenerative changes on magnetic resonance imaging (MRI) accompanied by positive findings such as disk bulging and protrusion, foraminal stenosis, and abnormal spinal cord contour. This evidence suggests that degenerative findings are common in both asymptomatic and symptomatic individuals, increase linearly with age, and cannot be assumed to be the definitive cause of neck pain in symptomatic individuals.7–9 One study comparing cervical spine MRIs of fighter pilots to age-matched controls showed premature cervical disk degeneration among pilots exposed frequently to high +Gz forces.10 Neck pain following whiplash-associated disorders is common with more than 300 persons per 100,000 population evaluated for this complaint each year according to recent data.11 Increased symptom severity and presence of neurologic signs is predictive of poor prognosis. Postinjury 3610

feelings of helplessness in controlling the consequences of pain, fear of movement, catastrophizing, and postinjury anxiety have also been found to be associated with higher risk of long-term disability,12 as has changing the insurance system from a no-fault to a tort system of compensation.13 Studies from hospital populations report that at an average follow-up of 2 years, 20% to 45% of patients with soft tissue neck injuries following whiplash reported discomfort sufficient enough to interfere with their capacity to work.14 Onset of neck and arm pain in the workplace varies widely across various occupations. Highly repetitive work, low job satisfaction, and a high level of fear avoidance are associated with development of neck and arm pain as are jobs which require prolonged bending or flexion of the neck such as computer work.15–17 Neck, shoulder, and arm pain associated with generalized pain or pain at other anatomical sites has been associated with greater persistence and disability than more localized neck, shoulder, and arm pain. Neck and arm pain associated with more generalized pain is also more likely to be associated with somatization, poor psychological health, older age, and less correlation with occupation or activity. More localized neck and shoulder pain is more strongly associated with use of keyboards at work and less frequent at older age.18

Evaluation of the Patient HISTORY AND PHYSICAL EXAMINATION The patient in pain is prompted to seek help not only to alleviate the suffering which accompanies their condition but also to address the accompanying condition of impairment or disability. The psychological, physical, or functional handicap which coexists with pain results in loss of ability to perform normal activities and fulfill roles that are fundamental to personal identity. Ultimately, the goal of a successful evaluation should be the ability to answer the patient’s three fundamental questions: (1) “What’s happening to me?” (2) “What’s going to happen to me?” and (3) “What can be done to improve what happens to me?”19 The differential diagnosis of neck and arm pain is broad and encompasses acute pain from work-related injury, motor vehicle trauma 3611

and infection, emerging symptoms from enlarging tumors, vascular abnormalities or infections, manifestations of complex systemic disease processes, and exacerbation of chronic degenerative or inflammatory processes. The initial evaluation should be comprehensive in order to ascertain not only the etiology of physical symptomology but also the impact the patient’s disability has on their psychosocial environment.

History A thorough history of the patient with neck and arm pain is essential to separate acute from chronic, emergent from urgent and routine complaints, and focal and regional injuries and degenerative changes from systemic disorders. Pain in the neck and arm may also be referred from the thorax or abdomen requiring a thorough review of systems. The differential diagnosis is frequently based on the history, which then guides further focus during the physical exam and diagnostic testing. Immediate consideration must be made regarding the severity and urgency of the complaint. Emergent conditions can often be discerned at the time of phone request for urgent evaluation or by nurses when the patient is screened at check-in. Severe neck pain accompanied by progressive disturbance of gait, progressive motor or sensory deficits, or urinary and fecal incontinence requires prompt physician evaluation. Enlarging tumor, acute infection, and unstable inflammatory spondyloarthropathy can progress to respiratory failure and death if not treated promptly and requires immediate surgical and medical intervention. Acute progressive neurologic and cognitive deficits accompanied by hemodynamic instability may also present with dissecting vertebral and extracranial carotid artery aneurysms.20,21 Other red flags include significant head trauma in the presence of a neurologic deficit. Night pain or unrelenting pain with associated weight loss is suggestive of a neoplastic or infectious process.

Location/Radiation Pain in the neck and arm may be skeletal, myofascial, or neuropathic. Neuropathic pain can be further divided into peripheral or segmental nerve pathology versus autonomic and central nervous system pathology or 3612

sensitization. Cohen22 suggests the diagnostic construct of mechanical versus nonmechanical pain. Mechanical pain is exacerbated by movement and occurs in the essentially well patient. Nonmechanical pain is often related to a medical source such as infection, neoplasm, or an inflammatory process generally seen in patients with systemic manifestations of their disease process. The purpose of a thorough history with determination of the location, pattern, and distribution of the patient’s pain is to establish an initial differential diagnosis which can subsequently be confirmed or ruled out by physical examination, diagnostic laboratory, radiologic, and electrophysiologic testing. Localized pain is usually caused by disorders of joints and muscles. Segmental pain conforming to dermatomal distributions may implicate lesions of nerve roots. Pain conforming to a peripheral dermatomal and/or myotomal distribution suggests lesions of the cervical or brachial plexus or their branches. Knowledge of dermatomal, myotomal, sclerotomal, and zygapophyseal referral patterns as well as distribution of peripheral nerves of the cervical and brachial plexus are essential for determining a rational differential diagnosis (see Figs. 68.11 through 68.19 and Tables 68.3 through 68.5). In addition to cervical nerve root inflammation or impingement, cervical and brachial referral patterns may be secondary to myofascial trigger points or referred pain from cervical zygapophyseal joints. Widespread pain may implicate fibromyalgia syndrome, rheumatologic disease such as mild systemic lupus erythematosus, polyarticular osteoarthritis, rheumatoid arthritis, polymyalgia rheumatica, hypermobility syndromes, and even osteomalacia. Nonrheumatologic syndromes must also be considered in patients presenting with widespread pain. These include neoplastic and neurologic diseases, hypothyroidism, and other endocrine disorders, chronic infections, and a variety of psychiatric conditions.23 Location of the patient’s pain cannot in isolation lead to a correct diagnosis. All aspects of the history of present illness; past medical and surgical history; family history of hereditary illness; and social, occupational, behavioral, psychological, and demographic information are necessary to identify predisposing factors or mechanisms of injury. A review of systems and detailed physical exam are essential to rule out 3613

manifestations of systemic disease and presence or absence of significant neurologic deficits. Even then, further diagnostic tests as well as pharmacologic and interventional trials may be required in complex cases to confirm or rule out etiologic hypothesis.

Onset Acute onset of pain may occur after trauma, injury, or following an unaccustomed increase in activity in a deconditioned patient; however, an acute exacerbation of a chronic condition cannot be excluded. More gradual or insidious onset is common in progressive degenerative, inflammatory, or malignant process. It is important to elicit the time at which the pain first occurred, characteristics of the pain during the interval between onset, and evaluation of precipitating events or factors. Intensity and Pattern of Severity with Time A cardinal principle of diagnosis is assessment of the intensity of pain both at baseline and in response to time, activities, and treatment. Although the visual analogue or numerical rating pain score system is subjective and may be influenced by psychological, social, and occupational factors, it is essential to evaluate the trend of each patient’s pain over time in order to assess the effects of pharmacologic, psychological, behavioral, physical, and interventional therapies. Patterns of pain severity over time are often associated with certain diseases. Chronic unrelenting pain may be due to inflammatory disease or a more centralized pain syndrome. Pain due to cervical spondylosis and stenosis may be severe with activities requiring neck flexion and rotation and absent or significantly reduced when the patient’s neck is held in a neutral position. Patient complaint of night pain or pain of spontaneous onset which is constant and not relieved by rest or modified by movement may raise suspicion for an infectious or neoplastic process. Quality Electrical, shooting, stabbing, lancinating, burning, tingling, and pins and needles are common terms used to describe neuropathic pain. Dull, aching, cramping, or throbbing pain is more often associated with pain of a musculoskeletal nature. Stiffness is often described in association with 3614

degenerative arthritis or diffuse idiopathic skeletal hyperostosis (DISH). It is not unusual for the patient to include sensory changes (numbness, pins and needles, or burning) as well as cramping and aching pain in their description of cervical radiculopathy. This is most likely due to both the cutaneous or dermatomal and muscular or myotomal distribution of the cervical nerve roots. Burning pain associated with allodynia and thermohyperesthesia suggests complex regional pain syndrome (CRPS). The more chronic the pain condition, the more likely the patient will report a poorly localized, widespread, nondermatomal pain pattern due to changes in central pain processing known to occur following persistent painful peripheral input.24

Modifying Factors and Drug History Asking the patient the question “What makes your pain better or worse?” will assist in further narrowing of the differential diagnosis. Coughing or sneezing and lateral head rotation and extension may cause exacerbation of cervical radicular pain. Chronic inflammatory pain is often worse after a period of inactivity and improves with exercise. Degenerative arthritis is often exacerbated by exercise and improves with rest. In patients with multiple pain complaints, response to medication may help guide diagnosis. In patients who have failed multiple medication trials, it is important to elicit specific reactions to medications, duration of use, dosages reached, and titration schedules implemented. An elderly patient, for example, who gives a history of intolerable sedation with an antiepileptic medication, may have been started at a standard adult dose and subsequently titrated upward using an aggressive titration schedule. This patient may be able to benefit from this same medication if it is titrated more gradually from a low dose.

Associated Symptoms A history of neck and arm pain associated with frequently dropping objects, difficulty with writing, or other fine motor skills is useful in separating motor weakness from guarding secondary to pain. Associated symptoms may help to broaden or further refine the differential diagnosis. A patient with neck and arm pain which occurs with increased activity and 3615

is associated with diaphoresis and shortness of breath may broaden the differential diagnosis to include coronary artery disease. Indeed, the first clinical description of cervical radiculopathy by Semmes and Murphy25 in 1943 was entitled “The Syndrome of Unilateral Rupture of the Sixth Cervical Vertebral Disc with Compression of the Seventh Cervical Root: A Report of Four Cases with Symptoms Simulating Coronary Disease.” Association of neck and radicular arm pain with positional headaches accompanied with nausea, photophobia, and blurred vision may lead the physician to rule out low-pressure headache.26

Family History In addition to more common hereditary arthritides such as rheumatoid arthritis (more common in females), ankylosing spondylitis (predominantly seen in males), psoriatic arthritis, and Reiter’s syndrome, there are also more uncommon hereditary diseases which can involve the cervical spine. Compression of the cervical cord from cervical root neurofibromas in patients with neurofibromatosis type 1 has been reported to present with progressive neurologic deficit.27 Tophaceous gout of the odontoid process and larynx, epidural, mediastinal, and subcutaneous emphysema in a patient with Marfan’s disease following forceful coughing, and cervical dystonia in spinocerebellar ataxia type 2 are other inherited disorders manifesting with neck pain.28–31

Age and Psychosocial History The patient’s age, sex, occupational, and social history is important in determining risk factors known to be associated with the development of persistent neck and upper limb pain. Whereas sports or trauma injury and congenital defects such as Chiari I malformations are common causes of neck pain in pediatric or adolescent patients, degenerative changes are common in older patients. Jobs or activities which require repeated lifting of heavy objects, prolonged bending of the neck, working with arms at/above shoulder height, and which involve little job control and little social support are associated with the development of neck pain. Specific jobs and activities associated with the development of neck pain include prolonged computer work and bicycling.16,17,32 Extensive neck and upper 3616

extremity pain is independently associated with psychological ill health, female sex, unemployed status, and smoking.18 Questions regarding use of pillows at night and bifocals as well as any other activities which put the patient’s neck under prolonged flexion strain should be included in the social and occupational history. In some cases, simple correction of repetitive strain with postural reeducation may result in relief of symptoms. Depression and anxiety may occur as a reaction to persistent pain and are also independent risk factors for the development of chronic pain. The depressed individual may lack the psychological and social capabilities to cope with the complex physical, emotional, cognitive, and behavioral components of the pain experience.33 Patients with coexisting histories of depression and anxiety may benefit from referral to a psychopharmachologist and from psychological consultation for cognitive and behavioral therapies to assist the patient with coping strategies.

Past Medical History and Review of Systems The past medical history, past surgical history, and review of systems may provide essential clues tying the patient’s symptoms to an associated disease process. Table 68.8 lists a few coexisting diseases which may present with neck pain and radiculopathy, whereas Table 68.9 lists a review of systems checklist which may identify systemic involvement or an urgent, rapidly progressing process. TABLE 68.8 Noncompressive Infectious, Inflammatory, and Neoplastic Causes of Neck Pain and Radiculopathy Infection (most common in immunosuppressed patients) Herpes zoster, human immunodeficiency virus, cytomegalovirus, tuberculosis, Borrelia burgdorferi (Lyme disease) Inflammatory Systemic lupus erythematosus, sarcoidosis, Bruns-Garland syndrome (diabetic radiculopathy), Parsonage-Turner syndrome (neuralgic amyotrophy), multiple sclerosis, “pseudopolyneuropathy,” gout

TABLE 68.9 A Comprehensive Checklist of Associated Features of Neck Pain that Might Indicate a Red Flag Condition System

Past History

Symptoms Of

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Feature or Condition

Nervous

Cardiovascular

Respiratory

Alimentary

Urinary Reproductive Endocrine Reticulo-endothelial Skin Musculoskeletal

Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No

Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No

Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No

Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No

Weakness Numbness Bladder dysfunction Impaired balance Impaired vision Altered speech Disorientation Altered consciousness Risk factors Chest pain Anticoagulants Transient ischemic attacks Carcinoma Tuberculosis Cough Weight loss Carcinoma Weight loss Loss of appetite Dysphagia Diarrhea Altered bowel habits Incontinence Obstruction Breast lump Uterine dysfunction Thyroid cancer Hyperparathyroidism Lymph nodes Rash Other joint pain Other muscle pain Risk of Paget’s disease Risk of myeloma

Reprinted from Bogduk N. The neck. Baillieres Best Pract Res Clin Rheumatol 1999;13(2):261– 285. Copyright © 1999 Harcourt Publishers Ltd. With permission.

Surgical History A past surgical history of neck fusion may signal risk of pseudoarthrosis or increased risk of recurrent disk disease above or below the level of fusion. Poststernotomy lesions following cardiac surgery with the clinical 3618

appearance of a C8 radiculopathy have been described. The causal mechanism is thought to be related to an occult fracture of the first thoracic rib. These are often mistaken for ulnar neuropathy at the elbow thought to be associated with surgical positioning.34

Physical Examination General Observations Many important observations can be made during the initial interview and even as the patient travels from the waiting area to the exam room. The general health and independence of the patient can be surmised from skin and muscle tone, posture, gait, and use of assistive devices. Cachexia may be a sign of debilitation due to cancer or long-standing depression. Mood, affect, and cognitive state can be ascertained during questioning as well as during the physical exam. Other important general observations include symmetry of the shoulders; abnormal head positions including lateral flexion, rotation, or protrusion; and evidence of muscle wasting or deformity of the neck, shoulders, or upper limbs. A complete physical exam is paramount in the patient with neck, shoulder, and arm pain. Inspection of the skin for lesions may reveal psoriasis which may be associated with psoriatic arthritis. Vesicles typifying herpes zoster may be found in a patient complaining of radicular symptoms. Lesions typical of erythema nodosum may be indicative of inflammatory disease or cancer, and needle marks (intravenous drug abuse) may raise suspicion for vertebral column infections. Acute pain from viscera sharing the same embryologic segmental derivation as the cervical spine can present as neck, shoulder, or arm pain. These include the submandibular glands, lymph nodes, thyroid, esophagus, heart, lungs, stomach, gallbladder, pancreas, and diaphragm, necessitating a general inspection and palpation of these areas.35 In general, a systematic approach which includes a neurologic exam, inspection and palpation of bony and soft tissue structures followed by range of motion and special tests used in the diagnosis of neck pain should supplement but not replace the full physical examination. Exam of the Neck

3619

Neurologic Exam. Examination of the neck must include a neurologic exam. Tumors, infections, and carotid dissections which present as neck pain are also associated with cranial nerve palsies and sensory deficits. Delay in recognition of neurologic deficits in these cases can lead to progression of tumor or infection with poor surgical or medical outcome and prognosis.36–38 A summary of the motor, sensory, and autonomic functions of the cranial nerves is found in Table 68.10. TABLE 68.10 Summary of the Motor, Sensory, and Autonomic Functions of the Cranial Nerves Cranial Nerve (CN)

Cranial Point Exit

Olfactory (CN I)

Cribriform plate Optic foramen Superior orbital fissure

Optic (CN II) Occulomotor (CN III)

Trochlear (CN VI)

Superior orbital fissure

Trigeminal (CN V)

V1—superior orbital fissure V2—foramen rotundum V3—foramen ovale

Peripheral Innervation of Head Mucosa of nasal cavity Retina of eye All extraocular eye muscles except superior oblique and lateral rectus Superior oblique (extraocular eye muscle) V1—cutaneous sensation of nose, eyes, and scalp V2—sensation of face: maxilla, nasal mucosa, upper lip, and teeth V3—cutaneous sensation of lower face: mouth mucosa, lower jaw teeth, TMJ,

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Function

Symptom/Sign of Damage

Smell

Anosmia

Vision Eye movement (elevation, adduction)

Blindness Eye deviates down and out. Loss of papillary accommodation reflexes

Eye movement (depression of adducted eye)

Diplopia, lateral deviation of eye

Facial sensation, mastication

Facial anesthesia Loss of pain sensation Weakness/loss of mastication

Abducent (CN VI)

Facial (CN VII)

Superior orbital fissure Entry: internal acoustic meatus Exit: stylomastoid foramen

Vestibulocochlear (CN VIII)

Internal acoustic meatus

Glossopharyngeal (CN IX)

Jugular foramen

Vagus (CN X)

Jugular foramen

Cranial accessory

Jugular foramen

Spinal accessory (CN XI)

—

Hypoglossal (CN

Hypoglossal

anterior twothirds of tongue Motor supply to muscles of mastication Lateral rectus (extraocular eye muscle) Motor: muscles of facial expression and scalp

Inner ear labyrinth structures (semicircular canal and cochlear apparatus) Posterior onethird of tongue Parotid gland Mucosa and elevator muscles of pharynx Palatal muscles, pharyngeal constrictors, vocal cords Taste and sensation to epiglottis Motor supply to larynx and pharynx Head rotation and shoulder shrugging Intrinsic and

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Eye movement (abduction)

Medial eye deviation

Facial expression, taste, salivation, lacrimation

Paralysis of facial muscles Loss of taste (anterior twothirds of tongue) Dry mouth, loss of lacrimation Vertigo, disequilibrium, nystagmus, hearing loss

Balance hearing

Taste salivation Innervation of pharynx

Loss of taste (posterior onethird of tongue) Loss of gag reflex

Swallowing and talking Cardiac, gastrointestinal tract Respiration Taste

Dysphagia and hoarseness Loss of cough reflex, loss of taste

Pharynx/larynx muscles

Head turning

Trapezius, sternocleidomastoid

Shoulder shrug weakness

Tongue movement

Atrophy of tongue

XII)

canal

some extrinsic tongue muscles

muscles, deviation on protrusion, fasciculations

TMJ, temporomandibular joint.

In addition to examination of the cranial nerves, general head, neck, and upper extremity sensory; motor and deep tendon exam; sensory, motor, and deep tendon exam of the lower extremities are essential. Exam findings signaling a possible cervical myelopathy include unilateral or bilateral spastic, ataxic, spastic-ataxic or Trendelenburg gait, hyperreflexia of lower extremity deep tendon reflexes and Babinski sign, and decreased sphincter tone or loss of the anal “wink.” Sensory Exam. The sensory exam is particularly useful in the patient with neuropathic pain. Sensory testing should include brush touch for allodynia; light pressure for tenderness and hyperalgesia; and palpation for painful areas as well as vibration, hot, cold, and sharp versus dull discrimination. Positive sensations, stimulus-evoked hypersensitivities such as allodynia to innocuous stimulation including light touch and cold, and hyperalgesia to noxious stimulation such as pinprick occur focally in mononeuropathies and distally and symmetrically in polyneuropathies. In neuropathic pain syndromes such as CRPS, allodynia, and hyperalgesia may spread outside the area of the original injury or to homologous sites in the opposite limb. These sensory findings are often associated with focal autonomic abnormalities such as sweating, skin temperature and color changes, and edema are also present in CRPS. In central pain and anesthesia dolorosa, allodynia, hyperalgesia, and aftersensation (persistence of pain after the stimulus has ceased) can occur in areas demonstrated to have loss of sensation. In small-fiber neuropathies, loss of thermal, pain, and sometimes touch perception with sparing of large-fiber functions such as muscle strength, deep tendon reflexes, and vibratory and proprioceptive perception is seen. These functions are all compromised in combined large- and small-fiber polyneuropathies.39 The sensory exam should include evaluation for dermatomal patterns of sensory abnormality and for altered sensation in peripheral nerve distributions in patients with suspected peripheral nerve injury or entrapment syndromes. A “cord” level 3622

of sensory disturbance may be confined to the upper extremities due to “central cord syndrome” with involvement of decussating anterior sensory fibers.40 Motor Exam. Motor exam is tested using the standard muscle strength scale from 0 to 5 (Table 68.11). TABLE 68.11 Muscle Strength Grading Grade 0: total paralysis Grade 1: palpable or visible contraction Grade 2: full range of motion with gravity eliminated Grade 3: full range of motion against gravity Grade 4: full range of motion with decreased strength Grade 5: normal strength NT: not testable

In addition to testing of motor function of the cranial nerves, myotomal or segmental nerve root motor supply should be systematically evaluated (Table 68.12).

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TABLE 68.12 Segmental Motor Function Evaluation C2: breathing C3–C4: spontaneous breathing, trapezius function C4–C6: shoulder flexion, extension Upper extremity strength C5: deltoid abduction at shoulder C6: biceps flexion at forearm C6: wrist extension (extensor carpi radialis) C7: wrist flexion C7: elbow extension (triceps) C7: finger extension C8: fingers flexion middle finger (flex dig profundus) T1: small finger abductors (abductor digiti minimi) T1: interossei (spread fingers)

Deficits consistent with peripheral nerve lesions or injury should also be ruled out (Table 68.13). TABLE 68.13 Manifestations of Peripheral Nerve Injuries of Upper Extremities Ulnar nerve: claw hand Radial nerve: wrist drop Median nerve: cannot make “OK” sign

Reflex testing should include upper and lower extremities because lesions of the cervical spine may manifest with hypoactive reflexes at the level of the lesion, hyperactive reflexes below the lesion, and pathologic reflexes. Cutaneous reflexes will also be lost below the lesion. Reflexes are tested using the following standard scale: • 0: absent reflex • 1+: trace or seen only with reinforcement • 2+: normal • 3+: brisk • 4+: nonsustained clonus (i.e., repetitive vibratory movements) • 5+: sustained clonus Using this scale, 1+, 2+, or 3+ reflex is considered normal unless there is a significant difference between sides. In contrast, 0, 4+, and 5+ are considered abnormal. Upper extremity normal and pathologic reflexes are outlined in Table 3624

68.14. TABLE 68.14 Upper Extremity Deep Tendon Reflexes and Pathologic Reflexes Reflex Scapulohumeral reflex

Nerve Root or Function Tested

Biceps reflex

Tests integrity of cord segments from C4 to C6 C5, C6

Brachioradialis reflex

C6

Triceps reflex

C7

Hoffmann sign (pathologic if positive; upper extremity equivalent of Babinski sign) Jaw reflex

Test for upper motor neuron lesion

Chvostek sign (pathologic if positive)

Hypocalcemia or other metabolic abnormality

Upper motor neuron lesions

Location

Response

Lower aspect of medial border of scapula Tap thumb placed over biceps tendon in antecubital fossa Proximal to radial aspect of wrist

Adduction and lateral rotation of the arm

Tendon of triceps muscle as it crosses olecranon fossa Patient’s long finger in slight extension DIP flicked downward by examiner’s thumb Tap finger placed over mental area of chin Tap over facial nerve anterior to ear

Flexion of forearm

Radial and dorsiflexion at wrist Extension at elbow

Involuntary flexion of thumb and little finger to make “OK” sign

Jaw closing (abnormal if hyperactive) Hyperactive response

DIP, distal interphalangeal joint.

Inspection and Palpation. After observation for abnormal posture such as abnormal loss of cervical lordosis, torticollis, and obvious atrophic musculature of the neck or upper extremity, the patient should be asked to lay supine to relax the musculature of the neck. This allows optimal examination of the bony structures of the neck.35 While standing at the patient’s side, one hand supports the neck from behind while the other is used to palpate the anterior neck structures. The most superior bony structure of the anterior neck is the hyoid bone. It is the only bone in the skeletal structure not articulated to any other bone. It supports the root of the tongue and in turn is supported by the 3625

muscles of the neck and suspended by the stylohyoid ligaments from the styloid processes of the temporal bones. The body of the hyoid bone is palpated in the midline, whereas the lesser and greater cornu are palpated laterally to each side of the body forming a horseshoe-like structure. The hyoid bone lies at the lower level of C3 or at the intervertebral disk between C3 and C4. Although injuries of the hyoid bone are rare outside of strangulation, fractures of the hyoid due to trauma, cardiopulmonary resuscitation, and sports injuries have been reported with complications including carotid pseudoaneurysm, pharyngeal laceration, and airway compromise.41–44 Insertion tendonitis of the hyoid bone has also been reported as an unrecognized source of neck pain with recognizable radiologic features.45 Below the hyoid bone, at the level of C4 to C5, is the thyroid cartilage. The first cricoid ring forms the upper border of the trachea. It lies at the level of C6. The carotid tubercle, also known as Chassaignac’s tubercle, is the anterior tubercle of the C6 transverse process and can be palpated approximately 3 cm lateral to the first cricoid ring. The carotid arteries overlie the tubercles. Caution should be taken to examine the carotid pulses individually to prevent bradycardia and/or syncope. Soft tissues of the anterior neck include the H-shaped thyroid gland which extends from the thyroid cartilage cranially to the fourth to sixth tracheal rings inferiorly. This area should be inspected to preclude generalized enlargement of the gland and palpated to exclude thyroid masses. The exam should include inspection for palpable lymph nodes which may be due to infection or metastatic disease. Unknown primary carcinoma presents as painless enlarged cervical lymph nodes and accounts for approximately 5% of all head and neck malignancies. If malignancy is suspected, the patient should be referred for more advanced imaging and diagnostic testing.46 By having the patient turn his or her head to the opposite side, the sternocleidomastoid muscle may be examined from the origins on the sternum and clavicle to its insertion on the mastoid process of the temporal bone. The anterior border of this muscle from origin to insertion defines the lateral limit of the anterior triangle of the neck and the posterior border, the anterior limit of the posterior triangle of the neck. The exam should include palpation for painful or painless 3626

masses, trigger points with associated referral patterns, and pain associated with swallowing. Palpation of the bony landmarks of the posterior cervical spine includes the inion or external occipital protuberance in the midline, which makes the midpoint of the superior nuchal line extending laterally from the inion bilaterally. The occipital nerves run medial to the occipital arteries over the occiput approximately 3 cm from the midline. Tenderness or pain with examination of this area may be seen with occipital neuralgia. Palpation of the cervical spine is performed in a systematic way, starting with the spinous processes, and followed by the zygapophyseal joints. Pain over the midline structures may indicate a structural problem of the cervical spine. The zygapophyseal joints are located 2 to 3 cm from the midline. Palpation of the lateral atlantoaxial joint of C1–C2 is undertaken by rotating the patient’s head to the ipsilateral side. C2, C3, C4, and C5 are usually difficult to palpate because of the normal cervical lordosis but can be easily identified if it is remembered that the C3–C4 joint is at the level of the hyoid bone and the C4–C5 joint is at the superior aspect of the thyroid cartilage. The C6 spinous process can be easily identified as it is usually easily palpable and disappears under the examining finger on extension of the neck. The level of the C6–C7 joint can also be confirmed by its location at the level of the cricoid ring. The largest “fixed” prominence is the spinous process of C7. Referral patterns from the zygapophyseal joints have recently been studied in patients with neck, head, and shoulder pain with the most common referral patterns based on areas in which patients are relieved of pain by controlled blocks are depicted in Figures 68.28 through 68.33.47

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FIGURE 68.28 Distribution of pain and pain frequency in each grid area as reported by patients with pain originating from C2 to C3. (From Cooper G, Bailey B, Bogduk N. Cervical zygapophysial joint pain maps. Pain Medicine 2007;8[4]:344–853. Reproduced by permission of American Academy of Pain Medicine.)

FIGURE 68.29 Distribution of pain and pain frequency in each grid area as reported by patients with pain originating from C3 to C4. (From Cooper G, Bailey B, Bogduk N. Cervical zygapophysial joint pain maps. Pain Medicine 2007;8[4]:344–853. Reproduced by permission of American Academy of Pain Medicine.)

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FIGURE 68.30 Distribution of pain and pain frequency in each grid area as reported by patients with pain originating from C4 to C5. (From Cooper G, Bailey B, Bogduk N. Cervical zygapophysial joint pain maps. Pain Medicine 2007;8[4]:344–353. Reproduced by permission of American Academy of Pain Medicine.)

FIGURE 68.31 Distribution of pain and pain frequency in each grid area as reported by patients with pain originating from C5 to C6. (From Cooper G, Bailey B, Bogduk N. Cervical zygapophysial joint pain maps. Pain Medicine 2007;8[4]:344–353. Reproduced by permission of American Academy of Pain Medicine.)

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FIGURE 68.32 Distribution of pain and pain frequency in each grid area as reported by patients with pain originating from C6 to C7. (From Cooper G, Bailey B, Bogduk N. Cervical zygapophysial joint pain maps. Pain Medicine 2007;8[4]:344–353. Reproduced by permission of American Academy of Pain Medicine.)

FIGURE 68.33 The probability of neck and head pain in areas depicted being secondary to C1– C2, C2–C3, and C3–C4 segments. (From Cooper G, Bailey B, Bogduk N. Cervical zygapophysial joint pain maps. Pain Medicine 2007;8[4]:344–353. Reproduced by permission of American Academy of Pain Medicine.)

Examination of the soft tissues of the posterior neck includes palpation of the suboccipital muscles and trapezius which, like the sternocleidomastoid, may be a source of CEH. The trapezius extends from the external occipital protuberance, the medial third of the superior nuchal line of the occipital bone, the ligamentum nuchae, spinous processes of the seventh cervical, and all thoracic vertebrae to the posterior border of the lateral third of the clavicle, the medial margin of the acromion, and the 3630

posterior border of the scapular spine. The scalene muscles should not be neglected in patients with neck ache, arm ache, and headache. Neck pain, occipital headache, extremity paresthesia, pain, and weakness may occur from scarring of the scalene muscles secondary to neck trauma such as whiplash injuries.48 As with examination of the anterior neck, a chain of lymph nodes lies along the anterolateral border of the trapezius. Enlargement or tenderness of these may indicate infection or metastatic disease. Special Tests for Neck and Upper Extremity Spurling’s Maneuver. This maneuver is used to confirm the presence of a cervical radiculopathy. It is performed by extending and rotating the head to the right or left. This narrows the intervertebral foramen by 20% to 30%. It has been shown to have a sensitivity of 30% and a specificity of 93% on 235 individuals referred for electrodiagnosis of upper extremity nerve pain.49 It also increases pressure on the cervical facet joints and may intensify facet mediated pain. Valsalva Test. This test is performed by having the patients place their thumb in their mouth and blow, as if to push the thumb out of their mouth. This maneuver increases the intraspinal pressure and may reveal the presence of space-occupying lesions of the cervical spine such as large intervertebral disk herniations, tumors, and stenosis due to spondylosis or osteophytes. If the mass involves the area of the spine adjacent to nerve roots, radicular pain may be reproduced. Distraction Test. This test reduces pressure on the intervertebral disk and exiting nerve roots and simulates the effect that traction may have on treatment of neck and radicular symptoms. It is performed by placing one hand underneath the jaws, the other beneath the occiput, and applying gentle upward pressure over 30 to 60 seconds. Increased pain with this maneuver may be due to inflammatory or degenerative disease or muscle or ligamentous pathology. Jackson’s Compression Test. As with Spurling’s maneuver, this test places increased pressure on the cervical facet joints and causes narrowing 3631

of the neural foramen. It may reproduce neck pain due to facet arthropathy and/or upper extremity radicular pain due to nerve root compression. To perform this test, the patient is instructed to rotate his or her head first to the right and then to the left. The examiner exerts gentle pressure to the top of the patient’s head after each movement. Lhermitte’s Sign. Lhermitte’s sign is the production of a sensation of lightening-like paresthesias or dysesthesias in the arms or legs upon flexion of the cervical spine. It may be caused by a large disk herniation or bony compression of the anterior cord in patients with a narrowed central canal. It may also occur in patients with rheumatoid arthritis with associated instability or in patients with multiple sclerosis affecting the cervical spinal cord, tumors, and syringomyelia.50 Shoulder Depression and Abduction Tests. The shoulder depression and abduction tests are useful for evaluation of radicular pain. The shoulder depression test is performed by having the patient laterally flex his or her neck while placing downward pressure on the shoulder opposite the direction of flexion. This produces stretch on irritated nerve roots and may accentuate or reproduce radicular symptoms. The shoulder abduction test relieves pressure on the cervical nerve roots and may relieve or reduce cervical radicular symptoms. It is performed by having the patient place the hand from the painful side on the top of their head. This maneuver shortens the distance between the cervical spine and the coracoid process, thus relieving tension on the nerve root. In vivo studies using kinematic MRI of 21 patients with cervical spine disk herniations or cervical spondylosis demonstrated an increase of foraminal size with flexion, axial rotation to the opposite side of pain, and flexion combined with axial rotation to the opposite side of the pain. Foraminal size decreased at extension combined with axial rotation to the side of the pain. A decrease or no change of foraminal size was observed at either extension or axial rotation to the side of the pain alone. Cervical cord rotation or displacement was noted with axial rotation in 24% of these patients.51 Active versus passive range-of-motion testing is advised in patients with neurologic symptoms or those at risk of instability of the cervical spine (i.e., patients with progressive rheumatoid arthritis involving 3632

the cervical spine). In these patients, limitation of active range of motion due to pain may be protective. Adson Maneuver. This test is used to rule out compression of the subclavian artery by an extra cervical rib or scalene muscle bands, which may result in TOS. It was first described by Alfred Washington Adson in 1927. It is performed by having the patient sit with his or her arms resting on the knees with his or her head extended and rotated toward the affected side. The patient is then instructed to breathe deeply and hold his or her breath while the radial pulse is monitored. The test is considered positive if the radial pulse disappears. More recently, the positioning often includes abduction and external rotation of the arm. Current testing methods include use of Doppler ultrasound to record significant changes in subclavian artery flow characteristics during the earlier mentioned maneuvers.52 Although the clinical validity of the Adson test has been questioned, a 2006 study showed complete relief of symptoms following surgery in 87% of patients with a positive Adson test using Doppler ultrasound compared to significant relief of pain in only 50% of patients with a negative Doppler-assisted Adson test.53 Halsted Maneuver (Exaggerated Military Position). The Halsted maneuver is a test of neurovascular compression at the costoclavicular space. The patient assumes a military posture with the shoulders rolled backward and downward so to narrow the costoclavicular space. The radial pulse is monitored. The maneuver is considered positive if the radial pulse disappears. Roos Test or Elevated Arm Stress Test. The Roos or elevated arm stress test (EAST) is a test for TOS during which the patient abducts both arms to 90 degrees with elbows flexed to 90 degrees thus narrowing the scalene triangle. The patient then opens and closes his or her hands for a period of 3 minutes. Patients without TOS will have pain, fatigue, or distress in the forearms only. Patients with TOS will have significant symptomology which replicates their normal TOS symptoms and may not be able to complete the test. Further diagnostic tests for shoulder pathology are outlined in Table 3633

68.15. TABLE 68.15 Tests Used in Shoulder Pain Diagnosis and Significance of Positive Findings Test

Maneuver/Description

Apley scratch test

Patient touches superior and inferior aspects of opposite scapula.

Neer test

The examiner should stabilize the patient’s scapula with one hand while passively flexing the arm while it is internally rotated. If the patient reports pain in this position, then the result of the test is considered to be positive. Patient is examined while sitting with shoulder flexed to 90 degrees and their elbow flexed to 90 degrees. Examiner grasps and supports proximal to the wrist and elbow; the examiner and the patient then quickly rotate the arm internally. Pain located below the acromioclavicular joint with internal rotation is considered a positive test result. Examiner will passively abduct the patient’s shoulder (humerus) to 90 degrees. The patient is then asked to slowly lower or adduct the shoulder to their side. If the patient is unable to perform this motion, the examiner can hold the humerus at 90 degrees of abduction and apply slight pressure to the distal forearm. The patient’s arm should be elevated to 90 degrees in the scapular plane, with the elbow extended, full internal rotation, and pronation of the forearm. This results in a thumbs-down position, as if the patient were pouring liquid out of a can. Examiner stabilizes the shoulder while applying a downwardly directed force to the arm; the patient tries to resist this motion. This test is considered positive if the patient experiences pain or weakness with resistance. Patient stands and places the dorsum of the hand against mid-lumbar spine. The patient then lifts his hand away from the back.

Hawkins-Kennedy test

Drop arm test

Empty can test

Lift-off test

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Diagnosis Suggested by Positive Result Loss of range of motion of the shoulder: rotator cuff problem Subacromial impingement syndrome

Subacromial impingement syndrome

Inability to controllably lower the arm can indicate a rotator cuff dysfunction.

Supraspinatus muscle/tendon tear or suprascapular nerve dysfunction

An inability to perform this action indicates a lesion of the subscapularis muscle. Abnormal

Cross-arm test (scarf test)

O’Brien test (active compression test)

Apprehension test

Relocation test

Sulcus sign

With the arm to be tested in 90 degrees of elbow flexion and 90 degrees of shoulder flexion (forward elevation), the patient then cross adducts/horizontally adducts, resting the hand on top of the opposite shoulder. The examiner pushes the arm into further cross/horizontal adduction. The position and movement mimics throwing a “scarf” over the shoulder, hence the name of the test. A positive test is indicated by localized pain over the acromioclavicular joint. The upper extremity to be tested is placed in 90 degrees of shoulder flexion and 10–15 degrees of horizontal adduction. The patient then fully internally rotates the shoulder and pronates the elbow. The examiner provides a distal stabilizing force as the patient is instructed to apply an upward force. The procedure is then repeated in a neutral shoulder and forearm position. A positive test occurs with pain reproduction or clicking in the shoulder with the first position and reduced/absent with the second position. Examiner stands either behind or at the involved side, grasps the wrist with one hand, and passively externally rotates the humerus to end range with the shoulder in 90 degrees of abduction. Forward pressure is then applied to the posterior aspect of the humeral head by the examiner or the table (if the patient is in supine). A positive test for anterior instability is if apprehension is presented by the patient or if the patient reports pain. With the patient supine, the examiner pre-positions the shoulder at 90 degrees of abduction and maximal external rotation. The examiner grasps the subject’s wrist and hand with his or her distal hand while applying a posterior force to the humeral head while externally rotating the shoulder. The test is considered positive if the patient is able to be moved into a greater range of external rotation before apprehension is expressed as compared to when there is no posterior pressure exerted by the examiner. With the arm straight and relaxed to the side of the

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motion of the scapula during the test may indicate scapular instability. A positive test commonly indicates acromioclavicular joint osteoarthritis or acromioclavicular joint ligament injury. Labral (superior labral tear from anterior to posterior or SLAP) lesion or acromioclavicular lesions as cause for shoulder pain

A positive test indicates a possible torn labrum or anterior instability problem.

Checks for glenohumeral instability, dislocation, and subluxation This test should be done following the apprehension test especially if anterior instability is suspected. A positive test

Yergason test

Speed maneuver

Clunk test

Crank test

patient, the elbow is grasped, and traction is applied in an inferior direction. With excessive inferior translation, a depression occurs just below the acromion. The appearance of this sulcus is a positive sign. The patient should be seated or standing, with the humerus in neutral position and the elbow in 90 degrees of flexion. The patient is asked to externally rotate and supinate their arm against the manual resistance of the therapist. Yergason test is considered positive if pain is reproduced in the bicipital groove during the test. The examiner places the patient’s arm in shoulder flexion, external rotation, full elbow extension, and forearm supination; manual resistance is then applied by the examiner in a downward direction. The test is considered to be positive if pain in the bicipital tendon or bicipital groove is reproduced. Have the patient lie supine. The examiner places one hand on the posterior aspect of the shoulder over the humeral head and places the other hand on the humerus above the elbow. Fully abduct the arm over the patient’s head and then push anteriorly with the hand over the humeral head while the other hand rotates the humerus into external rotation. A clunk or grinding sound is a positive test. With the subject standing, the examiner places the distal hand on the subject’s elbow and the proximal hand on the subject’s proximal humerus and then passively elevates the subjects shoulder to 160 degrees in the scapular plane. With the distal hand, the examiner applies a load along the long axis of the humerus while the proximal hand externally and internally rotates the humerus. A positive test is when there is reproduction of symptoms with or without a click during the maneuver (usually during external rotation).

indicates glenohumeral instability.

A positive test indicates biceps tendon pathology, such as bicipital tendonitis.

A positive test indicates a superior labral tear or bicipital tendonitis.

A positive test indicates a tear of the labrum.

A positive test indicates a glenohumeral ligament lesion and may also be used to assess anterior shoulder instability or a labral tear.

SLAP, superior labrum anterior and posterior.

Examination of the Shoulder and Arm Detailed anatomy of the neck, shoulder, and upper extremities, including normal range of motion, is covered in the initial part of this chapter and is essential to understanding the anatomic and functional correlates of this 3636

portion of the physical exam. Physical examination of the shoulder, arm, elbow, forearm, wrist, and hand should include the following: • Blood pressure • Inspection of position, shape, muscle atrophy, swelling • Inspection of skin for allodynia, changes in color, temperature, or trophic changes • Palpation of muscles and tendon for tenderness, pain, trigger points, dysesthesias, and radiation patterns • Palpation over joints during range of motion testing for crepitus, popping, or locking • Active and passive range of motion at shoulder: abduction, adduction, internal and external rotation, flexion, and extension at shoulder • Other tests for shoulder, see Table 68.15 • Range of motion at forearm: flexion, extension, pronation, and supination • Range of motion at wrist: dorsal flexion, palmar flexion, ulnar flexion, and radial flexion • Range of motion of fingers: flexion, extension, adduction, abduction, opponens, and grip • Observation of effect on pain of each movement Waddell Signs. In their study of illness behavior, Waddell et al.54 described five categories of nonanatomic signs (Table 68.16) and reported that the presence of at least three signs was indicative of significant psychosocial stress. Although the presence of three or more signs is often interpreted as a sign of malingering, no association with malingering or secondary gain has been demonstrated in controlled studies.55 Fishbain et al.56 reported that Waddell signs decreased following comprehensive pain management. Pain behaviors are known to be a means for patients to communicate pain and distress. They can be positively reinforced by attention from family members or by being excused from undesirable obligations. Pain behaviors may also be “unlearned” using cognitive and behavioral therapies.57,58 TABLE 68.16 Waddell Signs

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1. 2. 3. 4.

Superficial and widespread tenderness or nonanatomic tenderness (it is “one” sign) Stimulation tests: axial loading and pain on simulated rotation (it’s another “one” sign) Distracted straight leg raise Nonanatomic sensory changes: regional sensory changes and regional weakness (it’s another “one” sign) 5. Overreaction

LABORATORY EVALUATION Pain must be seen as a diagnosis of exclusion, for the consequences of treating pain symptomatically in the face of progressive systemic disease can result in a tragic delay of diagnosis and treatment. In general, laboratory testing is guided by the patient’s history of present illness, past medical history, and physical exam. A patient who is systemically ill requires more extensive testing guided by affected organs and systems. For example, patients who are febrile or those with weight loss, anorexia, and other signs suggesting infection or neoplasm would benefit from complete blood count and differential analysis. Those with a history of hepatitis or other risk factors for liver disease would benefit from a liver enzyme panel. Patients with cold intolerance, weight gain, and lethargy should undergo thyroid function test analysis. Morning stiffness, polyarticular involvement, rigidity, or cutaneous manifestations suggest an inflammatory arthritic component requiring a more extensive rheumatologic evaluation. Patients with a diagnosis of fibromyalgia should undergo testing of both thyroid function and vitamin D levels because hypothyroidism and vitamin D deficiency can both result in diffuse pain syndromes which mimic fibromyalgia. Laboratory analysis of the erythrocyte sedimentation rate and C-reactive protein may also assist in evaluating inflammatory phenomena such as an autoimmune disease, infection, or neoplasm. These may be significantly elevated with an upward trend in patients who are afebrile, who have a normal white blood cell count, and who culture negative (even in the face of sepsis).59,60 Other laboratory tests which may be useful in ruling out systemic disease in select patients include serum calcium, which among other diagnoses may be elevated in patients with malignancy, and serum alkaline phosphatase, which is elevated in metastatic spine tumors and Paget disease.1 3638

RADIOGRAPHIC STUDIES Diagnostic and functional imaging is covered in detail in Chapters 18 and 19. In general, imaging of the neck and arm should be performed in patients with a history of trauma, persistent or progressive pain, and in patients with neurologic deficits involving the neck and/or upper extremities in order to confirm or rule out treatable organic causes of pain or neurologic deficits and to guide therapeutic decision making. Although the clinical usefulness of cervical spine radiographs for evaluation of neck pain has been questioned,61,62 cervical spine fractures occur frequently following relatively minor trauma in the elderly patient63 with a relative risk of up to three times more fractures in elderly versus younger adults evaluated in the emergency room.64 Although significant cervical spine injury is infrequent in younger patients, diagnosis is often delayed following motor vehicle and sports trauma. In published series, missed cervical spine injuries following trauma have been reported to occur in 4.6% to 33% of patients.65,66 C2 and C5–C6 level fractures are the most commonly seen injuries.65,67,68 In a recent report of 100 consecutive patients who underwent operative fixation or halo stabilization for cervical spine injuries, 10% of injuries were missed due to failure to perform plain cervical films versus failure of interpretation or failure to utilize more advanced imaging techniques.67 A recent prospective, multicenter US study designed to validate clinical criteria developed to evaluate patients with neck pain following blunt trauma69–71 confirmed sensitivity of the set of five criteria (Table 68.17) approaching 100% for clinically important injuries.72 TABLE 68.17 NEXUS Criteria for Radiologic Evaluation of the Neck in Patients after Trauma No midline cervical tenderness No focal neurologic deficit Normal alertness No intoxication No painful, distracting injury NEXUS, National Emergency X-Radiography Utilization Study.

Even fewer injuries were missed in a more recent multicenter study, 3639

when the Canadian C-spine rule was applied (Fig. 68.34).73 Anteroposterior, neutral lateral, and odontoid plain film views are recommended. A patient with persistent neck pain or tenderness despite normal plain film radiology or suspected ligamentous injury may benefit from flexion-extension views to evaluate for listhesis or instability. These views may also be helpful in determining the amount of motion occurring with flexion and extension in patients with degenerative spondylolisthesis. Prior to flexion-extension imaging, the patient should perform active range of motion in the presence of a physician to confirm that no significant neurologic deficit occurs during these maneuvers.

FIGURE 68.34 Canadian C-Spine rule.

In patients with chronic neck pain, plain film views can reveal degenerative changes such as loss of disk height, bone spurs, endplate irregularity, and endplate sclerosis. In patients with prior cervical spine fusion, instability secondary to pseudoarthrosis can be appreciated. Computerized tomography (CT) is recommended for patients with acute or chronic neck pain who have normal plain films and clinically suspected cervical spine pathology or to further define abnormalities seen on plain films.74 It is also useful for evaluating the size and shape of the spinal canal, facet and uncovertebral joints, and transverse foramina.75,76 When possible, patients with neurologic deficits or pain due to suspected neurologic or soft tissue injury or pathology should undergo MRI. According to a systematic analysis and multicenter study comparing CT to MRI for assessment of cervical spine injuries following trauma to the cervical spine, midsagittal T1- and T2-weighted MRI provides an objective, quantifiable, and reliable assessment of spinal cord compression that cannot be adequately assessed by CT alone.77 MRI and magnetic resonance myelography are comparable to CT myelography in assessing spinal stenosis and spinal nerve roots. Although CT is superior in imaging 3640

canal foraminal osteophytes, MRI is superior to CT in assessment of spinal cord gray matter and nerve root signal changes and well as ligamentous and intervertebral disk changes.78 Use of gadolinium-enhanced MRI in symptomatic patients who have undergone surgery of the cervical spine is valuable in identifying changes consistent with postoperative infection in the acute postoperative period and in defining the extent of epidural scar formation versus reherniation of intervertebral disks in patients with recurrent neck and radicular pain.79 If MRI is contraindicated (i.e., due to a pacemaker or spinal cord stimulator), CT using 45-degree oblique reconstruction is superior to sagittal reconstructions oriented at 90 degrees for evaluation of the foramen for bony spurs.80 In regard to imaging of the shoulder, a standard series of shoulder radiographs excludes or confirms arthritis, bursitis, tendonitis, calcification, dislocation, tumor, and old or new fractures.81 CT is useful for diagnosing bony lesions, subtle dislocation, labral tears, and full rotator cuff tears. MRI is more expensive, time-consuming, and less readily available in some areas, and certain pathologies such as the glenoid labrum and the surrounding ligaments may be difficult to evaluate with MRI. MRI is able to evaluate partial or full rotator cuff tears and has the advantages of noninvasive nature, lack of contrast exposure, nonionizing radiation, high degree of resolution, and ability to evaluate multiple pathologies. Ultrasound is used to diagnose rotator cuff tears, is noninvasive, rapid, and relatively inexpensive; however, it has been shown to have more interoperator variability in performance and interpretation of imaging.81–85 Advanced imaging as well as electromyography and nerve conduction velocity testing should be performed as needed for the purpose of guiding treatment decision making. Electrodiagnostic evaluation of acute and chronic pain is discussed in Chapter 16. Multiple plain radiographic views are often needed to visualize the elbow, forearm, wrist, and hand and can also be used to confirm or rule out fractures, tendonitis, and dislocations. Minimal evaluation of the elbow should include anteroposterior views for the distal humerus and proximal forearm as well as lateral views in maximal flexion and extension. Additional views such as radiocapitellar, cubital tunnel, oblique, and stress 3641

views may be utilized based on history or mechanism of injury and physical exam findings.1

Common Causes of Neck and Arm Pain MECHANICAL NECK PAIN AND CERVICOGENIC HEADACHE Neck pain from similar mechanisms may be axial, associated with radicular pain, headache, and/or symptoms suggesting spinal cord compression. The complex and highly interdependent structures of the neck may preclude identification of a single pain generator in patients with advanced disease. Muscle and ligamentous injury or pain may result from factors related to posture, poor ergonomics, stress, injury, and/or chronic muscle fatigue. Pain may also result from degenerative changes of the cervical facet joints and disks and atlantooccipital and atlantoaxial joints and irritation, inflammation, and mechanical distortion of the cervical nerve roots and spinal cord. These processes may occur independently or concurrently and require a careful history and physical examination together with the judicial use of diagnostic tests to rule out systemic disease and rapidly progressive processes. Recent data reports a 12-month prevalence of 30% to 50% for neck pain and associated disorders in adults.3 A knowledge and application of recent prospective studies, systemic reviews, and meta-analysis proposing guidelines for evaluation and treatment of these patients may assist with assessing the risk versus benefit for effective conservative versus interventional and surgical therapies in this large and heterogeneous population.

Cervical Spondylosis and Radiculopathy Degenerative changes of the cervical spine reach a prevalence of nearly 95% by age 65 years. These changes are associated with positive changes such as disk protrusion, neural foraminal narrowing, and spinal cord contour changes in up to 78% of asymptomatic individuals.7–9,86 In symptomatic individuals, the risk versus benefit of surgery and other interventional therapy87 mandates an understanding of the natural course of symptomatic patients with cervical spondylosis and radiculopathy. 3642

Although the outcome of these patients when treated conservatively versus surgically is controversial,88,89 recent investigations reveal clinical and radiographic correlates with outcome in this population, which may be of assistance in timely surgical referral when symptoms continue to progress following conservative treatment.90–92 Cervical spondylosis was first distinguished from acute cervical disk protrusion by Brain et al.93 in 1948. The latter occurs more commonly in individuals younger than age 55 years, is often traumatic in origin, and most frequently compresses the nerve roots versus the spinal cord. The former is a chronic degenerative condition of the cervical spine associated with formation of osteophytes. It is a universal finding associated with aging and is associated with compression of the spinal cord in most symptomatic cases. Patients older than age 55 years are more likely to have central canal or neural foraminal stenosis due to spondylosis.94 In a population-based study conducted from 1976 to 1990 in Rochester, Minnesota, a confirmed disk herniation was found to account for approximately 20% of all cervical radiculopathies and approximately 70% of all spondylosis. The average age-adjusted incidence rate per 100,000 population was 107.3 for males, 63.5 for females, and reached a peak of 202.9 for the age group between ages 50 to 54 years.95,96 Spondylosis refers to degenerative changes of the spine involving the intervertebral disks, uncovertebral joints of Lushcka, zygapophyseal joints, ligaments, and connective tissue of the cervical vertebrae. Degenerative changes of the cervical spine are seen in approximately 10% of individuals by age 25 years and in 95% by age 65 years. The process is believed to begin with fibrosis and loss of elasticity of the disk which occurs with loss of water, protein, and mucopolysaccharides from the nucleus pulposus. Loss of disk space height initially occurs ventrally and leads to loss of cervical lordosis. This shift of biomechanical forces results in ventral vertebral body compression with resultant pathologic cervical spine kyphosis, dissection of the annulus fibrosus, posterior longitudinal ligament, and Sharpey’s fibers away from the edges of the posterior vertebral body, formation of reactive bone on the edges of exposed dorsal vertebral bodies, and increased axial load bearing by the uncovertebral and zygapophyseal joints, with resultant hypertrophy and osteophytic 3643

formation ventral and posterior to the neural foramen. Spondylotic spurs may eventually span the width of the vertebral canal in some patients. Because the osteophytes form in response to increased motion or segmental instability, the levels most commonly affected, both by disk herniation and chronic spondylosis are C6–C7 followed by C5–C6 because these are the cervical segments at which the most extension and flexion occur. The reduction in sagittal spinal canal diameter in cervical spondylosis results from a combination of static and dynamic factors. Static reduction of the sagittal diameter of the spinal canal occurs from disk herniation or bulging; vertebral body osteophyte growth into the anterior spinal canal; and degenerative hypertrophy of the uncovertebral joints, facet joints, and ligamentum flavum combined with calcification of the posterior longitudinal ligament. The addition of dynamic factors such as flexion, extension, or subluxation can further increase the risk for compression and injury to the contents of the spinal canal and neural foramen including the spinal cord, nerve roots, arteries, and veins. These combined pathologic features are thought to be responsible for the production of the wide spectrum of clinical symptoms associated with cervical spondylosis including neck and shoulder pain, occipital pain and headaches, radicular symptoms, and cervical radiculopathies and cervical spondylotic myelopathy (CSM). Compression of the spinal cord may occur from spondylotic bars and calcified posterior longitudinal ligament ventrally or from the hypertrophic ligamentum flavum dorsally. Cumulative repetitive injury to the spinal cord is thought to occur with flexion, due to a “bowstring effect” over the ventral spondylotic bars and kyphotic spine, and compression dorsally by buckling of the ligamentum flavum. MRI flexion and extension studies observed increased cervical stenosis in twice as many patients during extension versus flexion. Risk for compression of the spinal cord is increased in individuals with congenital narrowing of the spinal canal. CSM refers to clinically evident spinal cord dysfunction with the presence of long-tract signs due to compression of the spinal cord. Weakness or stiffness in the legs with unsteady gait together with weakness or clumsiness of the hands is pathognomonic of CSM. 3644

Progression of weakness may be gradual in some patients or sudden in others following minor trauma. In a prospective study at a UK regional neuroscience center, 23.6% of 585 patients admitted with tetraparesis or paraparesis were found to have CSM. Some patients may complain of hesitancy on urination; however, loss of sphincter control or urinary incontinence is rare and considered a late sign of myelopathy. Patients with CSM generally present with neck and shoulder pain and stiffness. The patient may also present with pain in the arm, elbow, wrist, or fingers described as combined or isolated sensations of stabbing, dull, or aching pain. Arm pain may be nondermatomal in distribution and accompanied by numbness or tingling in the hands. Pain which conforms to a dermatomal distribution with associated motor and sensory deficits is referred to a radiculopathy rather than myelopathy. Some patients may present with both myelopathy and radiculopathy. Signs of CSM on physical exam include an electrical sensation radiating down the back to the legs with flexion of the neck (Lhermitte’s sign); atrophy of the intrinsic musculature of the hands; and variable sensory, vibratory, or proprioceptive loss in the extremities. Deep tendon reflexes may be reduced or absent at the level of compression with hyperreflexia below the level of the lesion together with upper motor signs such as clonus, Hoffmann, and Babinski sign.76,93,97,98 There are two commonly used classification systems for CSM. The classification of Crandall and Batzdorf99 divides CSM patients into five groups of spinal cord dysfunction. These include the transverse lesion syndrome, the motor system syndrome, the central cord syndrome, the Brown-Séquard syndrome, and the brachialgia cord syndrome. These are summarized in Table 68.18. Ferguson and Caplan100 categorize CSM into four overlapping syndromes, which are summarized in Table 68.19. TABLE 68.18 Crandall and Batzdorf99 Classification of Clinical Syndromes in Cervical Spondylotic Myelopathy Transverse lesion syndrome Motor system syndrome

Most common lesion. Involves posterior column, spinothalamic and corticospinal tracts, and often anterior horn cells. Posterior column involvement uncommon and late. Involves anterior horn cells and corticospinal tracts primarily. Little sensory involvement. Upper and lower extremity weakness, gait disturbance, and spasticity.

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Central cord syndrome Brown-Séquard syndrome

Brachialgia cord syndrome

Upper extremities weaker than lower extremities. Profound hand weakness. Posterior column involved often presenting as painful paresthesias of hands. Unilateral spinal cord dysfunction. Involvement of corticospinal tract. Posterior column sensory loss (position, vibration) and long tract motor signs (hemiplegia) are found ipsilateral to the lesion, whereas pain and temperature are lost contralaterally. One or two levels below highest level of motor involvement. Upper extremity nerve root compression combined with long tract signs (analogous to Ferguson and Caplan’s100 combined medial and lateral syndrome).

TABLE 68.19 Ferguson and Caplan100 Classification of Clinical Syndromes in Cervical Spondylotic Myelopathy Lateral syndrome Medial syndrome

Combined medial and lateral syndrome Vascular syndrome

Represents a spondylotic radiculopathy. Absence of long tract signs. Upper motor neuron symptoms. Variable weakness of all extremities, gait abnormalities, spasticity below level of compression. Most common clinical presentation. Acute onset and rapid progression of myelopathy. Thought to represent insufficiency or compression of anterior spinal artery and its branches to the spinal cord.

The differential diagnosis of CSM includes amyotrophic lateral sclerosis, multiple sclerosis, hereditary spastic paraplegia, spinal cord tumors, and subacute combined degeneration of the spinal cord associated with vitamin B12 deficiency. MRI is the imaging technique of choice for evaluating the patient with CSM. T2- and T1-weighted signals on MRI have been found to correlate with various degrees of injury to the spinal cord on histologic studies. Edema is seen as a high-intensity T2-weighted image. Necrotic changes in the gray matter correspond to low signals on T1-weighted studies but high signals on T2-weighted studies. T1-weighted hypointensity is an expression of irreversible damage and, therefore, the worst prognosis.92,101 A less favorable surgical outcome is predicted by the presence of a T1weighted hypointense signal and the presence of clonus or spasticity. A high intramedullary T2-weighted signal without clonus or spasticity is associated with a more favorable surgical outcome with a greater 3646

likelihood of reversal of MRI signal changes.102 A recent investigation reported multiple regression analysis of various risk factors associated with surgical outcome. According to this analysis, the most significant prognostic factor was the transverse area of the spinal cord, followed by the duration of symptoms and the presence of multisegmental areas of high-signal intensity on T2-weighted MRI. The latter was associated with upper extremity muscle atrophy and less favorable surgical recovery of neurologic function.91 Controversy exists regarding optimal treatment for patients with CSM, and many authors recommend conservative treatment due to significant risks associated with surgery and lack of data supporting long-term improved outcome in patients undergoing surgery versus conservative care.103–106 A recent prospective 3-year follow-up study did not show, on average, that the effects of surgery in the treatment of mild and moderate forms of CSM were better than the conservative approach. Nevertheless, there was a slight but statistically significant increase in the number of patients with a negative trend in the score for daily activities in the conservatively treated group. The authors of this study recommend conservative treatment for patients with mild SCM along with careful follow-up evaluation and reassessment 3 months after the start of conservative treatment. Decompression surgery is recommended for patients who experience neurologic deterioration during this period.88 A prospective, multicenter study with independent clinical review evaluating conservative versus surgical treatment for patients with moderate to severe CSM found that although surgical treatment was not found to improve neurologic outcome, overall pain and functional status improved significantly. When medical and surgical treatments were compared, surgically treated patients appeared to have better outcomes, despite exhibiting a greater number of neurologic and nonneurologic symptoms and greater functional disability before treatment.89 Conservative treatment for CSM consists of intermittent cervical immobilization with a soft collar, the use of anti-inflammatory medications, active discouragement of high-risk activities, and avoidance of risky environments involving physical overloading, excess cold, movement on slippery surfaces, manipulation therapies, or vigorous or 3647

prolonged flexion of the head. Additional conservative measures include a rehabilitation program with physiotherapy and referral to a multidisciplinary pain team. Patients with moderate to severe symptoms on presentation and progressive neurologic symptoms should be referred for surgical evaluation. The aim of the surgery in these patients is to stop the progression of neurologic deterioration and prevent sudden deterioration after minor injury or in particular situations such as swimming, cycling, and physical overloading.88,89

Cervicogenic Headache The term cervicogenic headache (CEH) was coined by Sjaastad et al.107 in 1983. He later organized the Cervicogenic Headache International Study Group (CHISG), and diagnostic criteria for CEH were published by the CHISG in 1990.108 A revision of criteria for CEH was published by the CHISG in 1998.109 CEH was recognized as a unique category of headaches by the International Association for the Study of Pain in 1994, using criteria similar to that published by Sjaastad et al.110 Revised criteria for CEH were published by the International Headache Society (IHS) in 2004.111 Although controversy exists regarding the defining characteristics and prevalence of CEH, there is emerging evidence of valid clinical, diagnostic, and therapeutic criteria which differentiates this syndrome from migraine headache, tension-type headache, hemicrania continua, and chronic paroxysmal hemicrania.112,113 CEH is defined as unilateral head or face pain which starts in the neck and is triggered by neck movement or sustained awkward neck posture. Although pain begins in the neck or occipital region, it may spread to the retroorbital, temporal, and frontal areas of the head and face where maximum pain may be perceived. Pain may occur to a lesser degree on the contralateral side; however, profound unilateral dominance should exist. CEH is typically described as deep and nonthrobbing with intermittent attacks lasting hours to days. In time, headaches may become constant with superimposed attacks of more intense pain. Pain in CEH should be reproducible upon palpation or stimulation of cervical spine or neck structures. It is accompanied by reduced range of motion of the neck and 3648

ipsilateral nonradicular neck, shoulder, or arm pain. Nausea, vomiting, photophobia, dizziness, blurred vision, lacrimation, and conjunctival injection may occur. The new IHS criteria requires clinical, laboratory, or imaging evidence of a lesion or disorder within the neck or cervical spine known to be associated with the causation of headache. This should be validated by reproducible clinical signs or by controlled diagnostic blockade (Tables 68.20 and 68.21 show comparison of IHS and CHISG criteria for CEH). TABLE 68.20 International Headache Society Diagnostic Criteria for Cervicogenic Headache A. Pain referred from a source in the neck and perceived in one or more regions of the head and/or face fulfilling criteria C and D B. Clinical, laboratory, and/or imaging evidence of a disorder or lesion within the cervical spine or soft tissues of the neck known to be, or generally accepted as, a valid cause of headache C. Evidence that the pain can be attributed to the neck disorder or lesion based on at least one of the following: 1. Demonstration of clinical signs that implicate a source of pain in the neck 2. Abolition of headache following diagnostic blockade of a cervical structure or its nerve supply using placebo or other adequate controls D. Pain resolves within 3 months after successful treatment of the causative disorder or lesion.

TABLE 68.21 Cervicogenic Headache International Study Group Cervicogenic Headache Diagnostic Criteria109 Major Criteria A. Symptoms and signs of neck involvement; it is obligatory that one or more of the phenomena 1 to 3 are present. 1. Precipitation of head pain, similar to the usually occurring one: a. By neck movement and/or sustained, awkward head positioning, and/or b. By external pressure over the upper cervical or occipital region on the symptomatic side 2. Restriction of the range of motion in the neck 3. Ipsilateral neck, shoulder, or arm pain of a rather vague, nonradicular nature, or, occasionally, arm pain of a radicular nature B. Confirmatory evidence by diagnostic anesthetic blockages C. Unilaterality of the head pain, without side shift Head Pain Characteristics D. Moderate to severe, nonthrobbing pain, usually starting in the neck Episodes of varying duration, or Fluctuating, continuous pain Other Characteristics of Some Importance E. Only marginal effect or lack of effect of indomethacin

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Only marginal effect or lack of effect of ergotamine and sumatriptan Female sex Not infrequent occurrence of head or indirect neck trauma by history, usually of more than only medium severity Other Features of Lesser Importance F. Various attack-related phenomena, only occasionally present and/or moderately expressed when present 1. Nausea 2. Phonophobia and photophobia 3. Dizziness 4. Ipsilateral “blurred vision” 5. Difficulties on swallowing 6. Ipsilateral edema, mostly in the periocular area

The prevalence of CEH in the literature varies widely from 0% to 80%, depending on the population of patients studied, diagnostic criteria, and methodology.112 A recent Norwegian study reported that 75% of tractor drivers suffered from moderate to severe generalized headache only when working on their tractor because of consecutively turning or twisting their neck for many hours daily.114 In a series of 100 consecutive patients with neck pain following whiplash, Lord et al.115 reported a prevalence of associated headache in 88%. Of those patients with headache as the dominant symptom, 54% were found to have neck pain originating from a C2–C3 cervical zygapophyseal joint following diagnostic blocks. This was associated with tenderness over the affected joint on physical examination.115 In a study of 34 patients with the complaint of headache emanating from the occipital region, tenderness to exam over the tip of the transverse process of C1 and worsening of their usual headache with passive rotation of the C1 vertebra, 60% were found to have complete relief of their pain following diagnostic blockade of the atlantoaxial joint.116 Pain maps based on regions of the head and neck in which patients were relieved of pain following controlled blocks revealed radiation of pain from the C1–C2 through the C3–C4 facet joints to the suboccipital and occipital regions as well as the vertex, frontal, orbital, and temporoparietal region of the head.47 The anatomic basis by which pain from the cervical spine and neck can be perceived in the face and head derives from the convergence of afferents from the trigeminal nerve with those of the first three spinal 3650

nerves in the caudal aspect of the trigeminal nucleus in the brainstem.117,118 Musculoskeletal structures innervated by the first three cervical nerves are outlined in Table 68.22. Convergence with the spinal trigeminal nucleus and the extradural convergence of the first three cervical nerves may account for the difficulty encountered in localizing the pain in patients with CEH. TABLE 68.22 Musculoskeletal Structures of the Neck Innervated by C1 through C3 Muscles: capital flexors and extensors, cervical spine flexors including the scalenus medius, scalenus posterior, longus colli and sternocleidomastoid, cervical spine extensors, head rotators, and other neck muscles including the hyoid muscles, the sternothyroid, and diaphragm Periosteum and body of the atlas, axis and C3 vertebra and clavicle, atlantooccipital, atlantoaxial, intervertebral, Luschka, sternoclavicular and zygapophyseal joints associated with the C1–C3 spinal segments, associated ligaments

The anatomy of the sinuvertebral nerve may also contribute to the variation of pain patterns among patients and the presence of diffuse neck and head pain in the presence of discrete injuries. The sinuvertebral nerves supply structures within the spinal canal. They arise from the rami communicantes and enter the spinal canal by way of the intervertebral foramina. Branches ascend and descend one or more levels, interconnecting with the sinuvertebral nerves from other levels and innervating the anterior and posterior longitudinal ligaments dura mater and blood vessels as well as sending nociceptive fibers to degenerative intervertebral disks.119,120 Neurogenic inflammation from compression ischemia of the cervical nerve and inflammatory response following exposure of spinal tissues to proinflammatory mediators such as phospholipase A2 from extruded nucleus pulposus may also contribute to neck pain and CEH. In addition to the evidence of atlantoaxial and zygapophyseal joint evidence discussed earlier, there is evidence that CEH may arise from a discogenic origin. Reproduction of patient’s usual headache by cervical provocation discography has been reported, as has relief of headache following decompressive surgery of the upper and lower cervical spine.121,122 The mechanisms by which headaches are provoked by levels 3651

below C3 have caused speculation regarding the possibility of convergence of afferents from lower spinal nerves with trigeminal afferents in the spinal trigeminal nucleus. An alternate explanation could lie in the anatomy of the sinuvertebral nerves, which descend from higher levels in the cervical spine to communicate with those at lower levels. An inflammatory response could also be causative with proinflammatory mediators resulting from disk degeneration at lower cervical spinal segments precipitating a nociceptive response at adjacent spinal segments.119 Greater and lesser occipital nerve injections using local anesthetic and/or steroid have been reported as useful for diagnosis and short-term relief of CEH. Many authors consider entrapment of the greater occipital nerve to be one of the major underlying causes of CEH.123–125 A recent controlled trial of nerve stimulator-guided greater and lesser occipital nerve blocks with adjuvant agents provided greater than 50% relief versus placebo with significant reduction of associated headache features and medication use in the treatment group.126 A case report of pulsed radiofrequency for the treatment of intractable occipital headache reported 70% relief for 4 months followed by an additional 5 months of 70% relief with repeat pulsed radiofrequency.127 Percutaneous radiofrequency cervical medial branch neurotomy has been shown, in a rigorous double-blind controlled trial, to provide relief in 70% of patients diagnosed with cervical zygapophyseal joint pain following whiplash injuries. Other therapies found to have efficacy in the treatment of CEH include the physical therapy modalities of manipulation and/or mobilization in conjunction with exercise and intramuscular lidocaine injections. In chronic neck disorders associated with a radicular component, epidural injection of methylprednisolone and lidocaine improved pain greater than cervical intramuscular injections with the same solution at 1-year follow-up.128–130

DIFFUSE IDIOPATHIC SKELETAL HYPEROSTOSIS DISH is a form of osteoarthritis that is characterized by the calcification and ossification of soft tissues including ligaments and tendons. It may involve both the peripheral joints and the axial skeletal structures in 25% 3652

and 15% of men and women, respectively, who are older than 50 years of age. Its prevalence increases to 35% and 26%, respectively, in individuals older than 70 years. Classical axial involvement results in calcification of the ligamentum flavum in the lumbar spine, the anterior longitudinal ligament in the thoracic spine, and the posterior longitudinal ligament in the cervical spine. It is distinguished from degenerative spondylosis of the spine by earlier onset; sparing of the intervertebral disk; and its association with a number of risk factors including diabetes mellitus, obesity, hyperuricemia, dyslipidemia, hypertension, coronary artery disease, and prolonged use of isoretinal (vitamin A supplementation). The patient with DISH typically presents with stiffness and decreased range of motion. Older patients with cervical spine involvement may complain of dysphagia due to pharyngeal encroachment from large anterior osteophytes. Other potential sequelae include cervical myelopathy and cervical spine fractures following relatively trivial trauma. The diagnosis of cervical spine fractures is often delayed due to the presence of baseline neck and spine pain. The diagnosis of DISH is radiographic and is based on the criteria established by Resnick and Niwayama.131 These include the presence of “flowing” ossification along anterolateral margins of at least four contiguous vertebrae and the absence of changes associated with degenerative spondylosis. Treatment consists of conservative measures similar to cervical degenerative spondylosis. Operative treatment is reserved for those patients who fail to respond to conservative measures.132,133

CERVICAL RADICULOPATHIES The classical definition and clinical manifestation of cervical radiculopathies is pain, sensory loss, and motor weakness in the distribution of the affected nerve root. Although the cause of radicular symptoms has been presumed to be secondary to compression of the nerve root because of adjacent soft disk herniation or progressive degenerative changes of the cervical spine, the poor correlation between radiologic evidence of degenerative change and incidence of painful symptoms in the cervical spine has been well documented.134–138 Other factors thought to 3653

contribute to the pathogenesis of radiculopathic symptoms include vascular insufficiency, venous engorgement, nerve root fibrosis, and inflammation. Type-C cell distortion in dorsal root ganglion of cervical nerve roots has been proposed as a mechanism of accentuated neuropeptide production and increased hypersensitivity in patients with acute and chronic neural foraminal compression or edema.139 The patient with cervical radiculopathy typically complains of burning, aching, cramping, electrical, or sharp pain which radiates to the neck and head, shoulder, arm, or chest depending on the involved nerve root(s). In acute radiculopathy, pain classically presents in a myotomal distribution versus a distal dermatomal distribution. The pain is generally accompanied by numbness and paresthesias. Motor weakness and diminution or loss of deep tendon reflexes may also be seen. Spurling’s maneuver, Valsalva, coughing, and sneezing will often provoke or aggravate the patient’s symptoms, whereas the shoulder abduction sign (having the patient abduct the shoulder and place their hand on top of their head) will generally relieve their pain. The C1 nerve passes between the occiput and C1. It is also known as the suboccipital nerve and supplies sensory fibers to the periosteum and body of the atlas, occiput, atlantooccipital joint, and atlantoaxial joint. It is also distributed to the muscles of the suboccipital triangle. The C2 nerve passes between C1 and C2. The medial or sensory branch of C2 is also known as the greater occipital nerve. It supplies the scalp over the vertex and top of the head and supplies muscular branches to the semispinalis. C3 arises between C2 and C3. The medial sensory branch of the posterior division of the third cervical nerve forms the third or least occipital nerve. The anterior rami of the upper four cervical nerves communicate to form the cervical plexus. Pathologic processes which affect the C1 through C3 nerves cause pain radiating to the head and neck. Pain of the upper cervical spine was covered in more detail in the section on CEHs.140,141 The greater auricular nerve and the anterior cutaneous nerve are also derived from the second and third cervical nerves. Processes affecting these nerves can also result in pain involving the mastoid process, the lobule and concha of the ear, the skin of the face over the parotid gland, and the skin of the anterolateral aspect of the neck as far as 3654

the sternum. Via the deep cervical plexus, the second and third cervical nerves also communicate with the vagus, the hypoglossal nerve, the superior cervical sympathetic ganglion, and the diaphragm by way of the phrenic nerve (see Table 68.3). Radiculopathy of the fourth cervical nerve root results from pathologic changes between the C3 and C4 vertebrae and is more common than a C3 radiculopathy. The supraclavicular nerve arises mainly from the fourth cervical nerve and supplies the skin and superficial fascia of the clavicular region, the periosteum, and bony structure of the clavicle as far as the midline and the skin over the pectoralis major as far as the second or third rib. It additionally communicates with the cutaneous branches of the second and third rib. The lateral supraclavicular nerve supplies the skin of the top and dorsal parts of the shoulder. Involvement of the C3 nerve may be a cause of unexplained pain along the base of the neck that radiates to the superior aspect of the shoulder and posteriorly to the scapula. Pain in the distribution of the supraclavicular nerve may also be a cause of chronic breast pain in women. The rhomboid, trapezius, and levator scapulae muscles are supplied in part by the fourth cervical nerve root, but a motor deficit may be difficult to detect. A sensory deficit may be present over the anterolateral aspect of the neck, along the distribution of the transverse cervical and supraclavicular nerves. Because the C3, C4, and C5 nerve roots innervate the diaphragm, involvement of these three nerve roots may lead to diaphragmatic weakness. The brachial plexus is formed by the fifth, sixth, seventh, and eighth cervical nerves together with the first thoracic nerve and frequently contributing branches from the anterior division of the fourth cervical and second thoracic nerve. The variation of brachial plexus and extradural cervical nerve connections may contribute to variations in radicular patters among patients. Pathologic changes at the C4–C5 level result in a C5 radiculopathy. The principal motor deficit seen in classical C5 radiculopathy is supraspinatus and deltoid muscle weakness with impaired shoulder abduction. Weakness of the clavicular head of the pectoralis major, biceps, and infraspinatus muscles can also occur. The pectoralis reflex and the biceps reflex, which 3655

are innervated by the fifth and sixth cervical nerve roots, may be decreased or absent. The numbness follows the C5 sensory distribution, which is located over the top of the shoulder along its midportion, and extends laterally to the midportion of the arm. The component fibers of the suprascapular nerve are derived primarily from the fifth and sixth cervical nerves. It supplies sensory, motor, and sympathetic fibers which supply the supraspinatus and infraspinatus muscles, the shoulder joint, and periarticular structures as well as an area of skin at the apex of the shoulder. Patients often present with numbness and localized shoulder pain that can be confused with a pathologic shoulder condition. The absence of pain with a range of motion of the shoulder and the absence of impingement signs at the shoulder help to differentiate radiculopathy of the fifth cervical nerve root from a pathologic shoulder condition. The sixth cervical nerve root is the second most commonly involved in cervical radiculopathy. Patients with pathology at this level typically present with pain radiating from the neck to the lateral aspect of the biceps, lateral aspect of the forearm, dorsal aspect of the web space between the thumb and index finger, and into the tips of those digits. Numbness occurs in the same distribution. Motor deficits are best elicited in the wrist extensors, but weakness of the biceps, supinator, pronator, teres, and triceps muscles may be present. The brachioradialis and biceps reflexes may be decreased or absent. The pain and paresthesias of C6 radiculopathy may mimic carpal tunnel syndrome (CTS), which is caused by median nerve entrapment at the transverse carpal ligament. The seventh cervical nerve root is most frequently involved by cervical radiculopathy according to many clinical studies. The patient with C7 radiculopathy complains of pain radiating along the back of the shoulder, often extending into the scapular region, down along the triceps, along the dorsum of the forearm and into the dorsum of the long finger. Motor weakness is most often appreciated in the latissimus dorsi muscle, the triceps, wrist flexors, and finger extensors. The triceps reflex may be lost or diminished. Entrapment of the posterior interosseus nerve may be mistaken for the motor component of seventh cervical radiculopathy and presents with weakness in the extensor digitorum communis, extensor pollicis longus, and extensor carpi ulnaris. With entrapment of the 3656

interosseus nerve, sensory changes are absent and the triceps and wrist flexors show normal strength. Pathology at the C7–T1 level results in radiculopathy of the eighth cervical nerve root. Patients with a C8 radiculopathy generally present with sensory changes extending over the medial aspect of the arm and forearm and into the medial hand and the fourth and fifth digits. Numbness usually involves both the dorsal and volar aspects of the digits and hand and may extend proximal to the wrist over the medial aspect of the forearm. Weakness may involve the small muscles of the hand, particularly the interossei, and the flexors and extensors of the wrist and fingers (with the exception of the flexor carpi radialis and extensor carpi radialis muscles). This may cause patients to complain of difficulty using their hands for routine tasks such as buttoning shirts and grasping objects. Compression of the C8 nerve root may initially be difficult to differentiate from ulnar entrapment at the elbow. C8 nerve root compression may affect the function of the flexor digitorum profundus in the index and long fingers, the flexor pollicis longus in the thumb, and the pronator quadratus, but these muscles are not affected by entrapment of the ulnar nerve. Also, the short thenar muscles, except for the adductor pollicis, may be involved with C8 or T1 compression but are spared with ulnar nerve involvement. Furthermore, sensory changes seen with ulnar neuropathies include numbness, tingling, and/or pain in the fourth and fifth fingers and the hand just below these fingers but not proximal to the wrist (medial antebrachial cutaneous nerve distribution), as may be seen with C8 radiculopathy. Anterior interosseus nerve entrapment may also mimic C8 or T1 radiculopathy but lacks sensory changes, and thenar muscle involvement is absent. Although uncommon, occurrence of T1–T2 disk herniations or other pathology at this level may result in a T1 radiculopathy. The T1 nerve is the main contributor to the adductor pollicis, the thenar muscles, the interossei, and the first two lumbricals. Classic T1 radiculopathy results in intrinsic hand weakness. Numbness occurs in the axilla, and Horner syndrome can occur ipsilaterally.1,98,142 Epidemiologic data suggest that up to 90% of patients with cervical radiculopathy improve with conservative medical treatment 3657

alone.95,96,143–145 However, due to lack of standardized diagnostic criteria and comparative randomized controlled trials comparing conservative with surgical treatment, evidence-based guidelines have been difficult to establish. Conservative therapy in patients with cervical radiculopathy includes activity modification, education, and physical therapy with progressive passive and active modalities. Pharmacologic therapy requires a large armamentarium of medications due to the heterogeneity in this patient population and the various mechanisms involved in the production of neuropathic pain. Options include over-the-counter analgesics, anticonvulsants, tricyclic antidepressants, and selective serotonin norepinephrine reuptake inhibitors, topical anesthetic agents, nonsteroidal anti-inflammatory drugs, antiarrhythmics, muscle relaxants, nonnarcotic analgesics, and opioids.146,147 Multiple studies including a recent systematic review support the efficacy of interlaminar cervical epidural steroid injections for the management of cervical radiculitis, discogenic pain without facet joint pain, and postsurgery syndrome.130,148 Use of fluoroscopic guidance in interlaminar epidural steroid injections and use of nonparticulate steroid in transforaminal injections may significantly reduce the risk of complications.149–151 Outcome in patients with cervical radiculopathy following medical versus operative treatment was recently reported following a prospective, multicenter study with independent clinical review. Comparison of results of patients undergoing medical versus surgical treatments showed that, although both medically and surgically treated patients reported statistically significant improvement in their overall pain, more improvement was observed in the surgery group. Improvement in worst pain and average pain was also statistically significant in both groups. Surgically treated patients had more neurologic and nonneurologic symptoms and more functional disability before treatment. However, despite high satisfaction in surgically treated patients, a significant number of patients continued to report horrible or excruciating pain, multiple neurologic symptoms, and minimal or no work activity. These results are similar to those in patients with CSM in that the majority of patients improve with conservative therapy, whereas those with persistent severe 3658

pain and progressive neurologic symptoms are generally referred for operative management, which attempts to improve pain and arrest the progression of neurologic symptoms.89,145

UPPER EXTREMITY PERIPHERAL NERVE ENTRAPMENT SYNDROMES AND BRACHIAL PLEXUS NEUROPATHY Acute trauma with resultant fibrosis and scar tissue, chronic trauma from overuse injuries, or space-occupying lesions can result in entrapment of peripheral nerves. An understanding of peripheral nerve distribution and common entrapment sites is essential for the diagnosis and treatment of peripheral nerve entrapment syndromes. Entrapment typically occurs at sites where a segment of nerve passes through a fibro-osseous tunnel or through an opening in fibrous, tendinous, or muscular bands of tissue. Sustained mechanical compression and ischemia may result in neurapraxia. Peripheral nerve entrapment syndromes typically present with pain at the site of entrapment. Pain can radiate both distally and proximally to this point. Sensory, motor, or sympathetic changes can occur in the nerve distribution distal to the site of entrapment. The diagnosis of nerve compression or nerve entrapment is based on a careful history of the mechanism of injury or repetitive use and a thorough physical exam together with neurologic and electrodiagnostic examinations. MRI is helpful in identifying the cause of the neuropathy, identifying the site of entrapment based on muscle denervation patterns, and detecting unsuspected space-occupying lesions.152,153 Nerve entrapment and radiculopathies may infrequently exist simultaneously. In a retrospective analysis of 12,736 cases of CTS and ulnar neuropathy at the elbow, 435 (3.4%) of these cases were found to have a coexisting cervical root lesion. However, lesions were on the same nerve in only 98 (0.8%) of these cases.154 Upper extremity nerve entrapment syndromes are characterized in Table 68.23. Two most common nerve entrapment syndromes of the upper extremity, CTS and cubital tunnel syndrome (CuTS), are discussed in the following text in greater detail. TABLE 68.23 Upper Extremity Entrapment Syndromes 3659

Nerve

Usual Cause

Location of Pain

Dorsal scapular

Scalenus medius hypertrophy

Medial scapula, lateral arm

None

Suprascapular

Band in supraspinatus notch

Posterolateral, shoulder, lateral arm; tender at suprascapular notch

None

Long thoracic

Downward pressure on shoulder

None

Musculocutaneous

Entrapment by coracobrachialis

Not usually painful; can have diffuse ache in shoulder or scapula Anterior arm, proximal lateral forearm

Posterior interosseous

Entrapment at proximal forearm Entrapment at cubital tunnel

Proximal radial forearm

None

Elbow, ulnar forearm, and hand Ulnar side of hand, fourth and fifth

Ulnar hand, fourth and fifth digits Ulnar hand, fourth and fifth digits

Ulnar (at elbow)

Ulnar (at wrist)

Entrapment at Guyon’s canal

3660

Sensory Changes

Anterolateral forearm

Weakness Rhomboids, levator scapulae Weak with pressing elbow backward against resistance with hands on hip or pushing palm backward against resistance with arm folded behind back Supraspinatus, infraspinatus Weakness in abduction and external rotation of arm Serratus anterior Weak with raising arms above head

Biceps, brachialis Elbow flexor and forearm supination weakness Wrist and finger extensors and abductors Flexor carpi ulnaris and intrinsics Adductor pollicis, interossei,

digits Median (at elbow)

Entrapment at ligament of Struthers or pronator teres

Elbow, volar forearm

Radial hand; first, second, and third digits

Median (at wrist)

Entrapment at carpal tunnel

Anterior interosseous

Entrapment at pronator teres or flexor digitorum superior

Wrist; radial hand; first, second, and third digits Elbow, volar forearm

Radial hand; first, second, and third digits None

Digital nerve

Entrapment at intermetacarpal tunnel

Finger

Half of finger

hypothenar muscles Pronator teres, flexor carpi radialis, flexor digitorum superior Thenar muscles, first and second lumbricals Pronator quadratus, flexor pollicis longus, first and second flexor digitorum profundus None

Carpal Tunnel Syndrome CTS is the most common upper extremity entrapment syndrome estimated to affect 3% to 6% of adults in the United States. Risk factors for the development of CTS include age, smoking, obesity, rheumatoid arthritis, diabetes, lupus, hypothyroidism, acromegaly, flexor tenosynovitis, ganglion, pregnancy, multiple sclerosis, work with vibrating tools, and repetitive hand and wrist tasks. CTS is more common in women, with higher risk in those taking birth control pills and those going through menopause. The incidence of CTS is also high in wheel chair athletes, cyclists, wrestlers, and football athletes (from blocking technique). It is useful to review the anatomy of the carpal tunnel, the fibro-osseous outlet which lies between the flexor retinaculum, and the carpal bones. Its contents include the tightly packed median nerve and nine extrinsic flexor tendons of the thumb and fingers. Pressure within the carpal tunnel averages 2 to 31 mm Hg in healthy individuals and as high as 32 to 110 mm Hg in patients with CTS. Carpal tunnel pressure increases up to 8-fold with wrist flexion and 10-fold with wrist extension. The clinical diagnosis of CTS includes a history of paresthesia affecting 3661

the median nerve distribution (generally the thumb and first two and a half fingers although some patients complain of paresthesias radiating up the arm to the shoulder), often bilaterally but initially in the dominant hand in most patients. Other signs and symptoms may include brachialgia paraesthetica nocturna, thenar atrophy, loss of two-point sensory discrimination, and reduced manual dexterity. Clinical diagnosis includes a positive Phalen test (sustained wrist flexion for 60 seconds [78% to 80% sensitivity and 73% to 83% specificity]), Tinel sign (reproduction of paresthesias in median nerve distribution with percussion over the carpal tunnel at the wrist [20% to 50% sensitivity and 76% to 77% specificity]), and Durkan or carpal compression test (87% sensitivity and 90% specificity). Electrodiagnostic studies (EDS) have a 49% to 84% sensitivity and a 95% to 99% specificity. Although EDS are often used to confirm clinical diagnosis, other more expensive imaging modalities may be indicated in complex cases to rule out additional suspected etiologies of patient symptomology. In regard to treatment of CTS, although patients with mild to moderate symptoms may respond to conservative treatment, with splinting and steroid injections having the best evidence of nonoperative treatments, several high-quality studies have demonstrated superior outcome with operative versus nonoperative treatment of CTS.155,156

Cubital Tunnel Syndrome Second only to CTS, CuTS is the second most common nerve entrapment syndrome in both the general population and due to sports. CuTS occurs slightly more in males versus females, increases with age and is seen more frequently in occupations with frequent elbow flexion such as carpenters, musicians, and painters. It is seen in athletes from sports such as baseball, wrestling, and football. Risk factors also include prolonged pressure over the forearm with the elbows in a flexed position such as when resting forearms on a hard surface. The cubital tunnel consists of the medial epicondyle medially, the olecranon laterally, the elbow capsule at the posterior aspect of the ulnar collateral ligament which forms the floor of the cubital tunnel, and the deep forearm fascia of the flexor carpi ulnaris and the arcuate ligament of 3662

Osborne or cubital tunnel retinaculum which forms the roof. The ulnar nerve is most commonly compressed beneath Osborne’s ligament, although it may also be compressed proximately at the arcade of Struthers and distally by the deep pronator aponeurosis. Intraneural pressure sharply increases with elbow flexion greater than 90 degrees. Clinical signs and symptoms in patients with CuTS include pain localized to the elbow or radiating to medial forearm and wrist, atrophy of intrinsic hand muscles, flexion weakness of the fourth and fifth fingers, and sensory deficit in fourth and fifth fingers. Weakness of the interossei may result in Wartenberg sign (inability to fully adduct the small finger with finger held abducted and extended). Weakness of the adductor pollicis may result in Froment sign (positive Froment sign consists of flexion of interphalangeal [IP] joint of the thumb as compensation for weakness of adductor pollicis by using the flexor pollicis longus when asked to perform a pinch). Weakness of the ulnar lumbrical muscles may result in claw hand deformity. Routine provocative testing also includes ulnar nerve percussion at the retrocondylar groove and the elbow flexion test. In more severe CuTS, severe weakness, atrophy of intrinsic hand musculature, and loss of two-point sensory discrimination may also be seen. Electrodiagnostic and nerve conduction studies may be helpful in localizing the site of compression.153 Conservative or nonoperative treatment is recommended in patients with mild CuTS as up to 88% of patients with mild symptoms reported relief of paresthesia with nonsurgical management. A 2012 Cochrane review of treatment for ulnar neuropathy at the elbow found that giving information on avoiding prolonged movements or positions causing traction and compression on the cubital tunnel (avoid full flexion and direct pressure) was effective for mild to moderate symptoms. Nonoperative therapies which are commonly prescribed include discontinuing triceps strengthening exercises, avoidance of direct pressure to the medial aspect of the elbow on firm surfaces, maintaining a resting elbow position of 45 to 50 degree of flexion, and using a nighttime elbow towel orthosis to prevent elbow flexion beyond 50 degrees. In regard to surgical treatment, the 2012 Cochrane review found no difference between simple decompression and transposition of the ulnar nerve but higher rates of 3663

infections in the transposition cases.153 Early recognition is essential for timely diagnosis and treatment of nerve entrapment syndromes involving the upper extremity as they are thought to affect the function of many individuals, including musicians, athletes, and as many as one in four office workers.155 Most patients respond to conservative treatment including rest splints, rehabilitative exercises, passive physical therapy modalities, relative rest, and correction of training and equipment use errors. Other measures may include anti-inflammatory medications, protective padding or bracing, and injections with local anesthetic and steroids. In patients with severe or progressive neurologic deficit or intractable pain, surgical decompression may be necessary.156

LESIONS OF THE BRACHIAL PLEXUS Injury to the brachial plexus resulting in functional impairment of the upper extremity can occur secondary to penetrating or blunt trauma, severe traction, or acceleration-deceleration injuries. Other etiologies include congenital, developmental or exogenous compression, vascular or infectious disease, and neoplastic disease. The relative incidence of these lesions of the brachial plexus is presented in Table 68.24. TABLE 68.24 Causes of Brachial Plexus Lesions Incidence (% of cases)

Cause

Example(s)

Trauma

Penetrating injuries (e.g., gunshot, knife); closed injuries: obstetric (newborn), mechanical distortion Exogenous (knapsack paralysis); congenital abnormality; developmental abnormality Local disease of major vessels; generalized vasculopathy (lupus erythematosus, arteritis); secondary to radiation therapy Viral; bacterial (local sepsis, abscess, or cellulitis) Primary tumors of brachial plexus; secondary involvement of plexus by tumors of surrounding tissues (Pancoast’s tumor) Electric shock; parainfectious; following serum therapy; unknown

Compression Vascular

Infectious Neoplastic

Miscellaneous causes

70

10 5

3 10

2

Brachial plexus injury (BPI) can be classified into preganglionic lesions, 3664

postganglionic lesions, and a combination of preganglionic and postganglionic lesions. In a preganglionic lesion, the nerve root is avulsed. A postganglionic lesion involves the nerve distal to the sensory ganglion and is further divided into nerve ruptures or lesions in continuity. Clinical exam and electrodiagnostic and imaging studies may help in determining the location and severity of injury, which is essential in therapeutic decisions regarding these injuries. CT myelography is considered most reliable in detecting avulsion injuries. MRI, as well as new techniques such as MR myelography, diffusion-weighted neurography, and Bezier surface reformation, provides additional useful data in the evaluation and management of BPI.157,158 Treatment of traumatic BPI is conservative versus surgical and is based on various factors such as the degree of damage, the site and type of injury, the time interval between injury and surgery, and the patient’s age and occupation. Surgical treatment includes neurolysis, nerve grafting, nerve transfer, and other reconstructive procedures.159–161 Physical therapy and pain control is essential for recovery of function following operative cases and for optimization of function and palliation of pain in nonoperative cases. In addition to pharmacologic treatment options, successful treatment of pain related to brachial plexus lesions has been reported following implantation of spinal cord and deep brain stimulator systems.162,163

Acute Brachial Plexus Neuritis Acute brachial plexus neuritis is an uncommon disorder of unknown etiology that is commonly misdiagnosed as cervical spondylosis or cervical radiculopathy. It was first described by Spillane164 in 1943 and is also known as Parsonage-Turner syndrome or neuralgic amyotrophy due to the case series of this condition by Parsonage and Turner165 in 1948. Other names by which it is referred include brachial plexus neuropathy, paralytic neuritis, and acute shoulder neuritis. The classical presentation of the patient with acute brachial plexus neuritis is the acute onset of severe burning pain in the neck, shoulder, and upper arm not associated with a precipitating injury or trauma. The pain may or may not be associated with sensory deficit and generally subsides 3665

over the following days to weeks. It is followed by a profound weakness, sometimes to the extent of flaccidity, involving the supraspinatus, infraspinatus, and deltoid and/or biceps muscles. Involvement of the sternomastoid or diaphragm has also been described, as has isolated or single nerve involvement. Bilateral brachial plexus involvement is not uncommon. Gradual recovery of muscle strength over 3 to 4 months is the usual course of brachial neuritis; however, some patients may experience several years of permanent muscle weakness. Chronic scapulocostal pain syndromes may occur due to dysfunctional mechanics following profound weakness. Although a viral etiology has been proposed, various infections have been reported as preceding the onset of this disorder in up to 25% of cases. Onset following influenza, hepatitis B, or other vaccinations in up to 15% of cases suggests an immunologic etiology. Familial and recurrent cases are encountered. Other reported precipitating factors include childbirth, trauma, and surgery. Pathologic studies favor an immune-mediated demyelinating pathogenesis over an axon-loss mechanism.166,167 The annual incidence of acute brachial plexus neuritis is reported to be 1.64 cases per 100,000, although this figure is presumed to be low because of misdiagnosis. It occurs most often between age 20 and 60 years with a reported male predominance of 2:1 to 11.5:1.166 Diagnosis of brachial neuritis requires a high level of suspicion. A case series report of electrodiagnostic results reports no evidence of prolongation of F latencies and no reduction of conduction velocity or conduction block in conventional peripheral ulnar and median nerve motor studies. Proximal nerve stimulation of the cervical roots and brachial plexus revealed axonal degeneration in most cases as well as evidence of proximal conduction block consistent with demyelination. MRI is useful in evaluating muscle denervation, muscle signal intensity changes, and muscle volume loss.168 Treatment of brachial neuritis is primarily supportive with use of analgesic medications followed by range-of-motion exercises. An arm sling may be helpful in preventing injury and strain from the weight of the arm distracting the humeral head from the glenoid fossa.59 Full functional recovery is expected in 80% to 90% of patients, although the course may 3666

be protracted. Ten percent to 20% of patients may continue to have significant residual muscle weakness. In cases of profound and early weakness, intravenous immunoglobulin treatment has been proposed due to its usefulness in treating other focal demyelinating peripheral nerve diseases.169,170 Acupuncture may also be effective in treating pain and improving function.171,172

Thoracic Outlet Syndrome The definition, diagnosis, and treatment of TOS are among the most disputed of any clinical entity. The syndrome generally refers to a variety of symptoms in the upper extremity due to compression of the brachial plexus, subclavian artery, and subclavian vein. Compression of the neurovascular bundle can occur as it passes through the interscalene triangle, the costoclavicular triangle, and subcoracoid space during its passage from the base of the neck to the proximal aspect of the arm. Structural compressive etiologies include fibrous bands, scar tissue, hypertrophied or fibrous muscles, anomalous soft tissue, and cervical ribs. Previous to the coining of the term TOS in 1956 by Peet,173 the name of this syndrome was assigned according to the etiologies of compression including scalenus anticus syndrome, costoclavicular syndrome, hyperabduction, cervical rib syndrome, or first rib syndrome. The lower trunk of the brachial plexus (C8 and T1) is most often affected. Other factors associated with the development of TOS include repetitive trauma to the brachial plexus, median sternotomy, or traumatic events such as motor vehicle accidents.174 TOS is variably divided into arterial, venous, or neurogenic. Alternatively, it has been classified as vascular, neurogenic, and nonspecific. The latter classification system reflects both diagnostic criteria and therapeutic recommendations and outcome. Vascular TOS occurs in only 2% to 5% of thoracic outlet cases and is described most frequently in young individuals following vigorous arm activity or strenuous work. Patients with subclavian artery compression frequently present with pallor, pulselessness, and coolness of the affected upper extremity; transient ischemic attack; or infarcts of the hand and fingers. Decreased blood pressure in the affected arm when compared with 3667

the opposite arm of more than 20 mm Hg may also be present. Claudication may occur only with arm hyperabduction in some patients. Injury may include thrombosis, aneurysm, and/or stenosis. Subclavian vein compression typically presents with edema and cyanosis of the upper limb with hyperabduction of the upper extremity. Thrombosis of the axillary-subclavian vein (also known as Paget-von Schröetter syndrome), occurs in association with vigorous shoulder activity. Doppler and duplex ultrasonography, magnetic resonance arteriography, CT angiography, and arteriography are used to confirm the diagnosis of vascular TOS. Decompression procedures or vessel reconstruction may be indicated in urgent cases and in cases not responsive to conservative therapy.174–177 Neurogenic and nonspecific categories of TOS comprise 95% to 98% of cases. A syndrome of painless atrophy of the hand primarily involving the abductor pollicis brevis with lesser atrophy of the interossei and hypothenar muscles known as Gilliatt-Sumner hand is the classic presentation of the true neurogenic type of TOS. This is associated with positive neurologic and electrodiagnostic findings. Sensory loss typically involves the ulnar aspect of the forearm and hand consistent with lower trunk compression, although upper trunk compression has also been reported. Pain is not the primary symptom of true neurogenic TOS; however, the patient may complain of diffuse, dull pain in the neck, shoulder, axillary region, and arm which may worsen with overhead activities and repetitive use of the arm. The most common form of TOS is the nonspecific type. Patients generally present with the primary complaint of pain, often following a motor vehicle– or work-related injury. EAST, upper limb tension test, and Adson tests may be positive, but specificity is limited as they have been shown to be positive in many asymptomatic individuals. The specificity of Adson test and EAST tests was 76% and 30%, respectively, and 82% when combined. Physical examination findings are often inconclusive and nonspecific, although physical exam may guide further diagnostic electrophysiologic and imaging studies and subsequent treatment decisions.177–179 The differential diagnosis of TOS includes cervical 3668

radiculopathy or myelopathy, acute brachial neuritis, Reynaud’s disease, multiple sclerosis, ulnar or median nerve entrapment syndromes, acute coronary syndrome, and CRPS. The diagnosis of nonspecific TOS requires a detailed history and physical exam to rule out other causes of neck and upper extremity pain. Electrodiagnostic testing may help localize and quantify a brachial plexus lesion in true neurogenic TOS and rule out other segmental or systemic neuropathies.180,181 Radiographic studies used in evaluation with the patient with suspected TOS include cervical spine and chest radiographs to rule out bony abnormalities and MRI and CT to evaluate the cervical spine for soft tissue anomalies, tumors, or degenerative disease of the cervical spine.182 Conservative treatment of TOS is indicated in the majority of cases and consists of activity modification education with instructions to avoid provocative positions and activities. Physical therapy programs to restore normal posture and strengthen the muscles of the pectoral girdle have also been successful in alleviating symptoms in greater than 50% of cases.183 Surgical approaches to treatment are undertaken in intractable or urgent cases. Surgery in the nonspecific type of TOS is associated with the least favorable outcome and is generally discouraged due to the significant risks associated with surgeries in this region. New minimally invasive techniques are now being investigated and may offer reduced risk of complications.184,185 References 1. Loeser JD. Bonica’s Management of Pain. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2001:1008. 2. Wolfla CE. Anatomical, biomechanical, and practical considerations in posterior occipitocervical instrumentation. Spine J 2006;6(6 suppl):225S–232S. 3. Murray CJ, Barber RM, Foreman KJ, et al; for GBD 2013 DALYs and HALE Collaborators. Global, regional, and national disability-adjusted life years (DALYs) for 306 diseases and injuries and healthy life expectancy (HALE) for 188 countries, 1990–2013: quantifying the epidemiological transition. Lancet 2015;386(10009):2145–2191. 4. Cohen SP. Epidemiology, diagnosis, and treatment of neck pain. Mayo Clin Proc 2015;90(2):284–299. 5. Peterson C, Bolton J, Wood AR, et al. A cross-sectional study correlating degeneration of the cervical spine with disability and pain in United Kingdom patients. Spine (Phila Pa 1976) 2003;28(2):129–133. 6. Zapletal J, Hekster RE, Straver JS, et al. Relationship between atlanto-odontoid osteoarthritis

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CHAPTER 69 Chest Wall Pain NARASIMHA R. GUNDAMRAJ and STEVEN H. RICHEIMER

General Considerations The chest wall is a common site of pain encountered in clinical practice. The origin of pain can be from various structures of the chest wall. These include pain from skeletal components including the spine, muscles, and nerves or pain that is referred from outside the chest wall (Table 69.1). For instance, visceral pain from the chest can be perceived as chest wall pain. It is important to distinguish the origin of pain as arising from the chest wall or from the viscera inside. Focusing on some key points in the history and physical examination can assist in diagnosing the origin of pain. A thorough knowledge of the anatomy and physiology of the chest wall and its relationship to the vital organs enclosed inside is essential for any clinician involved in treatment of chest wall pain. TABLE 69.1 Chest Pain Caused by Neuropathic, Musculoskeletal, and Other Disorders I. Pain primarily of neuropathic origin A. Disease of the spinal cord (myelopathy) B. Lesions of the rootlets or roots of thoracic spinal nerves (radiculopathy) C. Lesions of the formed spinal nerves (neuropathy) D. Lesions of the intercostal nerves (intercostal neuropathy) E. Disorders of the peripheral branches of spinal nerves (peripheral neuropathy) II. Pain primarily of musculoskeletal origin A. Lesions or disease of bones 1. Disease or lesions of the thoracic vertebrae 2. Disease or lesions of the ribs 3. Diseases or disorders of the costal cartilages 4. Disease or disorders of the sternum 5. Disease of the sternoclavicular joint B. Disorders of muscles 1. Myofascial pain syndromes 2. Chest pain caused by other disorders of muscles

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III. Diseases of the skin A. Burns and other trauma B. Cicatrices C. Postoperative pain syndromes D. Mastodynia E. Deep axillary abscess F. Adiposis dolorosa G. Phlebitis of the anterolateral chest H. Other dermatologic painful disorders IV. Chest pain caused by extrathoracic diseases A. Disorders of the cervical spine and shoulder 1. Intervertebral disk disease 2. Thoracic outlet syndromes B. Abdominal diseases 1. Gas entrapment syndromes 2. Disorders of the gastrointestinal tract 3. Disease of the biliary tract 4. Disease of the pancreas 5. Other abdominal visceral disease C. Diseases of the diaphragm 1. Acute primary diaphragmatitis 2. Subphrenic abscess 3. Diaphragmatic flutter V. Chest pain primarily of psychological origin A. Abnormal emotional reactions to visceral disease B. Anxiety syndrome C. Depression syndrome D. Conversion reaction E. Hypochondriasis F. Psychiatric syndromes

Anatomy of the Chest Wall The chest wall is made up of skeletal structures, muscular elements, and neurovascular components. The skeletal structures of the chest wall include the ribs, vertebrae, and the sternum. From a functional standpoint, the skeletal components of the chest wall provide protection for the specialized organs that support the vital functions of the human body.

SKELETAL STRUCTURES OF THE CHEST WALL The chest wall is made up of the vertebrae posteriorly, ribs and costal cartilages laterally, and the sternum anteriorly. The superior boundary of the thorax includes the T1 vertebra posteriorly, 1st rib laterally, and superior margin of the sternum (Fig. 69.1). Inferiorly, the thorax is 3680

bounded by the T12 vertebra and the 12th rib posteriorly, 7th to 10th ribs and their cartilages laterally joining anteriorly to the xiphisternum.1,2 The anteroposterior and lateral diameter of the thorax is smaller at the top compared to the inferior portion. A compromise in the space at the thoracic inlet due to pathology of the skeletal structures or thoracic viscera can compromise the neurovascular structures and also result in chest wall pain.3,4

FIGURE 69.1 A: Anterior view of the sternum. B: Sternum, ribs and costal cartilages forming the thoracic skeleton. (Reprinted with permission from Snell RS. Clinical Anatomy by Regions. 9th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2011. Figure 2-1.)

Thoracic Spine The thoracic spine is made up of 12 thoracic vertebrae (Fig. 69.2). Each thoracic vertebra is heart-shaped with long and inclined spinous processes (Fig. 69.3). Costal facets are present laterally on either side of the body for articulation with the ribs. Costal facets are also present on the transverse processes (except T11 and T12) for articulation with the tubercles of the ribs.

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FIGURE 69.2 Magnetic resonance imaging normal thoracic spine, midsagittal T1-weighted image. (Reprinted with permission from Lee JKT, Sagel SS, Stanley RJ, et al. Computerized Body Tomography with MRI Correlation. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006. Figure 23.3A.)

FIGURE 69.3 Thoracic vertebra. A: Superior surface. B: Lateral surface. (Reprinted with permission from Snell RS. Clinical Anatomy by Regions. 9th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2011. Figure 2-3.)

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Ribs There are 12 pairs of ribs attached posteriorly to the spine. The upper 7 pairs of ribs are attached anteriorly to the sternum by costal cartilages and are called true ribs (Fig. 69.4). The 8th, 9th, and 10th ribs are attached to each other, and the 7th rib by their costal cartilages forming small synovial joints. These ribs are called false ribs. The 11th and 12th ribs have no anterior attachments and are called floating ribs. A typical rib is a long, curved, flat bone. The superior border is smooth and rounded. The inferior border is sharp and thin, and it overhangs the costal groove, which encloses the intercostals vessels and the nerves. The head of the rib has two facets for articulation with the corresponding vertebral body and the one above it. The neck is a constricted portion of the rib after the head. A prominence on the outer surface of the rib at the junction of the shaft and the neck is called the tubercle. It also has a facet for articulation with the transverse process of the corresponding vertebra. A cervical rib arising from the transverse process of the 7th cervical vertebra is seen in 0.5% of humans. It can cause pressure on the adjacent neurovascular structures— the brachial plexus and the subclavian artery.

FIGURE 69.4 Fifth rib as it articulates with the vertebral column posteriorly and the sternum anteriorly. (Reprinted with permission from Snell RS. Clinical Anatomy by Regions. 9th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2011. Figures 2-4 and 2-5.)

Sternum The sternum is a flat bone in the middle of the anterior chest wall. It is divided into three parts: manubrium, body, and xiphoid process. The manubrium is the upper portion of the sternum that articulates with the body of the sternum at the manubriosternal joint. It also articulates at the 3683

clavicles, the first costal cartilage, and the upper portion of the second costal cartilage. The body of the sternum on each side articulates with the second to seventh costal cartilages. The xiphoid process is a roughly triangular cartilaginous structure that becomes ossified in adulthood. The angle of Louis or sternal angle is the junction between the manubrium and the body of the sternum. This useful anatomic landmark is palpated by feeling for a transverse ridge on the anterior aspect of the sternum. It correlates to the second costal cartilage anteriorly and the intervertebral disk between the fourth and fifth thoracic vertebrae posteriorly.

JOINTS OF THE CHEST WALL The chest wall includes many joints. The manubriosternal joint and xiphisternal joints are fixed joints. The costochondral connections of ribs with costal cartilages are also nonsynovial joints. These costochondral joints can become the source of painful irritation. The costal cartilages often calcify with age, reducing the flexibility of the chest wall. The joints of the heads of the ribs with the vertebral bodies, and the joints of the tubercles with the transverse processes of the ribs, are synovial joints that allow for the expansion movements of the chest wall. The joints of the costal cartilages with the sternum are synovial (with the exception of the first rib), but these joints allow for only slight motion and they tend to disappear with age.

INTERCOSTAL SPACES The intercostal space between the ribs is covered with three muscles: the external intercostals, internal intercostals, and the innermost intercostals muscle (Fig. 69.5). The innermost intercostal muscle is lined by the endothoracic fascia, which in turn covers the parietal pleura. The intercostal nerves and blood vessels run between the internal and the innermost intercostals muscles in the intercostals groove. The intercostal muscles play an important role in the mechanics of respiration. They are supplied by the corresponding intercostal nerves. The neurovascular structures in the intercostal groove are arranged from above downward as vein, artery, and nerve.

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FIGURE 69.5 Intercostal space, its boundaries, and contents. (Reprinted with permission from Snell RS. Clinical Anatomy by Regions. 9th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2011. Figure 2-3.)

INTERCOSTAL NERVES The anterior rami of the first 11 thoracic spinal nerves form the intercostals nerves. The anterior ramus of the 12th nerve lies in the abdominal wall as the subcostal nerve. The rami communicantes connect the intercostals nerve to the sympathetic trunk. The collateral branch runs forward inferiorly to the intercostal nerve on the upper border of the rib below. The lateral cutaneous branch runs in the skin on the side of the chest and divides in to the anterior and posterior branches. The anterior cutaneous branch is the terminal portion of the intercostal nerves and reaches the skin near the midline anteriorly (Fig. 69.6). Muscular branches are given out to the intercostals muscles. Pleural sensory branches go to the pleura. Peritoneal sensory branches from the 7th to 11th intercostal nerves run to the parietal peritoneum. The 1st intercostal nerve has a branch joining the brachial plexus. The second intercostal nerve joins the medial cutaneous nerve of the arm by the intercostobrachial nerve. In coronary artery disease, referred pain to the arm might be through this nerve.5

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FIGURE 69.6 The distribution of two intercostals nerves to the rib cage. (Reprinted with permission from Snell RS. Clinical Anatomy by Regions. 9th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2007. Figure 2-12.)

Neoplastic Chest Wall Pain A thorough history and physical examination is necessary to rule out pain caused by neoplasms of the thorax. Associated symptoms of cough, dyspnea, brachial plexopathy, and hoarseness due to recurrent laryngeal nerve involvement or Horner syndrome should arouse the suspicion of possible neoplastic disease. Diagnostic radiologic tests can confirm the diagnosis and the extent of involvement. If there is a high level of suspicion for neoplastic disease in a patient presenting with chest wall pain, diagnosis of the condition should be undertaken prior to any interventional procedures. Pain due to neoplastic disease is treated with a comprehensive or multimodal approach with opioid and nonopioid analgesics, physical therapy, interventional treatment with intercostal nerve blocks or epidural injections, and psychotherapy. In patients with refractory cancer pain, neuraxial delivery of opioid and local anesthetics 3686

by continuous infusion pumps or neurolytic ablation may be necessary for pain control. Lung and breast cancers account for the majority of the thoracic neoplasms. Other neoplasms include metastatic lesions of the lung and the skeletal structures. Neoplasms of the lung present with symptoms of cough, dyspnea, hemoptysis, or obstructive symptoms due to compression of the neurovascular structures. Pain is not a common symptom with lung cancers except when there is pleural involvement. Nociceptive pain is usually localized, constant, or associated with chest wall movement and is caused by the invasion of the pleura, vertebrae, or other soft tissues of the chest wall. Deafferentation or neuropathic pain is caused by compression, infiltration, or damage to the involved spinal nerves and produces allodynia, hyperalgesia, dysesthesia, or hyperesthesia in a segmental fashion.6 Involvement of the superior pulmonary sulcus produces Pancoast syndrome. It is characterized by pain in the shoulder and arm, motor weakness and wasting of muscles of the hand, as well as Horner syndrome.7 A mass in the superior sulcus of the lung can cause compression of the lower trunk of the brachial plexus. Pain and motor symptoms are most commonly seen in the distribution of the ulnar nerve. Brachial plexopathy can also result from other causes such as metastatic tumors, radiation, or thoracic surgery.6,8

EPIDURAL SPINAL CORD COMPRESSION Epidural spinal cord compression is the second most common central neurologic complication of systemic cancer. Pain is the initial symptom before the development of other neurologic signs and symptoms. The pain can be misdiagnosed as musculoskeletal in origin. Appropriate imaging studies can aid in the diagnosis. Treatment includes corticosteroids and radiation. Surgical decompression with laminectomy or vertebral body resection is recommended in patients who are relatively healthy.9,10

SUPERIOR VENA CAVA SYNDROME Obstruction of the blood flow through the superior vena cava results in superior vena cava syndrome. The obstruction can be due to external compression from pathology of the lung, lymph nodes, or mediastinum. It 3687

can also result from internal obstruction due to thrombus formation. Chest wall pain, cough, dyspnea along with collateral venous engorgement of the chest wall and neck, and facial edema are the common signs and symptoms. Dyspnea is the most common symptom. Lung cancer is the most common cause followed by lymphoma. Malignancy accounts for 60% to 85% of all cases of superior vena cava syndrome with small-cell lung cancer serving as the most common type of lung malignancy causing this syndrome.11 Non-Hodgkin lymphoma is the most common type of lymphoma resulting in obstruction of the superior vena cava. The widespread use of central venous catheters, ports, pacemakers, and defibrillators has increased the incidence of benign superior vena cava syndrome (SVCS) due to endovascular obstruction.12 Diagnosis is made based on clinical symptoms and the findings of abnormal lesions in the chest radiograph. Confirmatory studies include contrast-enhanced computed tomography (CT) scan and venous angiography. Current treatment strategies include chemotherapy, radiation, or endovascular stenting.13 Surgical treatment is performed with spiral saphenous interposition graft or other grafts. Radiation treatment is indicated for emergency relief of airway obstruction.

COSTOPLEURAL SYNDROME Tumor invasion of the pleura, ribs, and soft tissues of the chest wall with or without involvement of the intercostals nerves can result in sharp, aching, or burning pain (Fig. 69.7). Pain is exacerbated by movements of the chest wall, deep breathing, and coughing. Lesions of the pleura closer to the diaphragm can cause localized pain in the shoulder region or referred dull aching pain in the back or upper abdomen. Mediastinal pleural involvement causes pain deep in the central portion of the chest or the shoulder region. This type of pain is often potently responsive to steroidal or nonsteroidal anti-inflammatory analgesics.

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FIGURE 69.7 Computed tomography image showing right pleural thickening due to mesothelioma. (Reprinted with permission from Lee JKT, Sagel SS, Stanley RJ, et al. Computerized Body Tomography with MRI Correlation. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006. Figure 8-71A.)

Nonneoplastic Chest Wall Pain Chest wall pain from other than neoplasms and visceral pain is discussed in this section. This section includes a discussion of chest wall pain due to neuropathy including neuraxial pain, myofascial, skeletal, and joint pain.

NEUROPATHIC PAIN Pain due to neuropathy can arise anywhere along the nervous system supplying the chest wall. The pain can be neuraxial involving the spinal cord and nerve roots or related to peripheral nerves (Table 69.2). TABLE 69.2 Chest Pain Primarily of Neuropathic Origin I. Diseases of the spinal cord (myelopathy) A. Intrinsic spinal cord diseases: primary tumors, metastatic tumors, syringomyelia, trauma, multiple sclerosis, infarction, abscess B. Extramedullary intrathecal disorders 1. Primary tumors: meningioma, neurofibroma 2. Metastatic tumors C. Epidural spinal cord compression 1. Primarily caused by vertebral pathology 2. Metastatic neoplasm from breast, lung, prostate 3. Epidural abscess 4. Hematoma 5. Adhesive arachnoiditis II. Diseases of the rootlets and roots of spinal nerves (radiculopathy) A. Infection and inflammation

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1. Herpes zoster 2. Syphilis (tabes dorsalis) 3. Meningitis 4. Systemic infection 5. Tuberculosis 6. Other infectious diseases B. Mechanical compression or injury 1. Osteoarthritis 2. Other arthritides 3. Ruptured intervertebral disk 4. Fracture of vertebra 5. Abscess or tumor of the vertebra 6. Paget disease of the spine III. Diseases of the formed thoracic spinal nerves (neuropathy) A. Vertebral compression (same as IIB) B. Paravertebral compression 1. Paravertebral adenopathy 2. Mediastinal tumors 3. Paravertebral abscess 4. Aortic aneurysm C. Primary nerve tumors 1. Neurofibroma 2. Schwannoma D. Systemic infection, neuropathy E. Other neuritides 1. Alcoholism 2. Avitaminosis 3. Intoxication by heavy metals, food, amoebae 4. Vitamin metabolic disorders and others IV. Disorders of the intercostal nerves (intercostal neuralgia) A. Compression or injury secondary to fracture or tumors of ribs B. External trauma (e.g., stab wounds) C. Postinfectious intercostal neuropathy D. Postoperative neuropathy 1. Postmastectomy syndrome 2. Postthoracotomy syndrome

Neuropathic Pain of Central Origin Thoracic myelopathy can cause chest wall pain, back pain, or abdominal pain. Lesions can be present within the spinal cord or extramedullary or epidural spaces. Thoracic disk herniation can also result in chest wall pain (Fig. 69.8). Pain is usually the initial symptom before other neurologic symptoms. Pain is worsened in the recumbent position. If pain is the only symptom, it is often confused as myofascial or skeletal pain. Prompt diagnosis is important in light of potentially evolving cord compression. 3690

Pain that is progressive and not relieved by conventional therapy for musculoskeletal pain requires prompt attention to rule out neoplasm. Acute neurologic symptoms are initially treated with corticosteroids and radiation therapy.14 Surgical decompression with laminectomy may be necessary if the symptoms are not relieved by nonsurgical methods. Lower cervical disk herniation can also present as neuropathic chest wall pain.15,16 A relatively rare cause of thoracic neuropathic pain is seen in the form of an extramedullary granuloma in patients with neuraxial infusion pumps. Stopping the implanted infusion pump and radiographic exam with contrast through the catheter, CT myelography, or magnetic resonance imaging (MRI) can help make the diagnosis. Stopping the infusion may decrease the size of the mass. Consensus guidelines to improve safety and mitigate risk of granulomas are available and updated every few years. Surgical removal of the symptomatic granuloma is rarely necessary.17

FIGURE 69.8 Sagittal T2-weighted magnetic resonance imaging showing a central thoracic disk herniation at T11–T12 (arrow). The cord is displaced posteriorly. The arrowhead shows a Schmorl nodule. (Reprinted with permission from Lee JKT, Sagel SS, Stanley RJ, et al. Computerized Body Tomography with MRI Correlation. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006. Figure 23-37B.)

Peripheral Neuropathic Chest Wall Pain 3691

Herpes Zoster and Postherpetic Neuralgia Acute herpes zoster, also called shingles, is caused by the DNA virus, varicella zoster virus (VZV). The incidence of herpes zoster is higher in older and immunocompromised patients. Factors that decrease immune function such as chronic corticosteroid use, human immunodeficiency virus infection, cancer, and chemotherapy can increase the risk of developing herpes zoster.18 Following a primary VZV infection, the virus remains dormant in the dorsal root ganglia. Acute herpes zoster is characterized by the reactivation of the latent virus in the dorsal root ganglion. It typically presents as a mononeuropathy involving the intercostal nerves. Clinically, the presentation begins with burning pain, hyperesthesia, or tingling followed by the characteristic vesicular rash. The prodromal sensory symptoms may be present for 1 to 2 weeks prior to the appearance of the rash.19 The characteristic rash is initially maculopapular and progresses into vesicles with erythematous bases. The rash of herpes zoster is commonly seen involving one or two contiguous thoracic dermatomes, almost always unilateral. T5 and T6 dermatomes are most commonly affected.20 Pain is sharp, burning, and superficial in nature. Pain can be worsened with ulceration and secondary infection of the vesicles. Associated muscle spasms can worsen the pain. Diagnosis of the condition is made by the clinical presentation of the characteristic rash. The main goal of treatment of acute herpes zoster infection is not only to treat the acute condition but also to prevent central sensitization and postherpetic neuralgia. Treatment of the acute condition is initially pharmacologic. Elderly patients are more susceptible to developing postherpetic neuralgia; therefore, more aggressive treatment with additional interventional modalities is recommended. Pharmacologic therapy involves initiating treatment with oral antiviral agents as soon as the diagnosis has been made. Studies have shown efficacy of antiviral agents if started within 72 hours.21,22 Interventional treatments include segmental epidural blockade with dilute local anesthetic solutions, intercostal nerve blocks, and sympathetic blockade of the cervicothoracic chain with stellate ganglion blocks are recommended. For an elderly patient suffering with a very painful bout of acute zoster, aggressive 3692

interventional treatment can reduce the severity of pain and may reduce the risk of severe pain of postherpetic neuralgia. The number of interventional treatments can range anywhere from three to four in a 2week period. Continuous segmental epidural blockade with thoracic epidural catheter is also recommended; however, it may require hospitalization of the patient. Continuous blockade of the intercostal nerves can be achieved by placing a catheter in the intercostal space connected to an isomeric infusion pump. Such therapy can be used effectively on an outpatient basis. Use of dilute local anesthetics with less toxicity can reduce complications due to local anesthetic toxicity in older patients. Postherpetic neuralgia presents with persistence of severe sharp, burning pain in the affected dermatomes after the disappearance of the acute rash. About 20% of elderly patients with herpes zoster develop postherpetic neuralgia. The pain may persist for months to years without treatment. Hyperalgesia and allodynia of the effected dermatome is seen. The chronicity of the pain can result in behavioral changes affecting sleep and mood. Psychosocial symptoms and depression can worsen the pain. Treatment of postherpetic neuralgia includes symptomatic treatment of pain with medications and interventions. Medical management involves the use of neuropathic analgesics which are discussed extensively elsewhere in this text. These may include tricyclic antidepressants, duloxetine, and anticonvulsants.23–25 Systemic corticosteroids are ineffective in preventing postherpetic neuralgia. However, their use during the acute phase has not been associated to worsening of the disease.26,27 Topical treatment with local anesthetic patches, local anesthetic ointments, preparations with capsaicin, and compounded creams can be used to achieve symptomatic treatment of the condition.28–30 Transcutaneous electrical nerve stimulation (TENS) can also be helpful.31 Interventional treatment with intercostal nerve blocks or epidural injections may be required. Permanent implants like dorsal column spinal cord stimulators and peripheral intercostal nerve stimulators offer a novel approach to pain control in patients who require repeated interventional treatments. A trial of such a stimulator is recommended before permanent implantation. Along with the interventional treatments, aggressive behavioral therapy is 3693

highly recommended. Chronic opioid therapy may be needed. A comprehensive approach using pharmacologic, interventional, rehabilitative, and behavioral treatments will help achieve pain relief and improve functional capacity of the patient. Intercostal and Peripheral Neuropathy Chronic intercostal neuralgia can result from trauma or compression of the intercostals nerves. Due to the proximity of the nerves to the inferior aspect of the ribs, any abnormalities of the ribs such as fractures and metastatic lesions can result in intercostal neuralgia. Prior thoracic or breast surgery and surgical lesion of the nerves can result in chronic intercostal neuralgia. Other causes include trauma or infection. Pain is characterized as sharp, superficial, burning, or lancinating in the distribution of the affected nerve. Pain is worsened by respirations and movements of the chest wall similar to the clinical presentation of pleuritic lesions. Localized tenderness to palpation may be appreciated in the intercostal space. A thorough history looking for previous trauma or surgeries can assist in the diagnosis. Medical management of intercostal neuralgia consists of treatment with nonsteroidal anti-inflammatory agents, tricyclic antidepressants, and anticonvulsants. Intercostal nerve blocks with long-acting local anesthetics and corticosteroids can be effective (Fig. 69.9). Cryoablation or radiofrequency neurolysis of the intercostal nerves can provide longer pain relief.32 Ultrasound guidance can provide accuracy in identification of the nerves for radiofrequency neurolysis.33 We avoid chemolysis of the intercostals nerves because of concerns of postlysis neuralgia and neuritis. Dorsal root ganglion radiofrequency ablation has been described for treatment of intercostal neuralgia.34–36 Long-term relief can also be achieved by implantable dorsal column or peripheral nerve stimulators.37

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FIGURE 69.9 Intercostal nerve block. (Modified with permission from Snell RS. Clinical Anatomy by Regions. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2003. Figure 28B.)

CHEST WALL PAIN OF SKELETAL ORIGIN Skeletal chest wall pain can originate from the thoracic spine, ribs, costal cartilages, or sternum.

Abnormalities of the Thoracic Spine Localized pain in the back can result from abnormalities of the thoracic spine. Pain is caused by stimulation of nociceptive fibers in the periosteum, joints, and ligaments. Reflex muscle spasms of the paraspinal muscles are also associated with pain. Deep palpation of the thoracic spinous processes, the paravertebral region, and movement of the spine can elicit pain. Congenital abnormalities of the spinal curvature resulting in scoliosis can cause chest wall pain as the patient ages. Structural changes in the thoracic spine due to postural kyphosis, trauma, or disease can result in pain. Correction of lateral scoliosis with surgical or nonsurgical interventions can help alleviate the pain. Posture training with strengthening exercises and relief of muscle spasms is helpful. Vertebral Fractures Fractures of the vertebral body can be very painful. The pain can be particularly severe and may radiate into the chest wall. Vertebral fractures are the result of trauma, metastatic disease, or osteoporosis. Compression fractures in younger patients are mostly due to trauma. However, 3695

corticosteroid use can also result in compression fractures in younger patients. Osteoporosis is a major public health concern in the modern world. It is estimated that by the eighth decade, 50% of all women will develop vertebral fractures.38 There is significant impact on the patient with an osteoporotic vertebral fracture resulting in pain, deformity, dependence, and fear of falling. More than 200,000 people per year with osteoporotic fractures require opioid pain medications.39,40 Radiologic diagnosis with plain films, CT scan, or MRI can assist in the diagnosis of a patient who presents with acute onset posterior axial pain with or without radicular symptoms (Fig. 69.10).

FIGURE 69.10 Thoracic spine compression fracture. A: Axial computed tomography shows compression fracture involving mainly the anterior aspect of T7 vertebral body. B: Midsagittal T1weighted image shows the wedged T7 vertebral body (arrow). The posterior margin is displaced into the spinal canal, producing spinal cord compression. (Reprinted with permission from Lee JKT, Sagel SS, Stanley RJ, et al. Computerized Body Tomography with MRI Correlation. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006. Figure 23-14B.)

Physical examination may reveal deformity of the spine. A prominent spinous process can sometimes be palpated above or below the level of the compression fracture. Pain may not be present initially, and about 50% of the patients present at a later time with the onset of pain. Most of the fractures are due to a combination of flexion with axial compression resulting in collapse of the anterior portions of the vertebral body. With osteoporosis, as the load-bearing capacity of the vertebral bodies 3696

decreases, minor movements such as bending or lifting can result in a fracture in older patients. Crushed fracture of the anterior and middle columns of the vertebral body, the so-called burst fractures, can result in neurologic compromise. The main goal of therapy is prevention. Treatment options for pain due to vertebral compression fractures include analgesics, bracing, and interventional treatments. Surgical treatment is indicated if there is neurologic compromise. However, surgery can be invasive and result in failure of fixation in the osteoporotic spine. Vertebral body augmentations with vertebroplasty or balloon kyphoplasty have had promising results. It involves mechanical augmentation of the compressed vertebral body by injecting acrylic bone cement material. Use of polymethylmethacrylate for vertebral compression fractures was reported in France in 1991 with good results of pain relief. Polymethylmethacrylate is injected into the vertebral body via a posterolateral approach. The posterior cortex of the vertebral body must be intact prior to injection. Studies have recognized the best timing of interventional procedures to be within 6 weeks of the fracture.41,42 No differences in pain were reported when vertebroplasty is compared to balloon kyphoplasty.43 Both techniques have their own advantages and disadvantages.44 Medial branch nerve blockade and radiofrequency ablation is an emerging option with lower risk than other interventional approaches described earlier, albeit without an extensive evidentiary basis.45 Ankylosing Spondylitis Ankylosing spondylitis results in a stiff spine due to arthritic changes in the intervertebral joints including the costovertebral, costotransverse, and apophyseal joints. The sternoclavicular joints can also be involved.46 Patients can typically present with mild to moderate pain in the posterior chest wall. Anterior chest wall pain has also been reported in patients with ankylosing spondylitis.47 Physical examination demonstrates limited movements of the spine with contracted tender paraspinal muscles. Diagnosis is made by plain films that show characteristic fused spine or “bamboo spine.” Occasionally, involvement of the nerve roots due to arthritic changes in the joints can result in radicular pain. Secondary 3697

contracture of the paraspinal muscles can worsen the pain. Effective treatment involves physical therapy, trigger point muscle injections, and muscle relaxants. Progression of the arthropathy should be addressed with the expertise of a rheumatologist. Paravertebral blocks can provide relief from radicular pain. Thoracic facet joint injections with corticosteroid and local anesthetics can provide significant relief of pain. If good results are encountered with facet joint injections, longer term relief of pain can be obtained with radiofrequency ablation of the nerve supply of the facet joint. The radiofrequency technique is generally considered to be safer than chemical ablation because there are additional risks associated with the potential unwanted spread of the chemolysis agent. Costovertebral Arthritis Arthritis of the costovertebral and costotransverse joints can cause posterior chest wall pain. Pain is localized, aching, and deep in character. Pain can be increased with deep breathing, coughing, or lateral compression of the chest. Physical examination may reveal localized deep tenderness that may be hard to distinguish from thoracic facet syndrome. Characteristics of pain and radiologic examination can delineate the pathology.48,49 Treatment is provided with nonsteroidal anti-inflammatory agents and physical therapy. Interventional treatment with injection of the joints with local anesthetic, corticosteroid mixture with fluoroscopic confirmation can alleviate the pain. It can also be diagnostic. Low-dose opioid medications may be needed for treatment of chronic pain from the arthritis.50 Rarely, resection of the joints is considered for refractory pain from isolated costovertebral joint arthritis.51 Diffuse Idiopathic Skeletal Hyperostosis Another cause of posterior chest wall pain in elderly patients can be due to diffuse idiopathic skeletal hyperostosis (DISH), also called Forestier disease. Patients present with dull aching thoracic back pain, posterior chest wall pain, dysphagia, myelopathy due to involvement of the posterior longitudinal ligaments, fractures, subluxation, and, rarely, intercostal neuralgia. Physical findings include slight increase in dorsal kyphosis, minimal reduction in motion, and localized tenderness. Diagnosis is confirmed with radiologic exams with plain films and CT scans showing 3698

spinal hyperostosis resulting in linear ossification and bridging osteophytosis along the anterior and anterolateral aspects of the vertebral bodies. DISH most commonly affects the thoracic spine. Absence of sacroiliitis, true syndesmophytes, and ankylosing apophyseal joints distinguishes this syndrome from ankylosing spondylitis.52,53 The syndrome of synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO syndrome) can also be a cause of anterior chest wall hyperostosis.54 Treatment is symptomatic with nonsteroidal anti-inflammatory drugs (NSAIDs) and physical therapy. Thoracic Facet Syndrome Thoracic facet syndrome results from abnormal locking or binding of the facet joints. Sudden or rapid turning movements of the trunk, working with hands over the head, or lifting with the trunk in a twisted position can result in this syndrome. Symptoms include moderate to severe pain on the side of the spine or anterolateral chest wall.55,56 The pain is worsened with extension of the spine and relieved with flexion. Localized deep tenderness can be elicited to deep palpation over the facet joint. Tenderness and spasms of the erector spinae muscles can exacerbate the pain. It can mimic the pain from costovertebral arthropathy. Injection of the joint can assist in making the correct diagnosis. Treatment includes NSAIDs, physical therapy, and injection of the facet joints and medial branches with corticosteroid and local anesthetics. Radiofrequency denervation offers long-term pain relief but for unknown reasons may be associated with higher rates of postlytic neuritis than comparable radiofrequency denervation of medial branch nerves in the lumbar or cervical regions.57–59 Chest Wall Pain Arising from the Ribs Rib fractures account for one of the most common causes of acute chest wall pain of skeletal origin. Blunt trauma to the ribs is the usual cause of fractures. Other causes include severe paroxysmal coughing (tussive fracture), metastatic disease, osteoporosis, osteomalacia, and Paget disease of the bone (Fig. 69.11). Elder or child abuse should be sought in unexplained rib fractures after all other etiologies are eliminated.

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FIGURE 69.11 Computed tomography showing rib destruction from multiple myeloma (arrow). (Reprinted with permission from Lee JKT, Sagel SS, Stanley RJ, et al. Computerized Body Tomography with MRI Correlation. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006. Figure 8-82.)

Fractures may involve several ribs or multiple fractures of the same rib. Acute pain from rib fractures is usually aching, sharp, and worsened with respirations. Pain from multiple fractures can restrict breathing leading to additional pulmonary complications. Acute pain from rib fractures is treated with NSAIDs, low-dose opioids, or continuous intercostal nerve blocks. Chest wall pain from multiple rib fractures in trauma patients, in which serious consequences might occur from hypoventilation due to painrelated splinting, are candidates for a thoracic epidural catheter with a continuous epidural infusion.60,61 Multiple studies in selected trauma patients have shown better outcomes of pain relief and reduction in pulmonary complications with thoracic epidural infusion compared to systemic opioids or intrapleural catheters.62–66 Ultrasound-guided serratus plane blocks have been used recently for pain control after multiple rib fractures.67,68 Occasionally, rib trauma without radiographically apparent fracture can cause localized pain and swelling with point tenderness in the area. If these are related to hypoventilation due to splinting from pain, they may be 3700

considered the same as rib fractures potentially requiring neuroaxial analgesia. Local injections with local anesthetics, intercostals nerve blocks, and NSAIDs can help relieve the pain. Topical local anesthetic patches with 5% lidocaine may be helpful for some with pain from single rib fractures or rib injuries without a fracture. Metastatic disease from the breast, lungs, and prostate can cause isolated rib tenderness. Plain radiographs and nuclear medicine bone scans can aid in the diagnosis. Slipping Rib Syndrome Slipping rib syndrome was described first in 1922 by Davies-Colley.69 It is characterized by chest wall or abdominal pain due to irritation of the intercostal nerves. The etiology is thought to be due to trauma. There is increased mobility of the costal cartilages of 8th to 10th ribs near the sternum. The syndrome is also referred to as clicking rib, gliding rib, or displaced ribs.70 It is also seen in children.71,72 The cause for pain is due to anatomic variation of the 8th to 10th ribs, which, instead of articulating directly with the sternum, articulate with the costal cartilages of the upper rib. As such, the sternal ends of these ribs are more prone to trauma. Injury can cause separation of the cartilages causing slipping movements of the ribs with respiration. A characteristic click can be felt with the movement of the ribs over the border of the upper cartilage. Diagnosis of the condition can be accomplished by the “hooking maneuver.” The examiner’s curled fingers are placed over the inferior border of the rib and the rib is pulled up anteriorly. A positive test produces a clicking noise and increases the pain.73 Slipping rib syndrome is treated conservatively with reassurance and nonopioid analgesics. Injection of the painful site (between the detached cartilage and the rib) with local anesthetic steroid combination medications may relieve pain for a longer period. Surgical excision of the involved rib and costal cartilages has also been suggested for refractory cases. Tietze Syndrome Tietze syndrome is characterized by a benign, nonsuppurative, painful swelling of the second or third costal cartilages.74 It was first described in 1921 by Tietze. Straining, severe cough, heavy manual work, nutritional deficiencies, and arthritic conditions have all been implicated as the 3701

possible causes. In 80% of the patients, the condition is unilateral.75 Pain is usually localized but occasionally can radiate over the anterior chest wall to the shoulder or neck. Pain is characterized as heaviness, tightness, or soreness. Pain is exacerbated by coughing and deep breathing. There is localized tenderness and swelling over the involved cartilage.76 The overlying skin is normal. Radiologic diagnosis by bone scans is nonspecific.77 Treatment includes use of nonopioid anti-inflammatory medications. The condition usually is self-limited with occasional exacerbations and remissions. Costochondritis Costochondritis is one of the most common causes of anterior chest wall pain often confusing or coexisting with the pain due to coronary artery disease.78–80 Pain is characterized as aching, sharp, or tightness in the anterior chest wall. Unlike Tietze syndrome, it involves multiple sites. No swelling is palpated. There is localized tenderness involving multiple costochondral regions of the anterior chest wall. Second to fifth costal cartilages are frequently involved. Pain is aggravated with movement of the chest. Pain can radiate anteriorly or to the back. In adolescents, it can cause chest wall or abdominal pain. Firm steady pressure applied over the sternum, intercostal spaces, costochondral junctions, and the ribs can reproduce the pain. The horizontal flexion test consists of having the arm flexed across the anterior chest wall and applying steady traction in a horizontal direction while the patient’s head is rotated toward the ipsilateral shoulder. The crowing rooster maneuver involves having the patient extend the neck as much as possible by looking toward the ceiling while the clinician, standing behind the patient, exerts traction on the posteriorly extended arms. It is important to distinguish pain due to costochondritis (especially leftsided) from that of coronary artery disease or abdominal pathology.78 Pain due to costochondritis is usually located to the lateral side of the sternum unlike substernal cardiac pain.81,82 Pain can radiate to the left arm or shoulder. The patient gives a history of pain with movement and postural changes. Localized concordant tenderness can be palpated. Pain usually lasts for a few minutes to hours, distinguishing it from pain of acute 3702

cardiac origin. Intercostal nerve blocks and injection of the tender costochondral areas with local anesthetic have been used for diagnostic purposes. Rarely, emergency room physicians experience a patient with both costochondritis and coronary artery disease. Careful history and physical exam along with treatment with sublingual nitroglycerin can aid in prompt diagnosis of the cardiac pain, which is relieved with the nitroglycerin. Treatment of costochondritis is initiated with NSAIDs, physical therapy, heat application, and less commonly with low-dose opioids. Once the diagnosis has been made, reassuring the patent about the benign nature of the condition can prevent patient anxiety and avoid unnecessary expensive diagnostic workup. Localized injection of the costochondral junction with local anesthetics and corticosteroids can help relieve the pain.

Costochondral Dislocation Costochondral dislocation is commonly seen after trauma in young patients.83 It is also encountered after thoracic surgery with rib retraction. The pain is typically dull, aching, or burning and is usually continuous. Localized tenderness is present. Sometimes, a mass is felt due to cartilaginous excess from the injury. Treatment is similar to other conditions as described earlier with oral analgesics and intercostals nerve blocks. Manipulation and reduction of the dislocation after adequate analgesia can correct the condition.

Chest Wall Pain of Sternal Origin Sternoclavicular joint arthritis can be caused due to various arthritic conditions (osteoarthritis, rheumatoid arthritis, psoriatic) and rarely infections due to central venous catheters.84–86 Infections are also seen in intravenous drug users. Traumatic subluxation and dislocation can also cause pain.87 Apart from trauma, such conditions are also seen after cardiac surgery when the sternum is retracted. Pain is localized to the affected joint. Localized tenderness of the joint is seen with palpation along with pain from shrugging the shoulders. Treatment consists of oral NSAIDs and injection of the joints with local anesthetic and corticosteroid. Such intervention must be avoided in infectious joints which are treated 3703

with antibiotics and analgesics. Blunt injuries to the sternum can cause subluxation of the manubriosternal joint.87 Manubriosternal arthritis can occur due to various arthritic conditions.88–90 Septic arthritis of the joint is also seen.91,92 Pain is localized to the anterior sternum or angle of Louis with occasional radiation parasternally. Pain is characterized as sharp aggravated with deep breathing, coughing, or yawning. Pain may mimic anginal pain. Diagnosis is made by physical examination. Bone scans can be positive.93 Treatment consists of systemic analgesics, topical lidocaine patches, heat, infiltration of the joint with local anesthetics, and corticosteroids. Rarely, surgical intervention to correct the manubriosternal displacement is necessary. Xiphoidalgia (Painful Xiphoid Syndrome, Xiphoid Cartilage Syndrome, Hypersensitive Xiphoid) Intermittent, inferior substernal, or epigastric pain associated with tenderness of the xiphoid to palpation is characteristic of xiphoidalgia.94,95 Pain is spontaneous without any obvious precipitating cause. It is sometimes seen along with coronary artery disease, intestinal disease, and metabolic disorders. Movements of the xiphoid with bending, stooping, or turning precipitates or exacerbates the pain more commonly after a full meal. Along with NSAIDs, local injection of the xiphisternal joint with local anesthetic and corticosteroid can alleviate the pain.

Chest Wall Pain of Myofascial Origin Myofascial strain can be caused by excessive muscular activity. Repeated stress due to exercise, coughing, straining, or repetitive movements (chopping wood, painting a ceiling) can result in generalized tenderness over the anterior chest wall. Pain in the intercostals or accessory thoracic muscles is usually due to trauma. Pain from the pectoralis muscles can be exacerbated with adduction movements of the shoulder. Pain between the scapula and spine from an injured rhomboid is increased with bracing of the shoulders backward. Treatment consists of reassurance, local heat or cold, NSAIDs, topical lidocaine patches, physical therapy, and avoiding precipitating activities. Infiltration of the muscle with local anesthetic can be undertaken if there is localized tenderness. Caution regarding the risk of 3704

pneumothorax is necessary for all chest wall injections. Precordial Catch Syndrome (Chest Wall Twinge Syndrome) This is characterized by episodes of sudden, brief, sharp precordial or periapical pain. This is a benign, self-limited condition.96,97 Sharp pains, stitches, or catches are felt in the chest wall in the left parasternal on or near the cardiac apex. Some patients report pain from assuming a slouching or bent position. Pain may last for a few seconds to up to 3 minutes. Deep breathing exacerbates the pain, whereas shallow breathing relieves it. There is no localized tenderness. The cause is unknown. Intercostal muscle spasms and pain from the pleura have been postulated as possible causes. Treatment consists of reassurance and correction of posture. Due to the unpredictability and the benign short duration of pain, analgesics are not necessary. Epidemic Myalgia (Bornholm Disease, Epidemic Pleurodynia, Devil’s Grip) This condition is characterized by paroxysms of intense sharp chest wall and upper abdominal pain due to viral infection with coxsackie or echoviruses.98 The paroxysms of pain are separated by pain-free intervals. Frequently, there is associated fever, headache, and pharyngitis. The condition is self-limited.

Breast Pain Pain arising from the breast is a common and nonspecific symptom in women.99,100 Usual causes include benign cysts, fibrocystic change, or cyclical pain due to hormonal cycle changes of the menstrual cycle. Other causes of breast pain include malignancy, mastitis, ductal ectasia, breast abscess, hormone replacement therapy, or large breasts. Careful clinical evaluation and mammography to rule out malignancy should be undertaken. Pain due to malignant breast lesions does not usually present until the tumor is large (greater than 2 cm in diameter). Axillary lymph node involvement can present as either localized or sharp pain in the arm with involvement of the intercostobrachial nerves. Extramammary sources of breast pain should be evaluated if no other etiology is suggestive. Causes include skeletal and myofascial pain from the chest wall, radicular 3705

pain, or pain from peripheral nerves. Chronic severe breast pain that persists for years without any obvious cause characterizes idiopathic mastalgia. Pain can be unilateral or bilateral, cyclical or noncyclical, which is usually seen in the third or early fourth decades of life. Without any organic diagnosis, the etiology is often misdiagnosed as psychologic.100 Cyclical mastalgia responds to danazol, bromocriptine, or tamoxifen. Hormonal events such as pregnancy, menopause, or use of oral contraceptives may lead to relief.101–103 Breast pain is often treated with NSAIDs and acetaminophen. Warm compresses, ice packs, or gentle massage can also help relieve pain. Pain arising from the cervical or thoracic spine requires appropriate treatment of the cause as discussed elsewhere in this book. Peripheral myofascial and skeletal pain, also discussed elsewhere in this book, can be treated with injection of local anesthetic and corticosteroid.104,105 Adiposis Dolorosa (Dercum Disease) This syndrome is characterized by painful subcutaneous fatty tumors in various parts of the body, including the breast.106 This can result in chronic pain in the breast. Treatment with intravenous lidocaine and resection of the fatty lesions is helpful. Mondor Disease Thrombosis of the superficial veins of the thoracic wall can cause pain in the anterolateral chest wall.107 This is seen occasionally in patients who abuse intravenous drugs.108 The disease is mostly seen in middle-aged women with pendulous breasts and can cause pain in the breast.109 Presence of a palpable tender cord is characteristic. The disease can cause anxiety in the patient. Mondor disease is self-limited. Treatment involves management of pain with NSAIDs.

Postsurgical Chest Wall Pain Pain can persist for several months to years after surgery. It is often additively perplexing for the patient to live with pain after the original pathology has been corrected with surgery. Chronic postsurgical pain is most commonly seen after thoracotomy, mastectomy, and cardiac surgery. Other rare causes of chronic postsurgical chest wall pain include video3706

assisted thoracoscopy, mediastinoscopy, breast reconstruction, and surgery of the cervical or thoracic spine. Postsurgical Breast Pain and Postmastectomy Pain Syndrome Persistent pain in the anterior chest wall, axilla, and the arm can be seen in a few patients after mastectomy.110–112 It can also occur after minor breast surgeries, such as lumpectomy. Breast reconstruction or other cosmetic breast surgeries can be also associated with such pain. Submuscular implants and capsule formation around the implant can cause injury or impinge on the thoracodorsal, long thoracic, lateral, or medial pectoral nerves. Postsurgical complications such as wound infection, fluid or hematoma retention, and reexploration can frequently result in pain. Although previous studies describe pain in less than 10% of patients, more recent studies report pain, paresthesias, and phantom sensations in about half of the patients.113,114 In about half of the cases pain resolves with time. Pain is described as burning, sharp, or tight constriction of the axilla. Pain can be associated with surgical scar sensitivity. There can be associated dysesthesia or hyperesthesia of the anterior chest wall. It is presumed that injury to the intercostobrachial nerves and, rarely, the intercostal nerves is the cause. However, pain management interventions have included intercostal nerve blocks and not blockade of the intercostobrachial nerves,115 but it should be noted that the intercostobrachial nerves are branches of the second and third intercostal nerves, so blocks of the second and third intercostal nerves will also block the intercostobrachial nerves. Patients are at risk for developing upper extremity problems due to restricted movement of the arm secondary to pain. Treatment consists of analgesic and neuropathic medications, physical therapy, reassurance, intercostal or paravertebral nerve blocks, or epidural analgesia.116,117 Intraoperative infiltration of botulinum toxin into the chest wall musculature has also been suggested.118 Ultrasound-guided pectoral blocks have demonstrated pain control similar to thoracic paravertebral blocks.119 Persistent pain should arouse suspicion for recurrent breast disease. Phantom breast syndrome has been a common occurrence after a mastectomy in the past.120–122 The incidence has decreased with adequate 3707

psychosocial supportive therapy.123,124 It can present as painful or nonpainful sensations in the region of the missing breast as if it is still present. It can develop within 3 months after the surgery. Risk factors for development of the syndrome include psychosocial factors, damaged body image, and impaired sexual function. Affected women are usually younger, premenopausal with children. Predisposing factors for phantom breast pain are similar to phantom limb syndrome and include pain in the involved breast prior to surgery.125 Preoperative analgesia may be effective in preventing this syndrome; however, it has not been significantly studied. Postthoracotomy Pain Chronic chest wall pain after thoracotomy can be disabling to the patient.126,127 Characteristics of postthoracotomy pain can be burning, aching, hyperesthesia, or allodynia along the surgical incision and the involved dermatome. Women experience more pain than men after major thoracotomy.128 No difference has been seen in the incidence of acute or chronic pain with different types of thoracotomy incisions.129 Prospective studies have predicted that adequate management of acute postsurgical pain can prevent the chronicity of pain.130,131 Preoperative psychosocial factors were not associated with development of chronic pain after thoracic surgery. There was no difference in the incidence and severity of chronic pain after thoracotomy versus thoracoscopy. 132 Management of acute pain with thoracic epidural placed prior to surgery has been shown to decrease the severity of perioperative pain and decrease the incidence of chronic pain. Other causes of radicular chest wall pain and recurrent cancer have to be excluded, especially in postthoracotomy patients who experience onset of severe pain several months after the thoracotomy. Management is similar to treatment for intercostal neuralgia.133,134 Thoracic paravertebral blocks are also helpful to control acute and chronic pain.135,136 Pulsed radio frequency of dorsal root ganglia or intercostal nerves is recommended for refractory pain.137 Prior to any injections of the surgical scar site, a careful examination is necessary to avoid injury to herniated lung tissue in rare cases.138,139 A multimodal approach to pain management provides higher success in controlling 3708

chronic postthoracotomy pain. Postcardiac Surgery Pain Persistent anterior chest wall pain has been reported in about 28% of patients after cardiac surgery.140,141 Myocardial ischemia, infection, sternal or costosternal instability, sternal wires, and intercostal neuralgia (especially after dissection of the internal mammary artery from the chest wall) can be possible causes.142 Pain can persist up to 2 years postoperatively. Initial attempts at treatment should be focused on eliminating obvious serious causes. Treatment consists of analgesic and neuropathic medications, costosternal joint injections, and surgical removal of sternal wires.143

CHEST PAIN AND PSYCHOLOGICAL FACTORS Patients with sudden acute chest pain, regardless of the cause, experience varying degrees of anxiety, apprehension, and fear, depending on their interpretation of the cause of pain. Those who believe they are experiencing a heart attack become extremely frightened of possible impending death. Patients with persistent angina develop reactive depression, which, if untreated, produces progressive physical and psychological deterioration.144 Musculoskeletal chest pain can cause a great deal of anxiety and apprehension until the patients are reassured about the benign nature of the condition.145,146 Adolescents can often present with chest pain that is mostly myofascial or psychogenic in origin. Chest pain can also result from psychological mechanisms. Because of the potential seriousness of a physical cause of chest pain, thorough history, physical examination, and diagnostic workup is essential. Some of the features of psychological chest pain include pain at the apex of the heart, patients describing the character of pain dramatically, development of pain unrelated to physiologic events, and possible presence of an emotional precipitating event prior to the pain. Once the diagnosis of psychological chest pain has been made, reassurance, relaxation techniques, anxiolytic drugs, sedatives, tranquilizers, and time can reduce the anxiety. Patients with chronic anxiety can present with chest pain and other 3709

symptoms. This syndrome has been called Da Costa syndrome, neurocirculatory asthenia, vasoregulatory asthenia, effort syndrome, and soldier’s heart.147,148 Patients can present with symptoms of apical chest pain, shortness of breath, nervousness, anxiety, fatigue, generalized weakness, and low energy level. Treatment consists of reassurance, behavioral therapy, and treatment of underlying psychiatric disorders, if any. Other psychiatric disorders, such as depression, conversion reactions, hypochondriasis, and learned behavior, can manifest as chest pain.

CHEST WALL PAIN OF CARDIAC ORIGIN In any patient who presents with chest pain, the differential diagnosis must include chest pain of cardiac origin. Angina presents as substernal chest pain or tightness. However, atypical presentations of chest pain or gastric symptoms can be seen from cardiac disease. Evaluation of risk factors may help assist in making the diagnosis in atypical presentations. Chronic refractory angina pectoris is a condition where patients present with chronic and disabling chest pain despite optimal medical treatment. In such patients who are not candidates for invasive cardiac procedures, spinal cord stimulation (SCS) offers adequate pain control and improvement in the quality of life.149,150 SCS is also mentioned as an available adjunct by the task force on the management of stable angina pectoris of the European Society of Cardiology.151 Angina due to acute myocardial infarction is not masked by SCS.152

Conclusion Chest wall pain can result from lesions within the chest wall or referred pain from the thoracic viscera (Figs. 69.12 and 69.13). A comprehensive assessment and examination is needed to differentiate these and to further determine if the lesion involves skeletal, muscular, or neurologic components of the chest wall or thoracic and abdominal viscera (Table 69.3).

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FIGURE 69.12 Common sites of anterior chest wall pain due to chest wall structures or referred pain.

FIGURE 69.13 Common sites of posterior chest wall pain due to chest wall structures or referred pain.

TABLE 69.3 Pain in the Chest: Summary of Differential Diagnosis International Association

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Important Diagnostic Features

Etiology (Disease) I. Pain caused by disease of the heart and aorta A. Angina pectoris (stable angina, unstable angina, variant angina)

for the Study of Pain Code Referencea

XVII-4

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Characteristics of the Pain

Mild, moderate, severe, or excruciating anterior chest pain felt predominantly retrosternally with radiation to parasternal region, left arm or right arm or both, epigastrium, and, less frequently, to the interscapular region, neck, and lower jaw; discomfort felt as severe oppression or heaviness on the chest, a sense of constriction or bandlike pressure, or a feeling of choking, strangling, or tight pressure on the neck; pain provoked by physical effort, severe emotional stress, or a large meal (except unstable angina, which occurs at rest or with little or no provocation); lasts 2–5 min with stable angina, 15– 30 min or longer with unstable angina and variant angina; promptly relieved with nitroglycerin or

Associated Symptoms and Signs

History of previous anginal attacks; can have normal ECG at rest, but ST depression and other ECG changes during stress test; positive evidence with radionuclide stress testing and coronary arteriography; demonstration of coronary artery spasm in variant angina

B. Acute myocardial infarction

XVII-5

discontinuation of effort Pain of same character, location, and reference as angina but of sudden onset, much more severe, and of longer duration (1–8 h or more); little or no relief with nitroglycerin; intense pain often accompanied by strong alarm reaction and feeling of impending death

C. Aortic stenosis

—

Dyspnea first symptom but angina occurs with severe aortic stenosis; chest pain occurs during physical exertion as a result of increased oxygen demand from increased myocardial mass and high ventricular systolic pressure

D. Aortic regurgitation

—

Asymptomatic early

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Frequent nausea, vomiting, and profuse sweating; many patients develop tenderness in pectoral muscle and deep muscle of interscapular region; some develop bradycardia and hypotension and others tachycardia and hypertension; ECG changes include Q-wave and ST-segment elevation and increased creatine kinase and other serum enzyme levels With severe disease, exertional syncope is caused by decline in arterial pressure; left ventricular failure, palpitation, fatigue, weakness, peripheral cyanosis, narrow pulse pressure, and palpable systolic murmur; increased QRS complex and STand T-wave alterations Dyspnea on

in disease; dyspnea on exertion; pain late symptom of severe disease that can occur at rest as well as with exertion and persists longer than angina of coronary artery disease; some patients have neck and abdominal pain

E. Mitral valve prolapse

—

Sharp, stabbing chest pain not provoked by exertion and unresponsive to nitroglycerin; more frequent in female subjects

F. Hypertrophic cardiomyopathy

—

Most patients asymptomatic; symptomatic patients have dyspnea on exertion because of increased stiffness of left ventricular walls; typical angina pectoris with exertion

XVII-6

Severe, sharp chest pain; worse in supine position, partially relieved by sitting; markedly aggravated by deep breathing; pain usually retrosternal (central), radiates

G. Acute pericarditis

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exertion, flushing, sweating, palpitation; increased fatigue progresses to orthopnea and eventually to paroxysmal nocturnal dyspnea; highpitched crescendo diastolic murmur along left sternal border Cardiac arrhythmia produces palpitation and rarely dizziness, syncope, or even sudden death; midsystolic click and late systolic murmur Atrial and ventricular arrhythmias produce palpitation, dizziness, and syncope; ECG shows QRS changes of left ventricular hypertrophy and abnormal Q wave Dyspnea occurs because of marked increase in pain with normal respiration; triphasic pericardial friction rub occurs with atrial

to the neck and trapezius ridge but not to the arms

H. Diseases of the thoracic aorta 1. Dissecting aneurysm

2. Nondissecting aneurysm

—

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Sudden, severe excruciating pain with maximal intensity at its onset; location of pain helps to localize dissection: ascending aortic dissection produces anterior chest pain in 65% of patients and posterior chest pain in 50%; dissection in descending thoracic aorta produces back pain in nearly all patients; radiation to the neck, throat, jaw, and abdomen in a small percentage of patients Mild to severe continuous burning, aching pain with bouts of lancinating pain; radiation to the chest, shoulder, and back caused by mechanical compression or

systole, ventricular systole, and ventricular diastole, occasionally only biphasic; ECG initially shows ST-segment elevation and later T-wave flattening

Nausea, vomiting, diaphoresis, bradycardia, and hypotension or tachycardia and hypertension; loss of one or more arterial pulses; sense of impending death, apprehension

Dyspnea, cough, dysphagia, hoarseness; Horner syndrome; pulsating mass; radiographic evidence

injury of thoracic spinal nerves; erosion of bone causes boring, agonizing, intractable back pain II. Diseases of the respiratory system A. Diseases of the tracheobronchial tree 1. Acute tracheobronchitis (infectious, irritative, thermal injury)

2. Bronchiectasis

—

Mild to moderate burning, aching pain in the retrosternal and parasternal regions; pain severe with thermal injury; associated with sore throat

—

Mild to moderate aching pain in retrosternal and parasternal regions

B. Diseases of the pulmonary circulation 1. Acute pulmonary — hypertension

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Severe crushing, gripping pain in the center of the chest simulating that of acute myocardial infarction, but does

Preceded by upper respiratory infection: coryza, malaise, chilliness, slight fever, back and muscle pain; with bronchitis, initially dry and nonproductive cough but later mucoid or mucopurulent, dyspnea might be present Chronic cough and sputum production; with progression, cough becomes more productive, hemoptysis common, recurrent pneumonia frequent; wheezing, dyspnea in severe cases Usually decrease in arterial PO2 can have dyspnea, cyanosis, sweating

2. Chronic pulmonary hypertension (primary, secondary)

—

3. Pulmonary embolism

—

not radiate to arms or jaw and seldom to back Pain in anterior chest, primarily retrosternal; radiation to neck; some patients have typical angina pectoris complicated by myocardial ischemia

With large embolus pain is sudden, severe, crushing, and of a visceral central type; simulates pain of myocardial infarction but does not radiate to the jaw or arms; lasts for minutes to several hours; small embolus produces localized severe pleuritic pain that is persistent and lasts a week or longer; aggravated by deep breathing or coughing

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Primary hypertension usually in female subjects; dyspnea, easy fatigue, less frequently syncope; right ventricular hypertrophy can progress to failure Feeling of impending death (angor animi), pressure on throat, desire to defecate; history of thrombi in leg, pelvis, occasionally in upper extremity; rarely, embolic fluid or fat emboli; initially the large embolus usually produces pulmonary hypertension from increased pulmonary vascular resistance, leading to decreased cardiac output, hypotension that can progress to shock, with sweating, tachypnea, dyspnea, arterial hypoxemia; hemoptysis,

pleural friction rub with small embolus; radiography reveals wedgeshaped shadow C. Diseases of the lungs 1. Pneumonia

—

With lobar pneumonia, patient develops pleuritis with moderate to severe pain in lateral chest or shoulder aggravated by deep breathing and coughing (because of involvement of central diaphragmatic pleura); little or no pain with bronchopneumonia

2. Lung abscess

—

Typical pleuritic chest pain if abscess produces pleuritis; characteristics similar to those of lobar pneumonia (see earlier)

3. Atelectasis

—

Rapid occlusion with massive lung collapse causes moderate to severe pain on the affected side

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Systemic symptoms and signs of infection: fever, cough, occasionally nausea, vomiting, malaise, and muscle pain; blood-streaked sputum, occasionally hemoptysis; rhonchi; percussion reveals dullness; radiographic evidence Malaise, anorexia, sputumproducing cough, sweats, severe prostration, and fever; putrid odor (anaerobic infection); fine moist rales Rapid collapse causes dyspnea, cyanosis, hypotension, tachycardia, fever, and shock; percussion, dullness, or flatness; diminished or absent breath sounds; decreased chest excursion of

affected side D. Disorders of the pleura 1. Pneumothorax (spontaneous)

—

Sudden moderate to severe stabbing, sharp pain felt across the chest or over abdomen or corresponding shoulder, can simulate pain of acute myocardial infarction or acute abdomen

2. Pleuritis (pneumonitis, pulmonary infarct, pleural tumors, lung abscess, actinomycosis, coccidiomycosis, other infectious processes)

—

3. Epidemic pleurodynia (Bornholm disease)

—

Localized, sharp, knifelike stabbing, piercing pain in various regions of the chest depending on the site of pathology (side, shoulder, epigastrium); markedly aggravated by deep breathing, coughing, laughing, movement of the chest; pain can be continuous with pleural carcinoma Severe paroxysmal sharp pain in side of chest wall, epigastrium, costovertebral region, and abdomen Location, quality, and severity of pain depend on location and type of spread: Endobronchial

E. Bronchogenic and metastatic carcinoma of the lung, bronchial pleura (squamous cell carcinoma,

—

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Dyspnea, absent breath sounds; with large or tension pneumothorax tympany on percussion; decreased excursion of affected side; cardiac dullness and apex felt away from affected side; radiographic evidence Diagnostic pleural friction rub; history and systemic symptoms and signs of infection; chest signs (rales, rhonchi); radiographic evidence

Fever, headache; occasionally orchitis, encephalitis, and pericarditis occur during epidemic pleurodynia Weight loss; paraneoplastic syndromes; other signs and symptoms:

undifferentiated small or large cell adenocarcinoma, bronchoalveolar carcinoma)

III. Diseases of the esophagus A. Esophagitis 1. Gastroesophageal reflux disease

2. Acute and chronic

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XIX-4

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carcinoma: sternal and parasternal pain Intrapulmonary carcinoma: vague central (visceral) pain Pleural spread: sharp, stabbing, chest wall pain markedly aggravated by breathing, coughing, movement Mediastinal spread: neuropathy with segmental pain Pancoast syndrome (brachial plexopathy): pain in shoulder, scapula, medial arm

Cough, hemoptysis Hypoxia, dyspnea, atelectasis Signs and symptoms of pleuritis (see earlier) Compression of superior vena cava Ø superior vena cava syndrome Horner syndrome, hoarseness, weakness of all muscles supplied by the ulnar nerve

Retrosternal pain extends from suprasternal notch to xiphoid process; radiation to epigastrium, neck and back, and, rarely, arms; simulates pain of myocardial ischemia; lasts seconds to many hours; aggravated by stooping or lifting, recumbency, citrus juices, exercise, heavy meal, coffee, alcohol, aspirin, tobacco, and obesity; relieved by antacids Corrosive agents:

Dysphagia, odynophagia, regurgitation, and occasionally aspiration; diagnosis helped by pH monitoring, acid perfusion test, and esophagoscopy

Infection: signs and

esophagitis caused by infection or chemical agents

B. Esophageal motor disorders (achalasia; diffuse spasm unclassified motor disorders)

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immediate, severe, burning pain in throat and behind the whole length of the sternum down to epigastrium, pain is constant with periodic increases in intensity produced by esophageal spasm; infection: pain appears gradually over a period of hours or days and is constant, mild to moderate, and burning in character; both are markedly aggravated by swallowing (odynophagia) and by citrus juices and other factors listed previously for gastroesophageal reflux disease Moderate to severe retrosternal pain; radiation to epigastrium and back, neck, jaw, teeth, left arm, or both arms; aggravated by cold liquids, solids, and emotional stress; partially relieved by nitroglycerin; lasts seconds to many hours and can awaken patient from sleep; simulates pain of myocardial infarction

symptoms of inflammation (e.g., fever, chills); chemical esophagitis: pharyngeal erythema; moniliasis; typical soft white patches in tongue, tonsil, and buccal mucosa; other associated symptoms as earlier (e.g., dysphagia, odynophagia)

Dysphagia, odynophagia; diagnosis aided by manometry, scintigraphy, provocative tests (e.g., edrophonium- or methacholineinduced esophageal spasm)

C. Esophageal laceration and rupture (MalloryWeiss syndrome, Boerhaave syndrome)

—

D. Carcinoma

—

E. Paraesophageal hiatal hernia

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Mallory-Weiss syndrome: laceration of distal esophagus and proximal stomach during retching, vomiting, or hiccup causes pain in lower sternum and epigastrium; Boerhaave syndrome: spontaneous rupture occurs during intense vomiting following a large meal and causes sudden, severe, excruciating crushing or tearing pain in lower retrosternal region and epigastrium, with radiation to the back Moderate to severe retrosternal pain; radiation to epigastrium with lower lesions and to upper sternum with upper lesions; radiation to neck, interscapular region; pain continuous and aggravated by food ingestion Generally asymptomatic; might be feeling of epigastric fullness and lower retrosternal discomfort; with incarceration and strangulation

Dysphagia, odynophagia; rupture Ø mediastinitis Ø acute illness, epigastric tenderness, and later subcutaneous emphysema and left pleural effusion

Dysphagia, odynophagia, weight loss; esophageal obstruction; radiographic, CT, and esophagoscopic evidence

Possible massive gastrointestinal hemorrhage; radiographic and esophagoscopic evidence

severe, excruciating epigastric and retrosternal pain IV. Diseases of the mediastinum and diaphragm A. Mediastinal disorders 1. Spontaneous mediastinal emphysema

—

Sudden intense, violent, agonizing retrosternal or precordial pain; radiation to nape of neck and shoulder associated with pleural pain; persists for hours

2. Acute or chronic mediastinitis

—

3. Neoplasms (anterior compartment, superior compartment, middle compartment, posterior compartment)

—

Continuous; mild to moderate; retrosternal, central; oppressive or burning, aching sensation; can be severe One-third of patients asymptomatic: remainder have chest pain, cough, dyspnea, and symptoms caused by compression or invasion of structures in mediastinum

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Signs of emphysema: crunching sound in area of pain, decreased or obliterated cardiac dullness, pneumothorax, subcutaneous emphysema (crepitus); radiographic evidence Systemic signs of infection; history of esophageal rupture or other trauma

Middle compartment: dysphagia, hoarseness; anterior compartment, superior compartment: retrosternal and suprasternal discomfort, local chest pain from pressure on sternum; posterior compartment: neurogenic tumors, vague chest pain, cough, radicular pain from

neuropathy, superior vena cava syndrome B. Diseases of the diaphragm 1. Diaphragmatic pleuritis

—

Sharp, stabbing pleuritic pain along the nape and shoulder or in the posterior and lateral parts of the lower chest and upper abdomen, or both; aggravated by diaphragmatic motion Moderate to severe pain in lower chest, upper abdomen, and shoulder

2. Acute primary diaphragmatitis (Hedblom syndrome)

—

3. Diaphragmatic spasm

—

Precordial pain; radiation to shoulder

4. Diaphragmatic flutter

—

Lower chest pain felt along the

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Signs and symptoms of pneumonitis or infectious processes with inflammation of diaphragmatic pleura

Chills and fever; muscle spasm of abdomen; decreased lung expansion on inspiration; radiographic evidence of flattened diaphragm Dyspnea during sustained spasm of the diaphragm can cause occlusion of esophagus; some patients develop progressive dyspnea, pallor, sweating, hypotension, and angor animi simulating that of acute myocardial infarction; occlusion of the esophagus causes dysphagia and odynophagia Dyspnea, palpitation;

diaphragmatic attachment in the epigastrium, precordium; radiation to the shoulder and occasionally to the neck and arm

symptoms and signs of various causative factors (e.g., encephalitis, intoxication)

I-6

Spontaneous, burning, diffuse, poorly localized pain; bouts of explosive pain; later radicular pain involving several segments, depending on the size of the lesion

2. Extramedullary lesion (primary or metastatic tumor; abscess; hemorrhage)

I-6

Initially localized back pain but subsequently pain is radicular; aggravated by increase in CSF pressure, such as that caused by straining, sneezing, coughing

3. Epidural spinal cord

—

Localized back pain

Dissociation of sensation, loss of pain and temperature sensation but little effect on proprioception; sensory changes often “spotty”; lower motor neuron signs; with multiple sclerosis spotty paresthesia, pain, symptoms and signs of other involved parts of CNS Paravertebral tenderness, paresthesia, followed by sensory loss, muscular weakness; lower motor neuron signs at level of lesion; increased deep reflexes; CSF changes early and marked; spinal cord compression with large lesion Back tenderness on

V. Pain of neuropathic origin A. Lesions or diseases of the spinal cord (myelopathy) 1. Intramedullary lesion (tumor, syringomyelia, trauma, multiple sclerosis, abscess, hemorrhage)

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compression (primary or metastatic tumor, hemorrhage, posterior disk protrusion, abscess, hemorrhage)

B. Lesions of rootlets or roots of T1–T12 (radiculopathy) 1. Herpes zoster

2. Postherpetic neuralgia

at level of site of lesion in 95% of patients; bilateral radicular pain in segments affected by lesion in 55%; aggravated by neck flexion, straight leg raising, coughing, sneezing, Valsalva maneuver

I-1

Continuous aching, itching, or burning pain, often with superimposed bouts of severe lancinating pain; hyperalgesia; aggravated by trunk motion, palpation of vesicles; persists until healing of rash (1–4 wk)

I-1

Severe, continuous, unrelenting burning pain, itching; accompanied by severe paroxysms of stabbing, lancinating pain that persist long after acute phase

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deep palpation, fist pounding; no other early signs, but later muscle weakness ranging from mild degree to paraplegia; numbness and paresthesia in 50%; bladder and bowel dysfunction with low thoracic epidural spinal cord compression

Appearance of rash, later vesicles form and then crust; hyperalgesia and hyperesthesia of skin in affected segments; occasionally systemic symptoms of infection; mood and behavioral changes with unrelieved pain Hyperalgesia, hypesthesia, hyperpathia; scar in area of vesicles; reactive depression, sleep disturbances, anorexia, lassitude, constipation, decreased libido; high suicide rate among those

3. Tabes dorsalis

I-6

4. Mechanical compression (tumor, disk protrusion, vertebral fracture, osteophyte, adhesive arachnoiditis)

—

C. Diseases of formed thoracic spinal nerves (neuropathy) 1. Vertebral compression (arthritis, metastatic or traumatic fracture, tumor of vertebrae, osteomyelitis)

2. Paravertebral compression (mediastinal tumors, aortic aneurysm, paravertebral abscess, or

Severe, sharp, lancinating, girdlelike (segmental) pain of brief duration with intervals of remission Segmental sharp, burning pain; aggravated by cough, sneezing, straining, and movement of trunk

—

Segmental neuralgia usually present: continuous burning or sharp pain affecting part or entire segment of nerve, associated with paroxysms of stabbing pain; compression of anterior root produces dull, aching, occasionally stabbing pain in part of affected segment; both aggravated by movement of thoracic spine; often worse at night Continuous moderate to severe burning, aching segmental pain; aggravated by movement of spine; occasional

—

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with unrelieved postherpetic neuralgia History of syphilis; CSF evidence; other symptoms of CNS syphilis

Hyperalgesia, hyperesthesia, hypesthesia, dysesthesia; radiographic evidence of pathology

Paravertebral tenderness and segmental hyperalgesia, hyperesthesia, hypesthesia; radiographic evidence (CT scan)

Paravertebral tenderness; segmental hyperalgesia, hypesthesia; radiographic

adenopathy) 3. Primary neurogenic tumors (neurofibroma, schwannoma, ganglioneuroma, neuroblastoma)

—

4. Other neuropathies (systemic infection, alcoholism, avitaminosis, diabetes, metals)

—

D. Lesion or disease of the intercostal nerves— intercostal neuropathy (compression or irritation secondary to rib fracture; trauma; primary or metastatic tumor of ribs; pleuritis)

VI. Pain of musculoskeletal origin A. Lesions of the thoracic spine 1. Fracture (trauma, neoplasm, osteoporosis, subluxation, dislocation)

bouts of lancinating pain Possibly localized back pain and tenderness but usually continuous burning, aching pain; associated with lancinating pain in distribution of affected nerve Continuous or intermittent mild to moderate burning pain; associated with paroxysms of stabbing pain in one or more dermatomes

—

Superficial continuous burning pain in distribution of affected intercostal nerve; also, local pain with rib fracture or tumor, pleuritic pain with pleuritis

—

Initially localized dull, aching pain, often referred to anterior part of chest; aggravated

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evidence Sensory deficit (hypesthesia), paresthesia, dysesthesia; CT scan and radiographic evidence

History of infection, alcoholism, nutrition deficiency, exposure to ingestion of metals; hyperesthesia, hyperalgesia, hypesthesia, paresthesia, dysesthesia; other signs and symptoms of primary disorder History of trauma or infection; paresthesia, hyperesthesia, dysesthesia, hypesthesia; superficial and deep tenderness; radiographic evidence; palpable tumor or fracture

History of trauma; radiographic evidence; localized tenderness

by motion, worse and throbbing at night; segmental pain with root compression

2. Metastatic or primary tumors

—

Intense aching, boring circumscribed pain; aggravated by motion and local pressure

3. Arthritis or deformity of spine

—

Usually circumscribed aching pain in back and side; segmental pain with neuropathy

4. Ankylosing spondylitis

—

5. Diffuse idiopathic skeletal hyperostosis

—

Usually circumscribed dull aching pain in back; later paraspinal contractures develop with compression of nerve root, which causes segmental pain Mild to moderate localized, dull, aching pain; aggravated by inactivity and cold

6. Inflammatory disease of vertebrae (osteomyelitis,

—

Circumscribed, continuous, aching pain; moderate to

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paravertebrally and over spinous processes; possibly segmental hyperalgesia, paresthesia Local tenderness or segmental hyperalgesia and hyperesthesia; CT scan and radiographic evidence Signs of arthritis in other areas; deformity of spine evident; local tenderness; reflex muscle spasm; radiographic evidence Tenderness on deep palpation; radiographic evidence

Tenderness and stiffness in thoracic spine; dorsal kyphosis; reduction of range of movement and in chest expansion; characteristic radiographic evidence Local and systemic symptoms and signs of

actinomycosis, tuberculosis, syphilis, subperiosteal hematoma)

severe; aggravated by pressure, often worse at night

7. Costovertebral joint arthritis

—

8. Apophyseal facet syndrome

—

B. Rib lesions 1. Fracture or trauma (severe cough, osteoporosis, metastatic tumor)

2. Primary metastatic rib tumor (myeloma, chondrosarcoma, granuloma)

Localized deep aching pain similar to that arising from vertebral pathology; aggravated by movement; relieved by local infiltration of joint Moderate to severe, dull, aching, localized pain and tenderness; aggravated by hyperextension; relieved by flexion of the spine

—

Localized sharp pain at site of lesion; widespread chest pain with multiple rib fractures; pain aggravated by deep breathing, coughing, movement of thorax

—

Mild to moderate or severe continuous unilateral dull, aching, chest pain;

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inflammation; localized tenderness paravertebrally and over spinous process Tenderness on deep palpation; radiographic evidence

Tenderness; limitation of motion, flattening of normal kyphotic thoracic curve; paraspinal muscle spasm History of accidental trauma or severe coughing; evidence of osteoporosis; exquisite tenderness on palpation of fracture site; radiographic evidence; with compound fracture can have pneumothorax and damage to lung, with respiratory symptoms and signs Palpable mass and tenderness to pressure; radiographic

relatively localized but can also produce intercostal neuralgia Localized continuous aching pain; intercostal neuralgia if lesion irritates nerve

3. Other bone diseases — (osteitis deformans, acromegaly, Paget disease, osteoporosis, hyperostosis) C. Disorders of the costal cartilages 1. Costochondritis — (anterior chest wall syndrome)

Unilateral or bilateral aching pain in lower anterior chest wall usually in region of cartilages of third, sixth, and seventh ribs; aggravated by deep breathing, coughing, palpation

2. Tietze syndrome

—

3. Slipping rib syndrome (rib tip syndrome, slipped cartilage)

XVII-10

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Localized moderate dull, aching pain in upper anterior chest in region of second and perhaps third costochondral junction; aggravated by palpation, movement of chest wall, coughing, respiratory infection; worse when lying down; recurs between intervals of remission Unilateral lower chest and upper abdominal localized aching or sharp pain; aggravated by hyperextension and raising of arms;

evidence

Evidence of disease elsewhere; tenderness on palpation; radiographic evidence No swelling of costochondral region; more frequent in younger than older people; development of anxiety and concern about heart disease if pain is on left side Palpable tender tumorlike swelling at site of costochondral joint; occurs mostly in people older than 50 y; radiography not diagnostic; development of anxiety, fatigue, concern about heart disease

Palpation produces tenderness and reveals upward curling of loosened end of cartilages of 8th, 9th, and 10th ribs; hooking

relieved by forward bending to the affected side

4. Fracture of cartilage or dislocation of costochondral joint

—

Sudden sharp pain from fracture or dislocation followed by continuous dull aching, burning discomfort in area of costal margin; reference to back

D. Lesions or disorders of the sternum 1. Fracture of sternum —

2. Rheumatoid arthritis or osteoarthritis

—

3. Xiphoidalgia (hypersensitive xiphoid syndrome, xiphodynia)

—

Localized pain in region of sternum, usually sharp initially but then continuous and aching; aggravated by deep breathing or palpation Continuous or intermittent pain localized to the angle of Louis; aggravated by deep breathing, coughing, sneezing, and yawning Spontaneous deep aching or sharp pain varying in intensity from a slight to agonizing discomfort that simulates pain of myocardial infarction; aggravated by movements that act on xiphoid process (e.g., bending, stooping, turning)

3732

flexed finger under costal cartilage and exerting pressure anteriorly produces clicking noise History of injury; tenderness on palpation; displaced cartilage is palpable and feels like lump

History of blunt trauma to anterior chest; tenderness to palpation; leads to manubriosternal arthralgia Mild swelling of joint; exquisite tenderness to palpation; systemic arthritis present; radiographic evidence of arthropathy Pressure on xiphoid process produces spontaneous pain that can radiate deep retrosternally and to the precordium, epigastrium, and across shoulder and back; persists for weeks or months but usually

4. Arthritis of sternoclavicular joint

E. Muscle disorders 1. Myofascial pain syndromes with trigger points a. Anterior chest (major and minor, pectoralis; scaleni; sternalis; intercostals)

b. Lateral chest (serratus anterior; intercostals)

and by increase in intragastric pressure caused by a large meal; can be constant or recurs several times a day; lasts for minutes to several hours Localized sharp or aching pain in region of joint; radiation to shoulder and upper chest

—

—

Frequent cause of pain in anterior chest; pain is deep and aching; aggravated by activity; sternalis and pectoralis pain can simulate pain of angina pectoris; pain relieved by injection of trigger points with local anesthetic Deep aching pain on the lateral aspect of the chest extending from the lower axilla to about the seventh to the sixth ribs; pain also in area near the inferior angle of the scapula; with intercostal syndrome site of pain varies with site of trigger points; relief with trigger point

—

3733

disappears spontaneously

Joint swollen, tender on palpation; radiographic evidence

History of severe strain by heavy lifting; local tenderness, trigger points present; unaffected body activity

Localized tenderness and trigger point about the level of the sixth rib; pressure on trigger points produces spontaneous pain

injection Deep aching pain in different parts of the back depending on the site of the trigger point and the muscles involved; aggravated by activity of muscles, unaffected by bodily activity Sharp localized pain in area of the spastic muscle; some radiation to anterior and posterior chest; complete relief with infiltration of muscle Constant deep aching pain, often associated with early spondylosis

c. Posterior chest (rhomboidei, latissimus dorsi multifidi, serratus posterior superior, iliocostalis thoracis)

—

2. Acute muscle spasm

—

3. Muscle contractures

—

4. Dermatomyositis and polymyositis

—

Rarely a cause of chest pain; when present, pain aching and aggravated by palpation

—

Sharp burning pain following burns, aching pain with trauma Fairly localized sharp, burning, aching pain primarily at the site of incision; can radiate to involve adjacent segments

VII. Pain of tegumentary origin (including the breast) A. Acute disorders 1. Burns and other trauma

2. Postoperative pain

—

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Localized tenderness and trigger points

Palpation of spastic muscle; generalized tenderness

Possible localized tenderness of affected muscle or in an area of reference Generalized weakness; elevated serum levels of skeletal muscle enzyme

History of injury or burn; emotional reactions Reflex muscle spasm, tenderness; hyperalgesia; tachycardia response; signs of neuroendocrine stress

3. Acute mastodynia (inflammatory)

4. Deep axillary abscess

5. Acute dermatologic disorders (vesicles, furuncles, bullae, pustules, ulcers, erythema, cellulitis) B. Chronic disorders 1. Postmastectomy syndrome

—

2. Postthoracotomy syndrome

3. Adiposis dolorosa

Sharp, aching, burning pain in chest; radiation to axilla and inner arm; aggravated by movement of the breast Sharp localized, diffuse dull, aching pain in axilla; radiation to anterior chest and medial arm Aching, burning, itching pain localized to lesion

Extreme tenderness, tumefaction; evidence of infection

Sharp, burning, aching pain and tingling in the chest wall, armpit or arm sometimes associated with numbness or unbearable itching.

Hyperesthesia, hyperalgesia, hypesthesia, paresthesia; neuroma often palpable; evidence of recurrent cancer by use of CT scan or other diagnostic procedures Hyperesthesia, hyperalgesia, hypesthesia, paresthesia; neuroma often palpable; evidence of recurrent cancer by use of CT scan or other diagnostic procedures

Sharp, burning, aching pain; accompanied by bouts of lancinating pain in distribution of the dermatomes supplied by the injured nerve or in part of the segment; aggravated by light touch of skin, palpation of neuroma, and emotional stress Enlarged painful fatty

—

3735

Tenderness, fluctuating mass; signs of infection

Possible evidence of local or systemic disease

Usually occurs in

(Dercum disease)

4. Chronic mastalgia

—

5. Scleroderma (dermatomyositis, disseminating lupus erythematosus, polyarteritis nodosa)

—

subcutaneous nodule most commonly in the chest and arms but can affect any part except the face; usually darting, shooting, or stabbing pain; occurs spontaneously or provoked by palpation Chronic persistent pain; cyclic in twothirds of patients and continuous in the other third; deep, aching, diffuse pain over entire breast without palpable evidence of pathology; about 20% have spontaneous intermittent relief, whereas others have relief at menopause or pregnancy or with use of oral contraceptives; those with noncyclic pain have pain that can persist for 2–3 y or for as long as 30 y Dull, aching, occasionally burning pain in the chest wall, usually in the area of the lesion; with scleroderma, chest pain can arise from skin, thoracic wall, or myocardial or

3736

obese women; weakness, fatigue, emotional instability, occasional dementia

Psychological tests usually reveal no abnormality; positive response to hormonal manipulation suggests a hormonal basis to the condition

Symptoms and signs of systemic disease; many types produce widespread visceral involvement

6. Other chronic dermatologic diseases 7. Mondor disease (phlebitis of anterolateral chest)

C. Cancer of the breast

esophageal lesions (See Chapter 31 for detailed discussion) Rare condition manifested by thrombosis of superficial vein of thoracic wall that produces palpable painful cord within the skin; usually sharp and persistent; intensified by deep inspiration or flexion of the trunk Early breast cancer not painful; in far advanced disease, skin nodule eventually breaks down and formation also causes localized breast pain; metastasis to the pleura produces pleuritic pain; metastasis to the ribs causes localized pain and can be associated with segmental neuralgia; metastasis to the spine produces back pain and later can cause epidural spinal cord compression or plexopathy

—

—

—

VIII. Chest pain referred from extrathoracic disorders A. Disorders of the cervical spine that cause neuropathy 1. Posterolateral

Pain in the neck,

3737

Presence of painful, tender, subcutaneous cord running obliquely across thorax in distribution of one or more superficial veins; lesion indolent after several weeks Early: retracted nipple, bleeding, distorted areola or breast contour, skin dimpling (peau d’orange); later: axillary supraclavicular adenopathy; metastatic lesion demonstrated by radiography and CT scan

Paravertebral and

protrusion of intervertebral disk (C7, C8)

2. Arthritis, osteophyte, fracture or other lesion that compresses root or nerve 3. Thoracic inlet syndromes (scalenus anticus syndrome; cervical rib or abnormal first rib; costoclavicular compression)

4. Pancoast syndrome

shoulder, medial aspect of the arm, and pectoral region of the chest; with left-sided lesion, pain can simulate that of myocardial ischemia but is differentiated by aggravation by lateral flexion and the Spurling test (see Chapter 54); unaffected by activity if neck and arms not moved

—

Pain most prominent in the shoulder and upper limbs; radiation to the upper pectoral region; aggravated by severe arm abduction and walking with swinging arms; unaffected by activity if arms not moved Pain in shoulder, scapula, medial aspect of arm, and superior anterior chest; aggravated by extreme abduction of the arm and paravertebral pressure; unaffected by activity if neck and limbs are not moved

—

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pectoral muscle tenderness; hyperalgesia, hyperesthesia, and paresthesia of the arm; decrease in reflexes and some muscle weakness in the upper limbs

Supraclavicular (scaleni) tenderness and fullness; neurovascular signs and symptoms in the upper extremities; radiographic evidence of abnormal cervical rib Signs and symptoms of plexopathy with paresthesia, dysesthesia, numbness in the medial aspects of the forearm and fourth and fifth fingers, also medial aspect of arm; marked weakness of muscles supplied

by ulnar nerve; radiographic and CT scan evidence of lesion B. Diseases of the abdominal viscera 1. Gas entrapment syndromes (e.g., caused by aerophagia, excess production of gas in bowel)

—

2. Peptic ulcer disease

—

3. Perforated ulcer

—

Bloated sensation associated with pain in the epigastrium and central lower chest; if diaphragm irritated, pain also in shoulder; dull, aching pain worsens as day progresses; transiently relieved by belching; gas entrapment in hepatic flexure of colon produces discomfort in right upper quadrant and lower part of right chest, gas in splenic flexure causes pain in left upper quadrant and left lower chest Ulcer in cardia of stomach produces pain in the epigastrium and central lower anterior chest, ulcer in other locations not associated with chest pain; duodenal ulcer causes pain that radiates to xiphoid process but not higher Sudden severe epigastric pain that

3739

History of aerophagia, abdominal tympany; radiographic evidence

Peptic ulcer confirmed by radiography and endoscopy

History, physical signs (e.g.,

4. Biliary colic

—

5. Acute cholecystitis

—

6. Acute pancreatitis

—

can radiate to lower chest with severe hypotension; myocardial ischemia; anginal pain Sudden moderate to severe epigastric pain; radiation to back; right subcostal region and low central portion of right chest; rarely, pain confined only to chest mimicking that of myocardial infarction, but no radiation to arm or jaw Pain usually localized to right upper quadrant; lasts few days rather than a few hours; chest pain rare except in patients with coexisting coronary artery disease: in these patients, biliary pain provokes angina pectoris and ECG changes (low amplitude and inversion of T wave) Sudden severe epigastric pain associated with retrosternal oppression; radiation to lower part of left side of chest; unaffected by effort; often provokes ECG

3740

muscle spasm, shock, diaphoresis, hematemesis)

Patient can have nausea but no vomiting; in distress but no fever; subcostal tenderness

Nausea, vomiting, fever, jaundice, and tender right upper quadrant mass; abdominal muscle spasm

Severe abdominal muscle spasm; often hypotension, hypoventilation, elevated blood amylase level

7. Subphrenic abscess

IX. Chest pain primarily of psychological origin A. Acute anxiety state

B. Chronic anxiety (cardiac neurosis, soldier’s heart, neurocirculatory asthenia, irritable heart, effort syndrome)

changes similar to those of myocardial ischemia and infarction Pus from perforated viscus produces subdiaphragmatic abscess with inflammation of the diaphragm; pleuritic pain in the lower chest and often the shoulder; intrapleural rupture of amebic liver abscess; sudden severe chest pain

—

—

Sudden acute diffuse pain in chest in the precordial region near cardiac apex (not retrosternal); severe, sharp, stabbing pain or dull, heavy pressure experienced after effort, not during

—

Pain usually at apex of the heart; felt as dull ache with or without attacks of sharp pain over same area; either of brief duration or continuous for hours and days; associated with fatigue rather than effort; responds

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Dyspnea, fever, pleural effusion and, occasionally, hepatomegaly

Dyspnea (air hunger) leading to hyperventilation, tachycardia, dizziness, palpitations, perspiration, tremor, weakness, chest tightness; psychological evaluation and testing reveal evidence of anxiety Chronic anxiety and apprehension; severe dyspnea; respiratory distress both at rest and with exertion, sighing respirations; possible ECG changes; low energy level;

poorly to all medication

C. Depression

—

Endogenous depression can cause atypical chest pain described as a heavy feeling or deep ache or tightness; possible radiation to left arm; usually worse in the morning, lessens as the day goes on

D. Hypochondriasis

—

Precordial or apical pain; pain described by patient in minute detail regarding location, quality, and duration but does not fit pattern of any organic disease, and description of the pain changes from one visit to another

E. Operant pain (learned pain)

—

Initially, patient has chest pain from disease of the heart or lungs that persists after

3742

psychological evaluation and testing reveal psychopathology Feeling of overconcern with the heart; in primary affective disorder, patient complains of feelings of depression, guilt, worthlessness, withdrawal, disinterest; occasional suicidal preoccupation, anorexia, weight loss, fatigue, low energy level, malaise, insomnia; psychological evaluation and testing reveal psychopathology Feeling of overconcern with the heart; many other complaints (e.g., dysfunction of gastrointestinal tract); may present different complaints at different visits; psychological evaluation and testing produces evidence of psychopathology Progressive physical deterioration over time because of

healing because of reinforcing environmental factors; develops chronic pain behavior and abnormal illness behavior

inactivity, muscle weakness, and other factors that cause pain and reinforce the behavior; psychological evaluation and testing reveal psychopathology

CNS, central nervous system; CSF, cerebrospinal fluid; CT, computed tomography; ECG, electrocardiogram; PO2, partial pressure of oxygen; a

See Table 2.2.

Our growing treatment armamentarium includes analgesic and neuropathic medications, nerve blocks and ablations, joint injections, implanted pumps, and transcutaneous or implanted peripheral or dorsal column stimulators as well as behavioral medicine approaches. In recent years, portable ultrasound has become an easily accessible, user-friendly tool in diagnosis and interventional treatment of chest wall pain. In most cases of chest wall pain, conservative, multidisciplinary approaches are initially preferred, saving invasive treatments for the more refractory cases. References 1. Snell RS, ed. The thorax: part I—the thoracic wall. In: Clinical Anatomy by Regions. 8th ed. Philadelphia: Lippincott Williams & Wilkins; 2007:45–73. 2. Standring S, ed. Gray’s Anatomy: The Anatomical Basis of Clinical Practice. 39th ed. London: Churchill Livingstone; 2005:951–968. 3. Sanders RJ. Thoracic Outlet Syndrome. Philadelphia: Lippincott; 1991. 4. Schaumburg HH, Berger AR, Thomas PK. Disorders of Peripheral Nerves. 2nd ed. Philadelphia: FA Davis; 1992. 5. White JC. Cardiac pain: anatomic pathways and physiologic mechanisms. Circulation 1957;16:644–655. 6. Watson PN, Evans RJ. Intractable pain with lung cancer. Pain 1987;29:163–173. 7. Pancoast HK. Superior pulmonary sulcus tumor. JAMA 1932;99:1391–1394. 8. Hepper NGG. Thoracic inlet tumors. Ann Int Med 1966;64:979–989. 9. Kori S, Foley KM, Posner JB. Brachial plexus lesions in patients with cancer: clinical findings in 100 cases. Neurology 1981;31:45–50. 10. Gilbert RW, Kim JH, Posner JB. Epidural spinal cord compression from metastatic tumor. Ann Neurol 1978;3:40–51. 11. Posner JB. Back pain and epidural spinal cord compression. Med Clin North Am 1987;71:185–205.

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86. Resnick CS, Ammann AM. Cervical spine involvement in sternoclavicular hyperostosis. Spine 1985;10:846–848. 87. Dastgeer GM, Mikolich DJ. Fracture-dislocation of manubriosternal joint: an unusual complication of seizures. J Trauma 1987;27:91–93. 88. Doube A, Clarke AK. Symptomatic manubriosternal joint involvement in rheumatoid arthritis. Ann Rheum Dis 1989;48:516–517. 89. Kernodle GW Jr, Allen NB. Acute gout presenting in the manubriosternal joint. Arthritis Rheum 1986;29:570–572. 90. Sebes JI, Salazar JE. The manubriosternal joint in rheumatoid disease. Am J Roentgenol 1983;140:117–121. 91. Gruber BL, Kaufman LD, Gorevic PD. Septic arthritis involving manubriosternal joint. J Rheumatol 1985;12:803–804. 92. Van Linthoudt D, De Torrente A, Humair L, et al. Septic manubriosternal arthritis in a patient with Reiter’s disease. Clin Rheumatol 1987;6:293–295. 93. Parker VS, Malhotra CM, Ho G Jr, et al. Radiographic appearance of the sternomanubrial joint in arthritis and related conditions. Radiology 1984;153:343–347. 94. Lipkin M, Fulton LA, Wolfson EA. Xiphoidalgia syndrome. N Engl J Med 1955;253:591– 597. 95. Howell JM. Xiphodynia. J Emerg Med 1992;10:435–438. 96. Miller AJ, Texidor TA. Precordial catch: a neglected syndrome of precordial pain. JAMA 1955;159:1364–1365. 97. Reynolds JL. Precordial catch syndrome in children. South Med J 1989;82:1228–1230. 98. Hopkins JH. Bornholm disease. BMJ 1950;27:1230–1232. 99. Preece PE, Mansel RE, Bolton PM et al. Clinical syndromes of mastalgia. Lancet 1976;2:670– 673. 100. Wisbey JR, Kumar S, Mansel RE, et al. Natural history of breast pain. Lancet 1983;2:672– 674. 101. Preece PE, Mansel RE, Hughes LE. Mastalgia: psychoneurosis or organic disease? BMJ 1978;1:29–30. 102. Mansel RE, Preece PE, Hughes LE. A double blind trial of prolactin inhibitor bromocriptine in painful benign breast disease. Br J Surg 1978;65:724–727. 103. Mansel RE, Wisbey JR, Hughes LE. Controlled trial of the antigonadotropin danazol in painful nodular benign breast disease. Lancet 1982;1:928–930. 104. Gately CA, Maddox PR, Mansel RE, et al. Mastalgia refractory to drug treatment. Br J Surg 1990;77:1110–1112. 105. Khan HN, Rampaul R, Blamey RW. Local anesthetic and steroid combined injection therapy in the management of non-cyclical mastalgia. Breast 2004;13:129–132. 106. Petersen P, Kastrup J. Dercum’s disease (adiposis dolorosa). Treatment of severe pain with intravenous lidocaine. Pain 1987;28:77–80. 107. Lunn GM, Potter JM. Mondor’s disease. BMJ 1954;1:1074–1076. 108. Cooper RA. Mondor’s disease secondary to intravenous drug abuse. Arch Surg 1990;125:807–808. 109. Camiel MR. Mondor’s disease in the breast. Am J Obstet Gynecol 1985;152:879–881. 110. Stevens PE, Dibble SL, Miaskowski C. Prevalence, characteristics and impact of postmastectomy pain syndrome: an investigation of women’s experiences. Pain 1995;61:61– 68. 111. Carpenter JS, Andrykowski MA, Sloan P, et al. Post mastectomy and post lumpectomy pain in breast cancer survivors. J Clin Epedemiol 1998;51:1285. 112. Vecht CJ, Vande Brand HJ, Wajer OJ. Post-axillary dissection pain in breast cancer due to a

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135. Kirvela O, Antila H. Thoracic paravertebral block in chronic postoperative pain. Reg Anesth 1992;17:348–350. 136. Kamakar MK. Thoracic paravertebral block. Anesthesiology 2001;95:771–780. 137. Cohen SP, Sireci A, Wu CL, et al. Pulsed radiofrequency of the dorsal root ganglia is superior to pharmacotherapy or pulsed radiofrequency of the intercostal nerves in the treatment of chronic postsurgical thoracic pain. Pain Physician 2006;9:227–236. 138. Meek JC, Bollen E, Koudstaal J, et al. Pain in scar as an early symptom of acquired thoracic lung hernia. Eur Respir J 1991;4:505–507. 139. Fitzpatrick C, Coppola CP, Eichelberger MR. Intercostal hernia and spontaneous pneumothorax in a liver transplant recipient: a case report. J Pediatr Surg 2007;42:E5–E8. 140. Eisenberg E, Pultorak Y, Pud D, et al. Prevalence and characteristics of post coronary artery bypass graft surgery pain (PCP). Pain 2001;92:11–17. 141. Bruce J, Drury N, Poobalan AS, et al. The prevalence of chronic chest and leg pain following cardiac surgery: a historical cohort study. Pain 2003;104:265–273. 142. Mailis A, Umana M, Feindel CM. Anterior intercostal nerve damage after coronary artery bypass graft surgery with use of internal thoracic artery graft. Ann Thorac Surg 2000;69:1455–1488. 143. Norgaard MA, Andersen TC, Lavrsen MJ, et al. The outcome of sternal wire removal on persistent anterior chest wall pain after median sternotomy. Eur J Cardiothorac Surg 2006;29:920–924. 144. Billings RF. Chest pain related to emotional disorders. In: Levine DL, Billings RF, eds. Chest Pain: An Integrated Diagnostic Approach. Philadelphia: Lea & Febiger; 1977:133–150. 145. Mukerji B, Mukerji V, Alpert MA, et al. The prevalence of rheumatologic disorders in patients with chest pain and angiographically normal coronary arteries. Angiology 1995;46:425–430. 146. Wise CM, Semble EL, Dalton CB. Musculoskeletal chest wall syndromes in patients with noncardiac chest pain: a study of 100 patients. Arch Phys Med Rehabil 1992;73:147–149. 147. Vaisrub S. Da costa syndrome revisited [editorial]. JAMA 1975;232:164. 148. Wheeler EO, White PD, Reed EW, et al. Neurocirculatory asthenia (anxiety, neurosis, effort syndrome, neurasthenia): a 20-year follow-up study of 173 patients. JAMA 1950;142:878– 889. 149. Borjesson M, Andrell P, Lundberg D, et al. Spinal cord stimulation in severe angina pectoris —a systematic review based on the Swedish Council on Technology assessment in health care report on long-standing pain. Pain 2008;140:501–508. 150. Di Pede F, Lanza GA, Zuin G, et al. Immediate and long-term clinical outcome after spinal cord stimulation for refractory stable angina pectoris. Am J Cardiol 2003;91:951–955. 151. Fox K, Garcia MAA, Ardissino D, et al. Guidelines on the management of stable angina pectoris: the Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology. Eur Heart J 2006;27(11):1341–1381. 152. Anderson C, Hole P, OXhoj H. Does pain relief with spinal cord stimulation for angina conceal myocardial infarction. Br Heart J 1994;71:419–421.

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CHAPTER 70 Lower Extremity Pain GAGAN MAHAJAN and DAVE LOOMBA The information in this chapter is presented in three major sections detailing (1) specific causes of lumbosacral plexopathy, (2) specific lower extremity peripheral nerve lesions, and (3) specific causes of foot pain.

Lumbosacral Plexopathy Although the lumbar and sacral plexuses are separate structures, they are often referred to as a single structure—the lumbosacral plexus—that provides motor and sensory innervation to the pelvis and leg (Fig. 70.1). The lumbar plexus, which is made up of the ventral rami of the T12–L3 and a portion of the L4 nerve roots, is contained within the psoas muscle and lies anterior to the L2–L5 vertebral bodies.1–3 The anterior and posterior divisions of the ventral rami form the terminal branches of the lumbar plexus and include the iliohypogastric (T12, L1), ilioinguinal (L1), genitofemoral (L1, L2), lateral femoral cutaneous (L2, L3), obturator nerves (L2, L3, L4), and femoral (L2, L3, L4) nerves.3 The saphenous nerve is a branch of the femoral nerve.

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FIGURE 70.1 A: Anatomy of the lumbosacral plexus. Anterior (B) and posterior (C) views of cutaneous innervation of the lumbosacral plexus.

The sacral plexus (Fig. 70.2), which is made up of the ventral rami of the S1–S5 nerve roots, connects with the lumbar plexus via the lumbosacral trunk. It is made up of the ventral rami of the L4–L5 nerve roots and lies just anterior to the piriformis muscle, posterior to the internal iliac vessels, and in close proximity to the hypogastric arteries and veins, lateral rectum, pelvic colon, and ureters.2,3 Similar to the lumbar plexus, terminal branches arise from the anterior and posterior divisions of the ventral rami of the sacral plexus. The tibial nerve (made up of the anterior divisions of the ventral rami) and the common fibular (peroneal) nerve 3751

(made up of the posterior divisions) form the terminal branches of the sciatic nerve on bifurcating from their common epineural sheath.3 Additional terminal branches of the sacral plexus include the superior gluteal (L4, L5, S1), inferior gluteal (L5, S1, S2), posterior femoral cutaneous (S1, S2, S3), and pudendal (S2, S3, S4) nerves.3

FIGURE 70.2 Oblique sagittal view of the sacral plexus.

There are multiple causes of lumbosacral plexopathy. These include space-occupying masses (invasive neoplasm, compression by retroperitoneal or pelvic mass), vascular/metabolic diseases (diabetes, chronic idiopathic peripheral polyneuropathy, vasculitis, aneurysmal dilation), trauma (pelvic fractures, complications from surgery or radiation therapy), and idiopathic causes.4 Nontraumatic lesions are the most common, as evidenced by one report of 86 cases revealing a neoplastic etiology in more than 50% and trauma in only 6%.3 Patellar reflex impairment along with hip flexion, knee extension, and/or dorsiflexion 3752

weakness suggests lumbar plexopathy, whereas ankle reflex impairment along with hip extension, knee flexion, and/or plantarflexion weakness suggests sacral plexopathy. Depending on the cause, diagnostic workup for plexopathy can include plain film x-ray imaging, detailed neuroimaging (computed tomography [CT] and magnetic resonance imaging [MRI]), angiography, ultrasonography, electrodiagnostic studies (electromyography [EMG] and nerve conduction study [NCS]), and laboratory studies. Diagnostic studies in isolation of the patient’s medical history and physical exam findings, however, have limitations. For example, neuroimaging may not be able to differentiate between benign tumor versus malignant tumor versus radiation-induced plexopathy. Likewise, electrodiagnostic studies may not be able to differentiate between peripheral neuropathy versus plexopathy.3 Electrodiagnostic studies, however, may be able to provide information on the extent of motor axon loss or on the presence of muscle denervation when clinical assessment is limited by the cause of injury. Treatment options depend on the cause, location, symptom severity, physical exam findings, and duration of the plexopathy.3 In certain situations, surgery may be the initial treatment of choice, whereas in other circumstances, observation and symptom management may be the preferred approach. Conservative therapy for symptomatic relief includes medications (corticosteroids, acetaminophen, nonsteroidal antiinflammatory drugs [NSAIDs], anticonvulsants, tricyclic antidepressants, opioids, topical analgesics, and lidocaine patch) and injections. Spinal cord stimulation or intrathecal therapies may be considered for those who have a suboptimal response to the aforementioned and/or those who are not surgical candidates. Physical therapy is important for those with evidence of motor weakness in order to minimize muscle atrophy, prevent muscle contractures, and maintain ambulatory status. Assessment for orthotic devices (e.g., ankle-foot orthosis [AFO]) and gait assistive devices (e.g., crutches, cane, walker) also may be necessary in order to prevent falls.

NEOPLASMS In comparison to neoplastic involvement of the lumbosacral spinal nerves, cauda equina, or conus medullaris, lumbosacral plexus involvement is 3753

relatively uncommon and has a reported incidence of 0.71%.5,6 Neoplastic plexopathies can involve the sacral plexus (50%), lumbar plexus (33%), or lumbosacral plexus (17%).3,7 Most are of malignant origin, with 75% occurring by direct extension (most commonly from gastrointestinal tumors, genitourinary tumors lymphomas, sarcomas), or metastasis.3,5 Breast cancer is the most common primary source, and rarely is the diagnosis of neoplastic plexopathy made before discovery of the primary neoplasm. Neoplastic plexus involvement portends a poor prognosis, with death often occurring within 6 months of diagnosis.5 Insidious onset of low back pain (lumbar plexus) and/or leg pain (sacral plexus) are often the primary heralding features and can precede other neurologic symptoms.1,3,5,7 At initial onset, unilateral leg pain is present in 90% of patients and tends to be more prominent than low back pain.8 The pain can have both nociceptive and neuropathic features and is worse with recumbency, movement, and Valsalva maneuvers.1 Lumbar plexus involvement, also known as malignant psoas syndrome, is suggested by localization of pain over the costovertebral angle, anterior abdominal wall, groin, or thigh and by painful fixed flexion of the hip worsened by passive or active hip.1,9,10 Within 13 months of pain onset, many patients develop additional neurologic symptoms: weakness (86%), gait dysfunction, sensory loss (73%), reflex impairment (64%), and paroxysmal or continuous paresthesias or dysesthesias.1,3,5,6,8 Additional physical exam findings may include (1) lower extremity edema (seen in 50%), (2) warm and dry foot (seen with sympathetic nerve involvement), (3) palpable rectal mass and perineal pain (seen in more than one-third with sacral involvement), (4) incontinence and impotence (seen in 10%, usually implying extensive sacral involvement with bilateral sacral plexopathy), and (5) abdominal and pelvic pain.1,3,6,11 The differential diagnosis, however, must also include radiation-induced plexopathy, peripheral neuropathy, radiculopathy, cauda equina syndrome, retroperitoneal hematoma, and vertebral compression fracture.1 Tumors can be broadly classified as intrinsic or extrinsic. Intrinsic tumors can be benign (e.g., neurofibromas and plexiform lesions) or malignant (e.g., schwannomas or neurogenic sarcomas).1 Neurofibromas, 3754

which are common in patients with neurofibromatosis type 1, are commonly seen in the paraspinal, sacral plexus, sciatic notch, and perirectal regions.12 Patients may or may not have symptoms with benign or malignant tumors, and an MRI alone may be insufficient to differentiate one from the other. Symptomatic relief with analgesic medications may be necessary until the tumor can be excised. Extrinsic tumors are malignant. Lymphoma can cause a plexopathy due to enlarged lymph nodes (most common), extranodal disease in the muscle (e.g., psoas, iliacus, piriformis, and gluteal muscles) or subcutaneous fat, or direct sciatic nerve involvement (rare).2 Carcinomas (colorectal, genitourinary, breast, lung, and prostate) and retroperitoneal sarcomas can cause a plexopathy by encasement of the plexus by the primary tumor itself, metastasis into the surrounding soft and bony tissue, or metastasis into the plexus itself.1,2 Sacral chordomas, which can cause constipation, urinary frequency, and sciatica, are the most common primary malignant sacral tumors.2 Imaging with MRI, CT, or positron emission tomography computed tomography (PET-CT) may help with the workup of these extrinsic tumors. Chemotherapy, radiation therapy, and/or surgical resection of the tumor is usually indicated.

RADIATION-INDUCED PLEXOPATHY Pelvic radiation therapy to treat urologic cancers, gynecologic cancers, and lymphomas can result in radiation-induced lumbar, sacral, or lumbosacral plexopathy. Unlike neoplastic plexopathy, which is often associated with significant pain and weakness, radiation plexopathy is primarily associated with weakness, with significant pain being present in fewer than 25% of patients.8 Weakness is noted predominantly in the distal L5–S1 innervated muscles and may be accompanied by reflex and sensory impairment, skin changes, and lymphedema; bowel or bladder disturbance is rare.8,11 The mean duration of symptom onset is 5 years but can vary from a few months to more than three decades.3,11 Skin changes and lymphedema are commonly seen.8 Because of obvious therapeutic implications, neuroimaging studies are critically important in order to discriminate between tumor recurrence, radiation fibrosis, and surgical scar tissue. Electrodiagnostic studies should be included to help establish the diagnosis 3755

when neuroimaging findings are nonspecific. Characteristic electrodiagnostic findings include demyelinating conduction block and myokymia.3 If electrodiagnostic findings are also nonspecific, the diagnosis usually needs to be confirmed by biopsy or surgical exploration. For those with only radiation-induced plexopathy, treatment is nonsurgical and involves symptom management.3

DIABETIC AND NONDIABETIC LUMBOSACRAL RADICULOPLEXUS Diabetic lumbosacral radiculoplexus (diabetic amyotrophy) involves microvasculitic ischemic nerve injury. It most commonly occurs in elderly patients with chronic type 2 diabetes mellitus and does not occur in isolation of diabetic peripheral polyneuropathy.3 Patients usually report weight loss and low back and/or leg pain that is worse at night. These symptoms are often followed by signs of weakness, atrophy, and sensory deficits involving the anterior thigh along with an absent patellar reflex. Electrodiagnostic findings include axonal loss, demyelination, and denervation changes in muscles innervated by the obturator and femoral nerves.3 Neuroimaging is necessary to rule out other potential causes of lumbosacral plexopathy. Because the plexopathy is due to ischemic nerve injury, treatment focuses on symptom management, physical therapy, and assessment for a gait assistive device. Nondiabetic lumbosacral radiculoplexus is an underappreciated cause of lumbosacral plexopathy. Similar to diabetic lumbosacral radiculoplexus, nondiabetic lumbosacral radiculoplexus involves microvasculitic (motor, sensory, and autonomic) nerve injury; initially involves the legs; and is associated with pain, weight loss, prolonged morbidity and mortality, and incomplete recovery.13 Both nondiabetic and diabetic lumbosacral radiculoplexus also share similar electrodiagnostic findings and treatment strategies. Unlike diabetic lumbosacral radiculoplexus, however, nondiabetic lumbosacral radiculoplexus is not associated with hyperglycemia and is probably due to an autoimmune phenomenon.13

ABSCESS Psoas, gluteal, and pelvic abscesses can present acutely or insidiously with 3756

painful fixed flexion of the hip or pain in the abdominal, pelvic, or gluteal regions. In their retrospective analysis of 23 retroperitoneal collections related to the psoas muscle, Paley et al.14 confirmed 5 were hematomas and 18 were abscesses, and of the abscesses, 3 were caused by primary infections and the remainder by infections of spinal, renal, or gastrointestinal origin. Because their appearance on MRI and CT can be confused with lymphoma or tumor deposits, image-guided percutaneous drainage can be of diagnostic and therapeutic value.2

RETROPERITONEAL HEMATOMA Retroperitoneal hematomas can occur from anticoagulant therapy, hemophilia, ruptured aortic aneurysms, idiopathically, or iatrogenically (e.g., cardiac catheterization).15 The degree of neurologic deficit depends on the size of the hematoma: (1) A small hematoma compresses the intrapelvic portion of the femoral nerve within the iliacus muscle; (2) a large hematoma compresses the lumbar plexus within the psoas muscle, affecting both the obturator and femoral nerves; and (3) a widespread hematoma affects the lumbosacral plexus.2 Signs and symptoms may include ecchymosis (flank, low back, and/or thigh) and acute or subacute onset of lower abdominal or groin pain radiating to the anterior thigh. Neuroimaging facilitates the diagnosis. EMG and NCS findings include abnormalities in the adductor muscle and axonal loss in the distribution of the femoral nerve or lumbar plexus (although involvement of the lumbosacral plexus can also occur).3 Even though retroperitoneal hematomas are considered compartment syndromes, treatment is nonsurgical.3

ANEURYSMS Aneurysms of the distal aorta, iliac arteries, intrapelvic arteries, and hypogastric arteries and arteriovenous malformations can injure the lumbosacral plexus via direct compression or ischemia from embolism of feeding vessels.2,3 Symptoms may include low back pain with or without radicular symptoms, sensory loss, and weakness. The initial diagnostic workup includes an abdominal and pelvic ultrasound, followed by neuroimaging and angiography. The electrodiagnostic finding includes 3757

axonal loss, but pinpointing the location is often challenging.3 Treatment involves surgical repair of the aneurysm.

TRAUMA Traumatic injuries to the lumbosacral plexus, in comparison to the brachial plexus, occur infrequently because the neural structures are (1) relatively distant to highly mobile structures and (2) well protected by muscle and bone.3 Therefore, trauma-induced lumbosacral plexopathy typically results from penetrating or violent injuries—gunshot blast, high-speed motor vehicle or motorcycle accident, pedestrian versus motor vehicle accident, or fall from a tall height—and is often associated with pelvic bony fractures. Isolated fractures involving the non–weight-bearing anterior one-third of the pelvic ring are often stable and do not result in neurovascular injury. Conversely, because the posterolateral two-thirds of the pelvic ring is involved with weight bearing and lays in close proximity to neurovascular structures, fractures in this area lead to instability and neurovascular compromise.3 Symptoms can include variable degrees of pain, sensory and reflex impairment, muscle weakness, atrophy, and gait abnormality. Treatment involves identifying the extent of neurovascular injury. Because most nerve traumatic injuries spontaneously improve (to a certain degree) and surgical repair can be technically challenging, surgery is not recommend as the initial treatment of choice.3 Of those who do require surgery, outcomes are relatively better with repair of the lumbar instead of sacral plexus.3 Neuropathic pain persisting beyond the anticipated healing process suggests the presence of a neuroma or scar tissue. Treatment may involve additional surgery to remove the neuroma or scar tissue, medication management, or implantation of a spinal cord or peripheral nerve stimulator.

OBSTETRIC-RELATED PLEXOPATHY Compression of the lumbosacral plexus between the pelvic rim and fetal head can occur during the latter stages of pregnancy or during delivery (Fig. 70.3).3 Katirji et al.16 described seven patients with intrapartum maternal lumbosacral plexopathy who shared common features: short maternal stature, prolonged labor, pain and demyelination in an L5 nerve 3758

root distribution, foot drop, and complete resolution of symptoms within 5 months. A large fetal head or the use of forceps can also cause compression of the lumbosacral plexus. Neuroimaging may be of limited benefit when the fetus is present. EMG and NCS abnormalities include abnormalities in muscles innervated by the L5 nerve root and a demyelinating conduction block of nerves supplying the muscles of the anterolateral leg.3 Aside from delivery of the fetus, treatment is nonsurgical.3

FIGURE 70.3 A–C: Site of nerve compression (circle) in intrapartum maternal lumbosacral plexopathy. (Reprinted with permission from Katirji B, Wilbourn AJ, Scarberry SL, et al. Intrapartum maternal lumbosacral plexopathy. Muscle Nerve 2002;26[3]:340–347.)

Specific Nerve Entrapment Syndromes LATERAL FEMORAL CUTANEOUS NERVE ENTRAPMENT The lateral femoral cutaneous nerve (LFCN), a purely sensory nerve, 3759

originates from the lumbar plexus and conveys fibers from posterior divisions of the ventral rami of the L2 and L3 nerve roots (Fig. 70.4). Near the anterior superior iliac spine (ASIS), the LFCN divides into anterior and posterior branches and conveys sensory information from the anterolateral and lateral surfaces of the thigh, respectively. Compression of the LFCN most commonly occurs as the nerve exits the pelvis and pierces or crosses the inguinal ligament and attaches to the ASIS.17 Entrapment of the LFCN, also known as lateral femoral cutaneous neuralgia, was first characterized by Bernhard in 1878. In 1895, Roth coined the name meralgia paresthetica (MP), which is derived from the Greek words meros (meaning thigh) and algos (meaning pain).18,19

FIGURE 70.4 Cutaneous branches of the lateral femoral cutaneous nerve. Anterior (A) view and posterior (B) view.

Although MP is not rare, its exact prevalence remains unknown. It can occur at any age but is most commonly seen in patients 30 to 60 years of age.19,20 After looking at the relationship between comorbidity (e.g., carpal tunnel syndrome, pregnancy, hip osteoarthritis, obesity, symptoms of the pubic bone, thrombosis of the leg, diabetes mellitus, and the use of corticosteroids) and the occurrence of MP, van Slobbe et al.20 concluded the incidence rate of MP is 4.3 per 10,000 person-years. Although probably underdiagnosed in children, it has been seen in as many as onethird of those treated for osteoid osteoma.19 Whether there is a true gender predilection remains unknown, as results vary depending on the study referenced.17,20–23 3760

Etiology Causes of MP have been categorized as spontaneous or iatrogenic.21 Spontaneous causes result from entrapment due to intrapelvic (pregnancy, pelvic or abdominal tumors, uterine fibroids, degenerative pubic symphysis, diverticulitis, and appendicitis), extrapelvic (seatbelt trauma, tight garments or belts, and obesity), or mechanical (prolonged sitting, prolonged standing, and leg length discrepancy) factors or from metabolic derangements (diabetes mellitus, hypothyroidism, alcoholism, and lead poisoning).19,24 The greatest risk factor is obesity.24 Mondelli et al.23 noted that obese patients (body mass index ≥30 kg/m2), but not overweight patients (body mass index 25 to 29.9 kg/m2), showed twofold greater risk for developing MP. Interestingly, some have even reported cases of MP in patients who have lost weight.25,26 Postulated mechanisms may include the presence of other compressive factors, lack of nutritional factors, or underlying systemic disease.23 Iatrogenic causes of MP result from orthopedic procedures (pelvic osteotomy, iliac crest bone graft harvest, spine surgery, and total hip replacement) and nonorthopedic procedures (gastric bypass surgery, laparoscopic inguinal herniorrhaphy, laparoscopic cholecystectomy, laparoscopic myomectomy, coronary artery bypass grafting, aortic valve surgery, and renal transplant).19,26

Symptoms and Signs Although the majority of patients usually complain of unilateral sensory loss, paresthesias, or dysesthesias, the incidence of bilateral symptoms can be as high as 20%.17 The symptoms rarely radiate proximally toward the spine.19 Hair loss over the anterolateral thigh due to constant rubbing may be present.19 Prolonged standing, walking, or hip extension may worsen the symptoms. Hip flexion may alleviate or worsen the symptoms. A Tinel sign (paresthesias radiating to the anterolateral thigh) sometimes can be elicited by percussing medial to the ASIS.23 For those patients in whom inguinal ligament LFCN entrapment is suspected, the pelvic compression test should be performed (Fig. 70.5). With the patient lying in a lateral decubitus position on the unaffected limb, the examiner maintains downward pressure on the pelvis for 45 seconds. Transient improvement of symptoms is considered a positive result.27 Nouraei et al.27 showed this 3761

test had a sensitivity of 95% and a specificity of 93.3% in those with electrodiagnostically proven MP.

FIGURE 70.5 Pelvic compression test. Place the patient in a lateral decubitus position (A) and apply downward pressure on the pelvis for 45 seconds (B). Transient improvement of symptoms is a positive test.

Symptoms extending beyond the territory of the nerve, reflex changes, muscle weakness, or muscle atrophy suggest an alternate diagnosis, such as a lumbar plexopathy, high lumbar radiculopathy, or other peripheral neuropathy.

Diagnosis Imaging and laboratory studies should be considered when a clear cause cannot be identified: radiograph or neuroimaging of the pelvis to rule out pelvic tumor or fracture and neuroimaging of the lumbosacral spine to rule out disk herniation.19 Although electrodiagnostic studies can play a role in the diagnosis of MP, some argue its utility may be hampered by inherent technical difficulty, challenges in obtaining a response in obese patients, and small recordable sensory responses (absent in 71% and prolonged in 24%).24 Furthermore, in order to obtain the best recordings one must use needle electrodes instead of surface electrodes. Others, however, claim that electrodiagnostics should play a central role in diagnosing MP. Instead of strictly looking at the absolute value of the sensory nerve action potential (SNAP) amplitude, Seror and Seror22 demonstrated a specificity of 98.75% in their study of 120 patients when the side-to-side amplitude ratio was greater than 2.3 and the amplitude was less than 3 microvolts. Because the nerve is purely sensory, EMG testing of muscles should be normal. The value of somatosensory-evoked potentials (SSEPs) in making the 3762

diagnosis is debatable.19 Ultimately, the greatest benefit of performing an electrodiagnostic is to rule out other entities—high lumbar radiculopathy, lumbar plexopathy, or other peripheral neuropathy—that can cause similar symptoms.

Treatment Nonsurgical treatment for MP is typically successful, as symptoms are often mild and self-limited. In their study of 277 patients, Williams and Trzil28 reported conservative management was successful in 91% of patients. Initial recommendations include advising patients to avoid wearing tight-fitting garments or belts, advising obese patients to lose weight, and correcting leg-length discrepancies. If symptoms persist, other treatment options include ice, transcutaneous electrical nerve stimulation (TENS) unit, and analgesic medications and injections. Because no controlled studies have been performed, the long-term efficacy of a local anesthetic LFCN block (with or without corticosteroids) is unclear. Furthermore, whether temporary relief of symptoms alters the long-term prognosis is unknown. Using a standard treatment algorithm in 79 patients, Haim et al.17 showed symptomatic improvement in 21 patients requiring conservative therapy and medical management, 48 patients requiring LFCN blocks using corticosteroid and local anesthetic, and 10 patients requiring surgery. At 1-year follow-up, the authors reported none of the patients had recurrence of MP symptoms. Traditionally, the target site of injection is identified based on anatomic landmarks (1 cm medial and 1 cm inferior to the ASIS), with a large volume of medication being injected using a fanning technique. Although large volumes may increase the success rate of blocking the LFCN to obtain useful diagnostic information, it can also come at the risk of inadvertently blocking the femoral and/or obturator nerves. However, absence of immediate analgesia does not necessarily rule out the diagnosis of MP given the LCFN’s anatomic variability and given failure rate of this technique being as high as 60%.29 In a prospective, randomized, crossover study involving 20 patients, the same authors demonstrated a 100% versus 40% success rate with blocking the LFCN using a stimulating needle versus a fanning technique, respectively.29 Ultrasound guidance can also 3763

improve the success rate of identifying the correct nerve. In their study of 20 patients, Tagliafico et al.30 described a technically successful LFCN block in 100% of the patients and no short-term or long-term complications. Similarly, Hurdle et al.31 reported a technically successful LFCN block in their study of 10 patients, 5 of whom were obese. The advantages to using ultrasound-guidance include real-time visualization of the needle position and the adjacent structures, use of lower volumes of injectate, and avoidance of blockage of the femoral and/or obturator nerves.30,31 For those who do not obtain long-term benefit from corticosteroid injections, other treatments that have been tried include cryoanalgesia, pulsed or continuous radiofrequency (RF), alcohol neurolysis, peripheral nerve stimulation, and spinal cord stimulation. The successful outcomes reported in some of these studies need to be interpreted with caution, though, as they tend to be case reports, case series, or retrospective studies.32–35 For those patients whose symptoms are refractory to analgesic medications, LFCN blocks, and neurostimulation, operative interventions may include transecting the LFCN at the level of the inguinal ligament (neurectomy) or incising the inguinal ligament to decompress the LFCN (neurolysis).28 Based on their systematic review of the literature, Payne et al.36 could not identify one treatment as being superior to the other due to the lack of high-quality studies. As with any neurodestructive procedure, there is a risk of nerve injury or neuroma formation.

FEMORAL NERVE ENTRAPMENT The femoral nerve is a sensory (Fig. 70.6) and motor nerve and is the largest nerve of the lumbar plexus. It originates within the psoas muscle and arises from the posterior divisions of the ventral rami of the L2, L3, and L4 nerve roots (see Fig. 70.1A).37 (The anterior divisions of the same nerve roots form the obturator nerve.) In the abdomen, the femoral nerve gives off branches to the iliacus and psoas muscles, and as it passes under the inguinal ligament, it gives off a branch to the pectineus muscle. The nerve then enters the femoral triangle lateral to the femoral artery, and upon exiting the triangle, it splits into an anterior and posterior division. The anterior division provides motor innervation to the sartorius muscle 3764

and sensory innervation (via the medial and intermediate femoral cutaneous nerves) to the anterior thigh as far distally as the knee. The posterior division provides motor innervation to the quadriceps muscles (rectus femoris, vastus lateralis, vastus intermedius, and vastus medialis) and sensory innervation (via the saphenous nerve) to the anteromedial aspect of the knee, medial calf, medial malleolus, and part of the medial arch of the foot and great toe.37,38

FIGURE 70.6 Cutaneous branches of the femoral nerve. Anterior (A) view and posterior (B) view.

Isolated femoral neuropathy, originally known as anterior crural neuritis, was first reported in 1822 in a thesis by Descot. Although most lesions are unilateral, bilateral involvement has been observed.26 Because an isolated unilateral femoral neuropathy is uncommon, its true incidence remains unknown. Kuntzer et al.39 reported that of 7,252 electrodiagnostic examinations performed at their institution between 1988 and 1994, 3765

femoral neuropathy accounted for the diagnosis is only 32 patients (0.5%). Femoral neuropathies can cause either motor and sensory disturbances or sensory disturbances only. The latter occurs when the saphenous nerve, which is the distal sensory continuation of the femoral nerve, is involved.

Etiology The causes of femoral neuropathy may be divided into the following categories: (1) direct nerve trauma (gunshot or knife wound, hip or pelvic fracture, hip replacement, hip prosthesis displacement, thermal energy from methyl methacrylate, inguinal herniorrhaphy, or femoral nerve block), (2) nerve ischemia due to interrupted vascularization at the intrapelvic level (common iliac artery occlusion, vascular or aortic surgery, or renal transplant with graft in the iliac fossa), (3) nerve compression (femoral artery injury in the femoral triangle, retroperitoneal hematoma, retroperitoneal mass, lithotomy positioning, prolonged hyperextension of the hip, or entrapment under the inguinal ligament with hip flexion), (4) metabolic (diabetes or pelvic radiation therapy), and (5) idiopathic.37,39–41 Because of a somewhat differential blood supply, the left femoral nerve is more susceptible to ischemic injury than the right.42 The most vulnerable site of injury is located 4 to 6 cm above the inguinal ligament, which is where the nerve exits from the psoas muscle.26 Because most pelvic surgical maneuvers occur proximal to the psoas muscle and out of the direct path of the nerve, neuropathy due to a compressive injury from retractors is more likely than that due to nerve transection and is independent of the type of incision (horizontal, midline, or lateral). Most surgery-related causes of femoral neuropathy are preventable as long as retractors are used with care and positional factors are taken into account.41 In their analysis of 32 patients with electrodiagnostically confirmed femoral neuropathy, Kuntzer et al.39 identified an iatrogenic cause in 65% of the cases, and of these, 87% were related the hip surgeries. The incidence of femoral neuropathy after total hip arthroplasty is estimated to be as high as 3%.42 A significant number of cases of femoral neuropathy occur with gynecologic, urologic, orthopedic, and vascular surgeries.26,39,42 The incidence of neuropathy after abdominal 3766

hysterectomy, for example, ranges from 7% to 12%.42 Based on their prospective study looking at femoral neuropathy subsequent to abdominal hysterectomy, Goldman et al.43 reported the incidence of femoral neuropathy decreased from 7.45% to 0.7% when self-retaining retractors were eliminated. The compression is often indirect, as the nerve becomes entrapped between the pelvic wall and the psoas muscle on which the retractor rests.26 In those instances where a compressive neuropathy has occurred, direct ischemia of vasa nervorum due to deficient vascularization is the most likely mechanism of action. Urologic procedures (renal transplant, radical cystectomy, transurethral resection of the bladder with exploration and biopsy of a tumor mass, percutaneous nephrolithotomy of a pelvic kidney, radical cystoprostatectomy and continent urinary diversion, and psoas hitch vesicopexy) can also be a cause of femoral nerve injury.37 For patients undergoing renal transplant with graft in the iliac fossa, the occurrence of femoral neuropathy ranges from 0.5% to 2.2%.26,42 Possible explanations for the cause include nerve compression combined with potential hematoma in the iliac space and prolonged vascular anastomosis or arterial clamping time.

Symptoms and Signs Unilateral sensory loss, paresthesias, or dysesthesias in the distribution of the femoral nerve and its branches, an impaired patellar reflex, and/or hip flexion and knee extension weakness may be present. Quadriceps atrophy may be noted in chronic and severe cases. Patients with hip flexion and knee extension weakness describe frequent buckling of the knee and/or falls while ambulating.37 Navigating stairs is often difficult, requiring patients to ascend by leading with the unaffected leg and to descend by leading with the affected leg. Kuntzer et al.39 reported weakness and dysesthesias in 88% and 44%, respectively. Pain, if present, can be at the site of the causative lesion (iliac fossa and inguinal region) or in the distribution of the nerve itself (anterior thigh or medial calf). Inguinal pain suggests a retroperitoneal mass.37 Pain may be exacerbated by hip extension and partially relieved with hip flexion and external rotation.24

Diagnosis 3767

If femoral neuropathy is noted in the immediate postoperative period, appropriate neuroimaging and radiographic studies should be ordered to determine the cause. Because motor weakness and reflex changes can also be seen with lumbar plexopathies or radiculopathies, these diagnoses must be included in the differential. Electrodiagnostic testing can help isolate the location and extent of nerve injury. Although the presence of EMG abnormalities in the vastus medialis muscle was not predictive of prognosis, the presence of NCS abnormalities, especially percentage of axonal loss, was predictive of prognosis.44 Axonal loss, which is indicative of axonotmesis, portends a slower and possibly incomplete recovery. Kuntzer et al.39 concluded that all patients with less than 50% axonal loss showed improvement within 1 year, whereas less than half the patients with greater than 50% axonal loss improved with conservative management alone. Irrespective of cause of injury, no improvement occurs after 2 years. Prognosis of recovery is greater if testing reveals only demyelinating abnormalities.41 However, if abnormal EMG findings are found in the lumbar paraspinal muscles, this suggests a lumbar radiculopathy or plexopathy and not a peripheral neuropathy.

Treatment If imaging studies identify a treatable cause, then the appropriate surgery should be performed as soon as possible to minimize the extent of neurologic deficit. Based on their retrospective series (1967 to 2000) of 119 surgically treated patients with intrapelvic or thigh-level femoral nerve lesions (89 traumatic injuries and 30 tumors), Kim et al.45 recommended surgery in the absence of improvement at 3 to 4 months: neurolysis if intraoperative nerve action potentials across the nerve lesion are present and resection with grafting if intraoperative nerve action potentials are absent.45 Although fewer patients underwent neurolysis compared to resection with grafting, the extent of recovery was greater in the former group, consistent with the severity of nerve injury. If there is no evidence of clinical or electrodiagnostic improvement after 3 to 6 months in those with iatrogenic or idiopathic femoral neuropathy, then surgical exploration with neurolysis should be considered.41 Assuming the femoral neuropathy is not due to traumatic injury or mass 3768

effect that necessitates surgery, recovery is typically the rule, and conservative treatment is usually sufficient. In their retrospective analysis of 2,175 patients undergoing a combined sciatic-femoral nerve block, Fanelli et al.46 found 45 patients (2%) experienced transient neurologic dysfunction and all, but 1, improved within 4 to 12 weeks.46 Extent of recovery (none, partial, or complete) and time to recovery after abdominal surgery is much more variable, the latter ranging from 2 weeks to 1 year.41 Nonoperative treatment options include rest, analgesic medications, injections, and physical therapy. Whether temporary relief of symptoms with medications or injections alters the long-term prognosis is unknown, as the extent of recovery depends on the causative factor, extent of nerve damage, and location of injury. Longer recovery times should be anticipated when nerve damage is extensive and/or more proximal. Recovery is excellent if the etiology is due to lithotomy positioning, but it is less than satisfactory when due to hip surgery or inguinal procedures.44,47 Kuntzer et al.,39 however, reported no association between etiology and outcome. Physical therapy is important for those with evidence of motor weakness in order to prevent muscle contractures, minimize muscle atrophy, and maintain ambulatory status. For those with significant quadriceps weakness and knee instability, orthotic and/or gait assistive devices should be considered.

SAPHENOUS NERVE ENTRAPMENT The saphenous nerve is the terminal sensory branch of the posterior division of the femoral nerve and is the longest cutaneous branch of the femoral nerve (Fig. 70.7). It originates near the inguinal ligament and descends within the quadriceps muscles in the subsartorial (Hunter’s) canal and emerges from the canal to become subcutaneous approximately 10 cm proximal to the medial femoral condyle. The canal, which is located in the middle third of the medial thigh, also contains the femoral artery and vein. The saphenous nerve along with its two main divisions, the sartorial and infrapatellar nerves, supplies cutaneous sensation from the anteromedial aspect of the knee, medial calf, medial malleolus, and part of the medial arch of the foot.37,38

3769

FIGURE 70.7 Cutaneous branches of the saphenous nerve. Anterior (A) view and posterior (B) view.

Etiology Saphenous nerve injury can occur anywhere along the course of the nerve. Most saphenous neuropathies are iatrogenic or related to surgical procedures, although spontaneous neuropathies with unidentified causes can also occur.37,48 Saphenous nerve trauma during femoral vascular surgeries and from saphenous vein harvesting for coronary artery bypass graft surgery can result in saphenous neuropathy.49–55 After undergoing vascular reconstructions below the inguinal ligament, Adar et al.49 reported variable degrees of saphenous neuropathy in 27 of 55 (49%) of patients, which were unrelated to surgical technical flaws. Inadvertent transection of the infrapatellar or sartorial nerves, such as during knee surgery (medial arthrotomy, medial meniscectomy, patellar realignment, total knee arthroplasty, and secondary repair for medial instability with pes transfer) can occur.38,48,56,57 Schwabegger et al.58 reported how a retained hemostatic clip on the infrapatellar nerve after a gracilis muscle flap resulted in neuralgia due to neuroma formation and moderate fibrosis within the subsartorial (Hunter’s) canal. Resection of the neuroma resolved the pain, but sensory impairment remained. Another case report describes nerve damage resulting following a medial knee joint injection.59 Saphenous nerve entrapment can occur as it travels through the

3770

subsartorial (Hunter’s) canal.37,48 One case report documents distal tibial pain mimicking a tibial stress fracture from entrapment of the saphenous nerve caused by pes anserine bursitis.60 Compression or thrombosis of the superficial femoral artery within the adductor canal can cause claudication pain in the lower leg.53 Neural compression from the femoral vessels and adductor magnus tendons, which is more proximal to the subsartorial (Hunter’s) canal, has also been reported.61 Other case reports describe compression of the nerve due to an osteochondroma and from sitting astride and gripping a surfboard between the knees.62,63

Symptoms and Signs Knee pain is the main complaint, occurring in 90% of patients in one study, and tends to be worst with walking or any exercise involving active knee extension.49,53,63 In another study involving 15 cases of saphenous nerve entrapment, patients most commonly reported medial knee and leg pain after prolonged walking (87%) and standing (47%).48 Additional symptoms reported by these same patients included hypoesthesia (47%), no change in sensation (47%), and hyperesthesia (6%). Point tenderness over the subsartorial canal may be elicited in some of those with a suspected entrapment neuropathy but it is unlikely to be present in those with a traumatic nerve injury.48,49,63 Because it is a purely sensory nerve, motor strength is unaffected. Therefore, sensory abnormalities or pain beyond the territory of the nerve, reflex changes, muscle atrophy, or muscle weakness suggests a lumbar plexopathy, lumbar radiculopathy, or other peripheral neuropathy.

Diagnosis Electrodiagnostic studies can be helpful, but performing a saphenous NCS can be challenging. Instead of strictly looking at the absolute value of the SNAP amplitude or latency in the affected limb, it is more important to compare the side-to-side SNAP amplitudes.37 A SNAP amplitude of less than 50% of the unaffected limb suggests the lesion is at or distal to the dorsal root ganglion.37 Because the nerve is purely sensory, the EMG result should be normal. The clinical utility of saphenous nerve SSEPs is low. A pelvic MRI or CT should be considered if one suspects a mass 3771

lesion in the subsartorial canal.

Treatment Nonsurgical treatment options include rest, analgesic medications, and injections. For those with a suspected entrapment neuropathy, a saphenous nerve block (with or without corticosteroid) over the subsartorial or transsartorial canal can be tried. Both of these approaches have been described as part of the anesthetic plan for lower extremity surgery.64,65 Although the long-term efficacy of doing a saphenous nerve block in the setting of saphenous neuralgia remains unclear, the nerve block might yield a diagnostic answer. A local anesthetic saphenous nerve block provided relief in 12 of 32 (38%) cases described by Mozes et al.,66 but they did not provide lasting relief in any of the 15 cases described by Worth et al.48 With corticosteroid added to the local anesthetic in 30 patients undergoing a series of saphenous nerve blocks, Romanoff et al.53 reported favorable outcomes (80%), no change (13%), and increased pain (7%). Whether temporary relief of symptoms alters the long-term prognosis is unknown. An ultrasound-guided saphenous nerve block can improve chances of obtaining a successful block.67 Of 39 patients undergoing an ultrasound-guided subsartorial saphenous nerve block, Tsai et al.64 reported a 77% success rate. For those with unremitting symptoms, neurolysis or neurectomy may be indicated, although which surgical approach offers the best outcome with the fewest complications is debatable.48,66

OBTURATOR NERVE ENTRAPMENT The obturator nerve, which is a sensory and motor nerve, originates from the anterior divisions of the ventral rami of the L2, L3, and L4 nerve roots (Fig. 70.8; see Fig. 70.1A). (The posterior divisions of the same nerve roots form the femoral nerve.) The obturator nerve emerges from the medial surface of the psoas major muscle at the pelvic brim and descends along the lateral pelvic wall where it passes through the fibroosseous obturator foramen. Within the foramen, the obturator nerve splits into an anterior and posterior branch, finally emerging through the obturator foramen and entering the thigh. At the point of origin, the anterior branch 3772

supplies an articular branch to the hip joint followed by motor branches to the adductor longus and brevis, gracilis, and pectineus muscles. The sensory fibers of the anterior branch convey cutaneous information from the distal two-thirds of the medial thigh. The posterior branch supplies motor branches to the obturator externus and adductor magnus muscles and sensory branches to the articular capsule, cruciate ligaments, and synovial membrane of the knee joint. A normal variant in approximately 8% to 13% of the population, the accessory obturator nerve supplies the pectineal muscles and hip joint.68

FIGURE 70.8 Cutaneous branches of the obturator nerve. Anterior (A) view and posterior (B) view.

Etiology An isolated obturator neuropathy is uncommon because the nerve is well protected within the pelvis and medial thigh.69,70 Causes of obturator neuropathy include entrapment (obturator hernia or local infection), compression (pelvic trauma, pelvic hematoma, pelvic tumor, retroperitoneal mass, fetal head or forceps in the pelvic canal during delivery, trauma or hematoma caused by cesarean section, acetabular labral cyst, extrapelvic synovial cyst, prolonged tourniquet use, or myositis ossificans), surgery (orthopedic, gynecologic, or pelvic laparoscopy), lithotomy positioning, and diabetes.37,68–76 Of 22 patients with 3773

electrodiagnostic evidence of obturator neuropathy, Sorenson et al.69 found perioperative complications or pelvic trauma were the most common causes. Because laparoscopic pelvic procedures could result in inadvertent electrocautery of the wrong nerve, careful visualization of the adjacent neurovascular structures should be undertaken.37,70 The mechanism of entrapment is unclear, but Bradshaw et al.68 concluded from their study of 32 athletes that electrodiagnostic and surgical findings (nerve entrapment by fascia and vessels over the obturator externus and adductor brevis muscles) suggest entrapment occurs at the level of the obturator foramen and proximal thigh, instead of within the obturator tunnel. Gender differences in the bony pelvic anatomy also play a role. Higher iliac bones, a smaller transverse pelvic inlet diameter, and a narrower subpubic angle, which all contribute to a greater bend in the obturator nerve within the obturator canal, probably accounts for the higher incidence of obturator neuropathy in men.68

Symptoms and Signs Symptoms of obturator neuropathy include weakness, paresthesias, sensory loss, and/or pain along the medial thigh with extension as far distally as the knee. Sorenson et al.69 reported that patients most commonly complained of medial thigh or groin pain (73%) followed by muscle weakness (27%) and sensory impairment (27%). Unfortunately, the complaints of pain can make it challenging to differentiate whether it is due to obturator neuropathy versus a traumatic or surgical procedure. Similar to Sorenson et al.,69 Bradshaw et al.68 found that self-reports of numbness or paresthesia among their 32 athletes were uncommon except in those with chronic obturator neuropathy. Additional symptoms included referred pain to the ASIS, exercise-induced exacerbation of pain with radiation from the medial thigh to knee, resolution of pain with rest, exercise-induced adductor muscle weakness and spasm, and wide-based gait. Because the femoral and sciatic nerves provide partial innervation to the adductor longus and magnus, respectively, muscle weakness may be difficult to appreciate on physical exam. With chronic and severe obturator neuropathy, though, medial thigh atrophy may occur. The adductor tendon reflex may even be diminished, but because this reflex can be absent in 3774

those without neuropathy, it must be obtainable in the unaffected limb.37 A positive Howship-Romberg’s sign—pain provocation along the medial thigh to the knee with passive abduction and extension of the affected hip or passive internal rotation of the hip—suggests the diagnosis.77 This neural tension maneuver is felt to be pathognomonic of an obturator hernia, occurring in 15% to 50% of cases.77,78

Diagnosis Because motor weakness and reflex changes can also be seen with lumbar plexopathies or radiculopathies, these diagnoses must be included in the differential. When the physical exam is nonspecific, sensory and motor findings can be confirmed with electrodiagnostic testing. Sorenson et al.69 were able to diagnose a different disorder in 15 of 38 (39%) of patients who carried a presumptive diagnosis of obturator neuropathy. Radiographs of the pelvis are typically normal, unless osteitis pubis is present, and bone scans may show increased uptake in the pubic ramus on the affected side that presumably represents an inflammatory reaction that tracks along the fascia to entrap the nerve.68 Alternatively, the periosteal changes may represent adductor insertion avulsion syndrome (“thigh splints”). If an intrapelvic or extrapelvic lesion is suspected, neuroimaging should be obtained.

Treatment Recovery after sustaining an obturator nerve insult appears good in those with an acute neuropathy and poor in those with a chronic neuropathy. Conservative treatment measures include rest, physical therapy to stretch the groin muscles and to strengthen the adductor and pelvic muscles, soft tissue massage, and analgesic medications. Physical therapy is important for those with evidence of motor weakness in order to prevent muscle contractures, minimize muscle atrophy, and maintain ambulatory status. Among patient with an acute obturator neuropathy, Sorenson et al.69 found that 93% of patients improved with conservative treatment or surgical exploration, indicating conservative management is the preferred course of care. Conversely, a chronic obturator neuropathy portends a poor prognosis as none of the patients with this diagnosis improved. 3775

Controversy exists as to whether severity of nerve injury affects long-term prognosis. Bradshaw et al.68 noted failure with conservative treatment in those with electrodiagnostic evidence of denervation, instead preferring definitive surgical neurolysis. Conversely, Sorenson et al.69 found three of four patients with electrodiagnostic evidence of a complete lesion improved without surgical exploration. For those who have limited benefit with noninjection therapies, a fluoroscopically guided obturator nerve block at the obturator foramen can be attempted.68 Successful treatment of groin pain, medial and lateral thigh pain, and hip joint pain with continuous RF and pulsed RF of the articular branches of the obturator and femoral nerves has also been described in various case reports.79–81 For those with persistent symptoms or severe injuries (pelvic trauma, intraoperative nerve laceration, or tumor), surgery is recommended.37

SCIATIC NERVE ENTRAPMENT The sciatic nerve arises from the lumbosacral plexus and is composed of the L4, L5, S1, S2, and S3 nerve roots (Fig. 70.9). It enters the lower extremity by exiting the pelvis through the sciatic notch. Variability exists, however, in the course the sciatic nerve takes as it exits the pelvis through the greater sciatic notch near the piriformis muscle. Beaton and Anson82 found that among 1,510 cadaveric extremities, in 88%, the sciatic nerve exited below the piriformis muscle; in 11%, the piriformis muscle was divided in two parts such that the fibular division of the sciatic nerve passed in between both parts of the piriformis muscle and the tibial division passed below the bottom-most part of the muscle; in 0.86%, the fibular and tibial division of the nerve either passed above and below the muscle, respectively; and in 0.13%, the entire sciatic nerve pierced an undivided piriformis muscle (Fig. 70.10). The two anatomic variations where the sciatic nerve or its divisions pass in between the nerves lead to the nontraumatic variant of piriformis syndrome. Upon leaving the gluteal region, the sciatic nerve travels posterior and medial to the hip joint.

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FIGURE 70.9 Cutaneous branches of the sciatic nerve.

FIGURE 70.10 A–D: Relationship of the sciatic nerve to the piriformis muscle in 1,510 extremities studied. (From Beaton LE, Anson BJ. The relation of the sciatic nerve and its subdivisions to the piriformis muscle. Anat Rec 1938;70:1–5.)

Commonly perceived of as a single nerve, the sciatic nerve is composed of lateral (fibular division) and medial (tibial division) trunks that actually lay adjacent to each other. Around the middle to distal aspect of the posterior thigh, the divisions diverge to form the common fibular and tibial 3777

nerves. Prior to diverging, the fibular division innervates the short head of the biceps femoris muscle, with tibial nerve branches innervating the remaining hamstring (semitendinosus, semimembranosus, and long head of the biceps femoris) muscles. With the exception of the saphenous nerve, branches of the sciatic nerve supply the sensory innervation below the knee, and branches of the sciatic nerve supply the entire motor innervation below the knee.

Etiology After fibular neuropathy, sciatic neuropathy is the second most common lower extremity peripheral neuropathy.83 Injury can occur anywhere along the course of the nerve from the gluteal region to the posterior thigh. Causes of sciatic neuropathy include compression (hematoma, abscess, piriformis syndrome, benign or malignant tumor, myositis ossificans, endometriosis, prolonged sitting or supine positioning without adequate pressure relief, lithotomy position, vaginal delivery due to nerve compression from the fetus’s head, or pneumatic thigh tourniquet), contusion (fall from a height without fracture or dislocation), trauma (gunshot wound, laceration, femur fracture, intramuscular injection of medication into the gluteal region), stretch injury (hip arthroplasty, hip dislocation, hip or femur fracture), nerve ischemia (vasculitis, arterial thrombosis, arterial bypass surgery, diabetes mellitus, postradiation therapy), and idiopathic.44,84–86 Based on 492 reported cases of sciatic neuropathy in the English literature from 1967 to 1997, Plewnia et al.86 found that the five most common causes were hip arthroplasty (34%), intramuscular injection of medication into the gluteal region (28%), hip fracture or dislocation (9%), benign or malignant tumor (8%), and external compression (8%). Sciatic nerve injury is the most common neurologic complication of total hip arthroplasty—with an estimated incidence of 0.6% to 6.7% of all arthroplasties—and can be caused by stretch injury, direct trauma from retractors or fixation screws, infarction, intraneural hemorrhage, hip dislocation, thermal injury from methyl methacrylate extravasation, or compression from the prosthesis or a bony prominence.84 In their study of 100 patients with electrodiagnostically confirmed sciatic neuropathy, Yuen 3778

et al.83 reported that hip arthroplasty occurred in 22% and accounted for the most common cause of sciatic nerve injury. Kline et al.,84 however, discovered that of 380 patients seen from 1967 to 1991, hip arthroplasty only accounted for a minority (3%) of cases and that injection injury from intramuscular drug administration accounted for the majority (36%) of cases. Although most cases of hip arthroplasty–related sciatic neuropathy occur in the perioperative setting, delayed onset can also be seen.85 Sciatic nerve entrapment by the piriformis muscle, also known as piriformis syndrome, can be another cause of sciatica. Although its diagnosis remains controversial, it is reported to occur with a 6:1 femaleto-male predominance.87 It is less commonly due to sciatic nerve entrapment by the piriformis muscle and instead is more commonly associated with direct trauma to the sciatic notch and the gluteal regions; prolonged sitting; prolonged combined hip flexion, adduction, and internal rotation; and certain athletes (cyclists who ride for prolonged periods of time, tennis players who constantly internally rotate their hip with an overhead serve, and ballet dancers who constantly externally rotate their hip while dancing).82,88–91 Although the mechanism of injury may be postulated, the etiology of the signs and symptoms remains less clear. Traumatic injury to the piriformis muscle may generate inflammatory and edematous changes to the muscle and surrounding fascia, subsequently compressing the sciatic nerve against the wall of the pelvis and leading to a compression neuropathy.90 The trauma itself may induce focal hyperirritability in the piriformis muscle, which can be further exacerbated by muscle spasm or hypertrophy.

Symptoms and Signs Signs and symptoms of sciatic neuropathy include weakness, impaired ankle reflex, paresthesias, sensory loss, and/or pain in the distribution of the nerve. Weakness of toe extension and flexion, ankle dorsiflexion and plantarflexion, and ankle eversion and inversion are the most prominent signs.85 Clinically, absence of complete weakness of ankle dorsiflexion and plantarflexion predicts earlier or better recovery.92 Of the two nerve trunks, weakness more commonly affects fibular-innervated versus tibialinnervated muscles.85,93 This is especially true in sciatic neuropathy after 3779

hip replacement.83 Although it is not entirely understood why the fibular division is more selectively injured compared to the tibial division, various reasons have been postulated: (1) superficial and lateral position, thereby placing the fibular division in closer proximity to the hip joint and exposing it to injury from hip joint trauma or surgery; (2) smaller blood supply; (3) fewer and larger fascicles; (4) less supportive endoneurium and perineurium between fascicles; and (5) relative tethering of the nerve at the sciatic notch and fibular head, thereby making it vulnerable to stretch injuries.84,94 The exception to this rule appears to be femur fractures or gunshot wounds to the thigh, in which case the tibial division can be involved to an equal or greater extent.83 Because of preferential fibular involvement, knee flexion weakness is commonly insignificant, and isolated injury to the fibular division can masquerade as a fibular neuropathy at the knee or fibular head. The most common presenting symptoms with piriformis syndrome are a deep, aching buttock pain that is often associated with a limp and sitting intolerance on the affected side.90 Squatting, climbing stairs, walking, and prolonged sitting (especially on hard surfaces) typically worsen the pain. In addition, the piriformis muscle’s compression of the pudendal nerve and blood vessels may cause labial pain and dyspareunia in females and scrotal pain and impotence in males. Painful bowel movements have also been reported, presumably due to the close proximity of the piriformis muscle and the rectum.95 The two most consistent physical exam findings are tenderness to palpation in the greater sciatic notch and reproduction of pain with maximum flexion, adduction, and internal rotation of the hip.90 Various physical exam maneuvers can be tried in an attempt to reproduce these findings: Freiberg sign (buttock pain with passive, forced internal rotation of the hip), Lasègue’s sign (pain and tenderness to palpation in the greater sciatic notch with the hip passively flexed to 90 degrees and the knee passively extended 180 degrees), Pace’s maneuver (buttock pain with resisted abduction of the affected leg while in the seated position), and Beatty’s maneuver (while lying in a lateral decubitus position on the unaffected side, buttock pain is elicited in the affected extremity when the patient actively abducts the affected hip and holds the knee several inches off the table).87,96,97 3780

Diagnosis Because the differential diagnosis can include radiculopathy, plexopathy, or fibular neuropathy, neuroimaging of the pelvis and/or lumbosacral spine may be necessary to help establish the cause of nerve damage based on the mechanism of injury. Electrodiagnostic testing can be performed to confirm the location of the lesion and to offer prognostic information based on the chronicity and severity of nerve damage. Because muscles innervated by the nerve roots are uninvolved, the lumbar paraspinal muscles are unaffected. In their retrospective analysis of 100 patients, Yuen et al.83 noted greater severity of injury of the fibular division (64%), significant axonal loss (93%), tibialis anterior muscle EMG abnormality (92%), and low or absent extensor digitorum brevis (EDB) compound muscle action potential (CMAP) amplitude (80%). A more favorable prognosis—earlier or better recovery—was noted in those with a recordable EDB, CMAP, and presence of demyelination instead of axonal loss.83 Because normal sural and superficial fibular SNAP amplitudes were obtained in 29% and 9% of patients, respectively, the authors concluded that sparing of the tibial division does not necessarily exclude the diagnosis of sciatic neuropathy. To diagnose piriformis syndrome, the symptoms and clinical exam findings must be correlated with neuroimaging of the pelvis (asymmetry of the piriformis muscle, mass effect, or anatomic variation consistent with entrapment) and electrodiagnostic studies (evidence consistent with extrapelvic compression of the sciatic nerve at the level of the piriformis muscle).95,98,99

Treatment Conservative therapy for symptomatic relief includes analgesic medications, injections, and physical therapy. Physical therapy is important for those with evidence of motor weakness in order to prevent muscle contractures, minimize muscle atrophy, and maintain ambulatory status. An AFO should be considered for those with significant ankle dorsiflexion and plantarflexion weakness. Spinal cord stimulation or intrathecal therapies should be considered for those who have a suboptimal response to the aforementioned and/or those who are not surgical 3781

candidates. Surgical treatment of sciatic neuropathy is directed at identifying the cause of nerve injury. Surgery should be considered for cases of compression due to obvious mass effect or traumatic neuropathy that fails to improve with time. Surgical exploration for trauma-induced injuries, however, requires careful deliberation. Kline et al.84 found that medical management in those patients with a partial deficit and/or improvement in function and pain resulted in an 80% and 60% chance of useful return of function in the tibial and fibular divisions, respectively. In those patients in whom surgery (neurolysis, suture repair, or nerve graft) was performed because of evidence of a nerve action potential distal to the lesion, goodto-excellent outcomes were common for the tibial division but less common for the fibular division. Kline et al.84 suggested that the paucity of successful functional outcomes with fibular division surgeries may be related to uncoordinated muscle reinnervation (as opposed to insufficient nerve regeneration), further calling into question the practicality of fibular division surgery. If the diagnosis of piriformis syndrome is confirmed and conservative management with physical therapy and medication fails to adequately relieve symptoms, an intramuscular piriformis injection of corticosteroid and local anesthetic can be undertaken with image guidance (fluoroscopy, CT, or ultrasound) alone or in combination with EMG guidance or nerve stimulation.88,100–104 Comparing ultrasound guidance versus fluoroscopic guidance, Finnoff et al.105 found the accuracy of needle placement was 95% versus 30%, respectively. Because the duration of analgesia with corticosteroid can be short-lived, some have even advocated the use of botulinum toxin for prolonged analgesia in those that at least respond diagnostically to the local anesthetic.106–109 The use of botulinum toxin for this diagnosis, though, is an off-label use of the medication. Surgical consultation for evaluation of piriformis tendon release and sciatic neurolysis should be considered as a last resort.90,110

FIBULAR (PERONEAL) NERVE ENTRAPMENT The fibular nerve is derived from the L4, L5, S1, and S2 nerve roots as a part of the sciatic nerve (Fig. 70.11). The fibular nerve, along with the 3782

tibial nerve, is a division of the sciatic nerve. Approximately 8 cm proximal to the popliteal fossa, the fibular nerve separates from the tibial nerve and forms the common fibular nerve. As it descends into the popliteal fossa, it innervates the short head of the biceps femoris muscle. Proximal to the fibular head, the common fibular nerve gives off two branches: the sural communicating branch and the lateral cutaneous branch. The sural communicating branch becomes part of the sural nerve after receiving a branch from the tibial nerve. The lateral cutaneous branch conveys sensory information from the proximal and lateral aspect of the leg. As it winds around the fibular head, covered only by skin and a thin layer of subcutaneous tissue, the common fibular nerve is most vulnerable to injury. Approximately 1 to 2 cm distal to the fibular head, the common fibular nerve dives into the fibular tunnel which is made up of the aponeurosis of the soleus muscle and a wide, thick, and inflexible fibrous arch.111 Distal to the fibular tunnel, the common fibular nerve separates into the superficial and deep fibular nerves. The superficial fibular nerve innervates the ankle evertors and plantar flexors (peroneus longus and brevis muscles), after which it divides into the medial and intermediate dorsal cutaneous nerves to provide sensory innervation to most of the dorsal aspect of the foot, with the exception of the web space between the first and second toes. (Ankle inversion is unaffected because the tibial nerve innervates the tibialis posterior muscle.) The deep fibular nerve innervates the ankle and toe dorsiflexors (tibialis anterior, extensor hallucis longus, extensor digitorum longus, and peroneus tertius muscles). Distal to the ankle mortise, the deep fibular nerve gives off lateral and medial branches. The former innervates the EDB and extensor hallucis brevis, and the latter supplies cutaneous sensation to the web space between the first and second toes.

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FIGURE 70.11 Cutaneous branches of the fibular nerve.

Etiology Fibular neuropathy is the most common lower extremity mononeuropathy, but its exact gender or age prevalence is unknown.112 In a retrospective analysis looking at 5,777 trauma patients, Noble et al.113 noted 79 lower extremity peripheral nerve injuries involving the fibular (39), sciatic (28), tibial (8), and femoral (4) nerves. Although fibular nerve trauma most commonly occurs at the fibular head where it is superficially protected only by the skin and thin underlying fascia, injury to the fibular nerve and its branches can occur anywhere along the course of the nerve. Aprile et al.112 demonstrated that most (83%) causes of fibular neuropathy are identifiable, with the majority (31%) being due to perioperative issues. Various causes of fibular nerve injury include entrapment, compression (improperly applied casts or braces, tight stockings, vascular abnormality, osteophytes, and intraneural or extraneural tumor), traction (leg-crossing, prolonged squatting or kneeling, prolonged ankle plantarflexion, surgical positioning, high-heeled shoes), trauma (fracture of the proximal fibular head, knee dislocation, ankle sprain or fracture, nerve laceration, and gunshot injury), metabolic (rapid weight-loss, hyperthyroidism, diabetes mellitus, vasculitic disorders, and leprosy), surgery (orthopedic surgery, vascular surgery, and plastic surgery), or idiopathic.24,111,113–128 In their study of 146 fibular nerve injuries requiring surgery, Piton et al.129 classified the causes as fibular tunnel syndrome (62), external compression (16), trauma (33), iatrogenic injury (16), tumor (9), wound injury (7), 3784

contusion (2), and burn injury (1). In a larger and more recent study involving 318 fibular nerve injuries requiring surgery, Kim et al.130 classified the causes as stretch or contusion without fracture or dislocation (141), tumor (40), laceration (39), entrapment (30), stretch or contusion with fracture or dislocation (22), external compression (21), iatrogenic (13), and gunshot (12). Looking at 60 patients who only had entrapment, Fabre et al.111 classified the causes as idiopathic (53), postural (5), and dynamic (2). True entrapment can be classified as postural (which is associated with kneeling, crouching, squatting, or ankle plantarflexion) or dynamic (which is associated with activities such as running).24,131–133 For those with entrapment, it is postulated that chronic nerve irritation within the fibrous arch of the fibular tunnel causes edema, which subsequently causes scar tissue formation as the nerve glides in the narrow tunnel during knee flexion and extension.111 Superficial fibular nerve entrapment is relatively uncommon and usually is due to compression of the nerve as it exits the anterolateral compartment 10 cm proximal to the ankle.134–136 Although deep fibular nerve entrapment can occur anywhere along its course, it is known as “anterior tarsal tunnel syndrome” when it becomes compressed beneath the inferior extensor retinaculum.136–138 Postural causes of deep fibular entrapment include prolonged plantarflexion, such as with wearing high-heeled shoes.24

Symptoms and Signs Symptoms of fibular neuropathy may include weakness, paresthesias, sensory loss, and/or pain in the distribution of the fibular nerve and its various branches. Patients with dynamic entrapment report activity-related leg pain with or without sensory impairment.24 The degree and extent of neuromuscular deficit and atrophy depends on the location (common vs. superficial vs. deep fibular), severity, and chronicity of nerve injury. Common fibular injury typically causes dorsiflexion (ankle and toes) and eversion (ankle) weakness, leading to tripping due to dragging of toes, excessive hip and knee flexion in an attempt to clear the foot (steppage gait), and foot slap.136 When the injury is proximal to the knee, knee flexion weakness also occurs because the biceps femoris muscle is 3785

affected. A positive Tinel sign at the fibular head, 10 cm proximal to the ankle, or over the dorsal aspect of the ankle suggests a common fibular, superficial fibular, or deep fibular neuropathy, respectively. Fabre et al.111 noted a positive Tinel sign at the fibular head in 60 of the 62 (97%) cases of common fibular entrapment. Sensory abnormalities, motor weakness, or pain beyond the territory of the nerve suggest an alternate diagnosis, such as a lumbar plexopathy, a lumbar radiculopathy, or other peripheral neuropathy.

Diagnosis Electrodiagnostic studies can be performed to confirm the diagnosis, location, and extent of fibular neuropathy. Without axonal loss, the NCS reveals slowing of the nerve conduction velocity. However, when longstanding compression or direct nerve injury results in axonal loss, a decreased SNAP amplitude, a decreased compound muscle action potential amplitude, and a conduction block can be seen on NCS. The EMG portion of the study not only helps confirm axonal loss but the extent of muscle involvement can also aid in determining whether the lesion involves the common fibular, superficial fibular, or deep fibular nerve. For those with exercise-induced (dynamic) fibular neuropathy, electrodiagnostic studies may need to be done before and after exercising.24 Once a fibular neuropathy has been confirmed electrodiagnostically, additional imaging (radiograph, CT, and MRI) or laboratory studies may be needed to isolate the cause of nerve injury.

Treatment Nonsurgical treatment options include rest, modification of footwear or garments, analgesic medications, injections, and physical therapy. Physical therapy is important for those with evidence of motor weakness in order to prevent muscle contractures, minimize muscle atrophy, and maintain ambulatory status. Whether temporary relief of symptoms with medications or injections alters the long-term prognosis is unknown, as the extent of recovery depends on the causative factor, extent of nerve damage, and location of injury. The degree of pain relief after doing a fibular nerve block at the fibular head can provide diagnostic information. 3786

Significant fibular nerve damage resulting in ankle and foot weakness may necessitate an AFO and customized orthopedic shoes to correct any gait disturbance. Depending on the etiology of fibular nerve injury, surgery is advocated within 2 to 4 months if there is lack of clinical and electrophysiologic improvement.111,129,130 In their retrospective analysis of 318 patients with preoperatively confirmed EMG evidence of knee-level common fibular nerve lesions, Kim et al.130 reported recovery of useful function in 88% and 84% of those undergoing neurolysis and end-to-end suture repair, respectively; recovery of useful function in 75%, 38%, and 16% for those requiring nerve grafting less than 6 cm, 6 to 12 cm, and 13 to 24 cm, respectively; and preservation of preoperative clinical function in 80% of those requiring tumor resection.130 For patients with idiopathic entrapment, surgical decompression is recommended when symptoms fail to resolve within 3 to 4 months because the time needed for recovery is shorter than that associated with conservative management.111

Foot Pain PES PLANUS Etiology Pes planus, a condition also known as flatfoot, refers to the loss of the normal longitudinal arch of the medial foot (Fig. 70.12). The most common cause of pes planus is insufficiency or dysfunction of the posterior tibial tendon.139 Congenital flatfoot is used to describe a flatfoot present since birth. Trauma, such as Lisfranc joint injuries and calcaneal fractures, can also lead to pes planus due to joint subluxation. Degenerative changes secondary to arthritis can also lead to pes planus. Tarsal coalition—a congenital fibrous union or fusion between the bones of the hindfoot and midfoot—has also been implicated as a cause of flatfoot.140

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FIGURE 70.12 Pes planus.

Symptoms and Signs Symptoms of pes planus can vary among patients with different forms of anatomic pathology and biomechanics leading to the condition. Examination of the feet should begin with the patient in standing position. Typically, the longitudinal arch flattens upon standing and appears when the foot is not bearing weight. Heel eversion often accompanies pes planus. Severe pes planus may result in significant pain, particularly along the course of the posterior tibial tendon, which may be tender upon palpation.141

Diagnosis and Treatment Radiographic imaging should be performed of the foot and ankle in three weight-bearing views—anteroposterior, oblique, and lateral. Loss of the longitudinal arch is best visualized on the weight-bearing lateral radiographs.142 MRI can also be useful in assessing this condition, particularly in evaluation of the posterior tibial tendon. Treatment is often conservative through the use of arch supports and plantar inserts. Surgical treatment may involve posterior tibial advancement, subtalar fusion, or osteotomies, depending on the initial cause of the condition.

PES CAVUS Etiology Cavus foot deformity is an abnormal elevation of the longitudinal arch (Fig. 70.13). This results in increased stress forces on the metatarsal heads and decreased weight bearing by the plantar region of the foot.143 Causes 3788

of pes cavus include neuromuscular disease (such as muscular dystrophy, cerebral palsy, and spinal tumors), residual clubfoot, malunion of calcaneal or talar fractures, and burns.143

FIGURE 70.13 Pes cavus.

Symptoms and Signs Symptomatology varies based on the extent of the deformity. Lateral foot pain can develop as a result of increased weight bearing by the lateral foot. Metatarsalgia is frequently associated with pes cavus. Intractable plantar keratosis is often seen as well. Clawing of the toes—hyperextension at the metatarsophalangeal joints and flexion of the proximal and distal interphalangeal joints—may also be present.143 Patients may experience generalized stiffness of the joint, leading to disuse of the affected foot.

Diagnosis and Treatment Physical examination should elucidate if the deformity is flexible or rigid. This can be determined by performance of the Coleman block test.142 A 1in wood block is placed beneath the heel and lateral foot while the first, second, and third metatarsals are allowed to hang freely into plantarflexion and pronation. If heel varus corrects in this stance, the deformity is flexible. If the hindfoot does not correct, the deformity is rigid. Weightbearing radiographs of the ankle and foot aid in the diagnosis through demonstration of hindfoot varus. MRI of the spine may be necessary to 3789

evaluate for possible spinal tumor presence if the deformity is unilateral and no inciting traumatic event is noted. In addition, a neurologic consultation and an EMG/NCS can be obtained to evaluate for polio, Charcot-Marie-Tooth disease, and other neurologic causes of pes cavus. Conservative therapy for pes cavus includes the use of orthotic shoe inserts to offset increased weight-bearing forces on the metatarsal heads. Surgical intervention is warranted if the condition is severe and is aimed at construction of a plantigrade foot. This may be accomplished through tendon transfers, osteotomies, and arthrodesis.142

PLANTAR FASCIITIS Etiology Plantar fasciitis is a painful inflammatory condition involving the insertion of the plantar fascia on the medial process of the calcaneal tuberosity. Pes planus, pes cavus, leg-length discrepancy, overpronation, and running all involve increased stress forces placed on the plantar fascia and thus can lead to plantar fasciitis.144

Symptoms and Signs Patients typically complain of intense sharp heel pain after the first few steps in the morning or after a period of rest. The pain is usually located along the anterior portion of the heel, with radiation into the sole of the foot.145 The pain is exacerbated by weight-bearing activities and relieved by rest. Patients may also experience generalized stiffness of the foot and swelling of the heel.

Diagnosis and Treatment Pain can be reproduced on palpation of the anteromedial aspect of the calcaneus as well as the proximal plantar fascia. Passive dorsiflexion of the toes and toe walking can also reproduce pain secondary to plantar fasciitis.145 Radiographic imaging can reveal soft tissue calcifications in the heel and may be more useful to investigate for bony tumor or fractures as an underlying cause. Ultrasound may reveal a thicker heel aponeurosis, which can be associated with plantar fasciitis. MRI can demonstrate thickening of the plantar fascia. Because of the poor sensitivity and 3790

specificity of these imaging techniques, diagnosis of plantar fasciitis is usually made through the history and physical examination. Conservative treatment involves the use of medial arch support inserts in footwear, shoe modifications, stretching exercises focusing on the plantar fascia, ice therapy, and NSAIDs.145,146 Night splints can be worn to allow the plantar fascia to heal in an elongated position as opposed to the natural plantarflexed position of the foot during sleep. Some studies have demonstrated that corticosteroid injections, botulinum toxin injections, and autologous platelet-rich plasma therapy can also be useful in treating plantar fasciitis.147,148 It should be noted that injection of botulinum toxin for plantar fasciitis is considered an off-label use of the medication. The injection of either corticosteroid or botulinum toxin is performed with a medial or lateral approach into the site of maximal tenderness. Complications of corticosteroid injections include plantar fascia rupture and fat pad atrophy.149 When these treatment modalities are unsuccessful, surgical release of the plantar fascia may be indicated. However, extracorporeal shockwave therapy (ESWT) could be an alternative to a surgical remedy that also happens to be noninvasive and safe. In their systematic review of ESWT (2005 to 2016), Roerdink et al.146 found no complications at 1-year follow-up.

HEEL PAD DEFICIENCY Etiology The fat pad of the heel is made of individual fibrous septa containing fat and elastic fibrous tissue. The fat pad absorbs shock and distributes mechanical forces to the calcaneus. The fat pad atrophies with age, multiple glucocorticoid injections, and trauma.150

Symptoms and Signs Patients typically experience deep, diffuse plantar heel pain that is exacerbated upon standing and walking/running on hard surfaces. Direct palpation of this area reproduces this pain. There is palpable atrophy of the heel pad, and underlying bone may be palpated. Scar tissue and calcification can be observed.

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Diagnosis and Treatment Diagnosis is usually made through history and physical examination. NSAIDs can provide significant analgesia. Long-acting local anesthetics, such as bupivacaine, can be infiltrated into the affected area for severe, painful crises. Corticosteroids are contraindicated, as they can worsen the condition.149 Shock-absorbing footwear inserts can be helpful by providing cushion and absorbing shock.

TARSAL TUNNEL SYNDROME Anatomy The tarsal tunnel is bounded by the flexor retinaculum, a strong fibrous band that extends from the medial malleolus to the margin of the calcaneus, and the medial surfaces of both the calcaneus and talus.151 The posterior tibial nerve courses beneath the flexor retinaculum through this tunnel and divides into the medial and lateral plantar nerves, which innervate the small muscles of the foot and the skin on the plantar aspect of the foot and toes (Fig. 70.14).

FIGURE 70.14 Anatomy of the tarsal tunnel and posterior tibial nerve.

Etiology Compression of the posterior tibial nerve as it passes behind the medial malleolus in the tarsal tunnel may lead to tarsal tunnel syndrome, a painful 3792

condition of the ankle and plantar aspect of the foot. The branches of the posterior tibial nerve are vulnerable to compressive injury (restrictive footwear), entrapment from space-occupying lesions (i.e., ganglion cysts, osteophytes, and tumors), direct trauma, overuse injuries, and inflammation within the tarsal tunnel.152 Hindfoot valgus deformities can further exacerbate tarsal tunnel syndrome symptoms due to increased neural tension that is secondary to an increase in eversion and dorsiflexion foot positioning. All of these conditions can lead to edema and scar tissue formation, which further limit the vascular supply and cause increased traction of the nerve between joint movements. This ultimately can result in axonal and wallerian degeneration.

Symptoms and Signs Pain or paresthesias in the heel, medial malleolus, or plantar surface of the foot may occur, depending on which nerve branch is compressed and the severity of the compression. When both plantar nerves are affected, symptoms extend from the posterior malleolus to the plantar aspect of the foot and dorsal surfaces of the distal aspect of the toes. Pain can be experienced in both the standing and reclining positions and may be worse at night.151 Simultaneous dorsiflexion and eversion of the ankle exacerbates the pain due to increased nerve tension. Advanced disease leads to weakness of the intrinsic muscles of the foot and of the toe plantar flexor muscles. Physical examination typically reveals tenderness to palpation of the tibial nerve. Percussion at the medial malleolus (Tinel sign) causes radiation of pain and paresthesias along the path of the posterior tibial nerve and its branches.151 In addition, symptoms may be reproduced through continuous compression of the nerve for 30 seconds (Phalen’s sign).151 Sensory deficits are uncommon but can affect the sole of the foot if present.

Diagnosis An EMG/NCS often reveals prolonged motor terminal latency of the medial or plantar nerves to the abductor hallucis and abductor digiti quinti muscles, absent nerve potentials, or slow nerve conduction velocities.153 Although electrodiagnostic testing can aid in the diagnosis of tibial 3793

neuropathy, neuroimaging may still be necessary to demonstrate whether a space-occupying lesion within the tarsal tunnel is the source of the symptoms.153 An MRI demonstrates the anatomy of the tarsal tunnel and its contents and can prove useful in planning for surgical decompression.

Treatment The initial treatment includes nonsurgical measures such as avoidance of exacerbating activities, medications (corticosteroids, acetaminophen, NSAIDs, antiseizure medications, opioids, tricyclic antidepressants, topical analgesics, lidocaine patch), TENS, physical therapy, shoe inserts, and night splints with the foot in plantarflexion. An injection of local anesthetic and corticosteroid into the tarsal tunnel may provide analgesia.153 Surgical decompression with release of the flexor retinaculum, is employed if nonoperative measures fail. If present, spaceoccupying lesions of the tarsal tunnel, such as varicose veins and ganglions, are removed along with release of the flexor retinaculum. Decompression may also be accomplished through division of the proximal ridge of the abductor hallucis.152 Surgical complications primarily involve incomplete release of the flexor retinaculum, resulting in persistent pain.152

LISFRANC JOINT INSTABILITY Etiology The Lisfranc joint (tarsometatarsal joint or metatarsal cuneiform joint) is a six-bone complex that connects the forefoot and the midfoot. It is made up of the articulation of the bases of the first three metatarsals with the cuneiforms and the fourth and fifth metatarsals with the cuboid. The joint aids in pronation and supination of the foot.154 The great majority of Lisfranc joint injuries are associated with fractures, especially the metatarsals. Although injury to the joint is generally associated with highenergy mechanisms (e.g., falls or motor vehicle collisions), resulting in severe inversion or plantarflexion, low-impact mechanisms (e.g., direct trauma in sports-related injuries) are also known to cause injury.155 The Lisfranc injury may be classified by the direction of the dislocation.

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Symptoms and Signs Lisfranc joint instability is characterized by severe midfoot pain and the inability to bear weight. Point tenderness over the midfoot is noted on exam. Bruising on the plantar surface of the midfoot represents an occult sign of an injury. Depending on the mechanism of injury, there may be soft tissue damage, such as edema, a wound, or vascular impairment. Pain or edema that persists after soft tissue healing is expected to have occurred should raise the index of suspicion for a Lisfranc joint injury.155

Diagnosis Conventional radiography is the initial imaging modality of choice. Radiographs will reveal fractures of the joint and displacement of the metatarsals. Because sprains are more difficult to detect, weight-bearing plain radiographs and stress radiographs taken with the foot plantarflexed and inverted have been suggested to establish the diagnosis.156 Advanced imaging, however, should be considered in the following circumstances: (1) CT for identifying occult fractures or subtle subluxations and (2) MRI for soft tissue and ligamentous injuries.157

Treatment Treatment depends on the type and severity of the injury as well as the length of time between injury and diagnosis. Ligamentous injury can benefit from casting or a fitted boot. If these conservative treatments fail, surgical open reduction or joint fusion may be required.

POSTERIOR TIBIAL TENDON INSUFFICIENCY Etiology Posterior tibial tendon insufficiency is the most common cause of acquired adult flatfoot deformity.158 Flatfoot deformities result from flattening of the medial longitudinal arch of the foot with failing of the supporting soft tissue structures of the ankle and hindfoot. The posterior tibial tendon is the principle supporting mechanism of this arch, although ligament involvement is extensive.139 Dysfunction of the posterior tibial tendon leads to the collapse of the arch and the formation of a pes planovalgus deformity. Arthritis may develop secondary to the foot deformity. 3795

Insufficiency of the posterior tibial tendon may result from a variety of insults, including trauma and arthritic damage. Patients are most often middle-aged females and are often obese.159

Symptoms and Signs Initially, patients report pain along the medial aspect of the foot and ankle due to stretching of medial ligaments and soft tissues. On physical exam, erythema, edema, and tenderness to palpation along the course of the posterior tibial tendon can be appreciated. Later, as the arch begins to collapse, the ankle starts to roll inward, resulting in pain along the lateral aspect of the foot.159 There may be difficulty in performing a single leg heel rise. Persistent dull aching pain due to destruction of the midfoot may culminate in difficulty with standing and ambulation.

Diagnosis Radiographic imaging should include weight-bearing anteroposterior and lateral radiographs of the foot to evaluate the biomechanical relationships and detect secondary arthritic changes.159 MRI is utilized to assess the integrity of the posterior tibial tendon.

Treatment Initial treatment is supportive and involves immobilization, analgesic medications, and orthotic devices to correct pronation. Steroid injections have not been proven to be efficacious and remain controversial. When supportive measures fail, treatment consists of surgical augmentation of the posterior tibial tendon alone or in combination with osteotomy or arthrodesis.159

DORSAL FOOT GANGLIA Etiology The etiology of dorsal foot ganglia is uncertain. However, they are the most common nodules found in the foot, with women accounting for up to 85% of the cases.160

Symptoms and Signs 3796

Ganglia are generally asymptomatic. However, pain can occur as a result of inflammatory pressure points created while walking or from wearing tight-fitting footwear.160

Diagnosis and Treatment Ganglia are fluid-filled nodules that typically arise from a joint or tendon sheath and are most commonly located over the dorsum of the midfoot, forefoot, and toes.160 Upon palpation, they are firm and wellcircumscribed. Nonsurgical treatment options include use of footpads, compression of the ganglion with an arch strap, or fine needle aspiration of the ganglion. Recurrence of the ganglion after aspiration is not uncommon. When conservative measures fail, surgical excision of the ganglion and stalk from its origin on the ligament or joint capsule and capsular excision should be performed.

METATARSALGIA Etiology Metatarsalgia refers to pain involving one or more of the metatarsal heads and distal metatarsal shafts secondary to chronically elevated stress forces as the total body weight is transferred to the forefoot during the midstance and push-off phases of walking and running.161 Abnormal biomechanics resulting from excessive pronation, cavus deformities, foot surgeries (e.g., osteotomies), and high-heeled shoes can further increase the weight distribution on the metatarsal heads.162 The increased prevalence of metatarsalgia among women is likely due to wearing high-heeled shoes. Other causes of metatarsalgia include intermetatarsal bursitis/neuritis, metatarsal stress fracture, metatarsophalangeal joint stress syndrome, sesamoiditis, inflammatory arthritis, interdigital neuroma, and aseptic necrosis of the second metatarsal head (Freiberg disease).162

Symptoms and Signs Pain severity is gradual in nature and is aggravated with walking and running activities. Over time, calluses can form over the second and third metatarsal heads and can further increase weight bearing on the metatarsal heads. On physical examination, palpable point tenderness is elicited at the 3797

distal end of the plantar metatarsal fat pad and also can be reproduced by squeezing the metatarsal head between the thumb and index finger.162 Interdigital neuromas can lead to metatarsalgia and should be considered when pain is present in the interdigital web spaces. Over time, the pain may progress to diffuse forefoot and midfoot pain.

Diagnosis Laboratory and imaging studies are not performed to confirm the diagnosis of metatarsalgia but instead are performed to rule out other diagnoses that may have a similar presentation. Radiographic imaging (weight-bearing anteroposterior, lateral, and oblique views) of the affected foot should be obtained to exclude metatarsal stress fractures, which may also lead to forefoot pain. Ultrasound and MRI may be necessary if a neuroma, cyst, bursitis, or other soft tissue anomaly is suspected. A serum C-reactive protein, uric acid level, and erythrocyte sedimentation rate should be obtained to exclude gout, which often presents as metatarsal pain at the base of the great toe.

Treatment Conservative treatment includes the use of analgesic medications and semirigid orthotic inserts to reduce pressure on the metatarsal heads. Kang et al.163 showed that the use of metatarsal pads resulted in decreased maximal peak pressures and pressure time intervals during exercise, which translated to improved function and analgesia. Athletes can achieve significant pain reduction through the use of metatarsal bar appliances that can be placed in footwear. Surgical procedures are aimed at equalizing weight-bearing forces on the metatarsal heads and may include metatarsal shaft osteotomy or metatarsal head condyle excision.164

HALLUX VALGUS Etiology Hallux valgus, also known as bunion deformity, is the most common deformity of the metatarsophalangeal joint.165 Subluxation results in lateral deviation of the proximal phalanx of the great toe and the formation of a medial prominence by the first metatarsal head (Fig. 70.15). The 3798

deformity can be congenital or can result from biomechanical instability. Use of improper footwear, such as high-heeled shoes with tight-fitting and small toe boxes, may explain the higher prevalence hallux valgus among women.165

FIGURE 70.15 Hallux valgus. See text for details.

Symptoms and Signs Pain occurs in the first metatarsophalangeal joint and can be described as deep, aching, and/or lancinating. Pain is worsened with ambulation and relieved upon shoe removal. Physical examination reveals a prominence on the medial aspect of the first metatarsal head and valgus deformity of the great toe. Adventitial bursa formation over the prominent medial metatarsal head can also be observed.166 Bursitis and overlying skin inflammation may be present. Osteoarthritic changes that occur over time may result in significant reduction in joint range of motion associated with pain.

Diagnosis Radiographic imaging (weight-bearing anteroposterior, lateral, and oblique views) should be obtained in order to measure the angular degree of deformity, which provides diagnostic and prognostic information.166 3799

Treatment Conservative treatment involves wearing footwear with wide toe boxes and placing pads in the first web space and over the median prominence to relieve pressure-induced pain. Oral analgesic medications and corticosteroid injections into the first metatarsophalangeal joint can be used to address acute, painful inflammatory states. Surgical treatment is indicated for intractable pain associated with significant functional impairment. Surgical options include osteotomy, exostectomy, resectional arthroplasty, resectional arthroplasty with implant, capsulotendon balancing, first metatarsophalangeal joint arthrodesis, and first metatarsocuneiform joint arthrodesis.166 A majority of these techniques involve excision of the medial prominence of the metatarsal head (bunionectomy), adductor hallucis tendon release, and occasional excision of the lateral sesamoid bone. Major surgical complications include overcorrection and recurrence.166

HALLUX RIGIDUS Etiology Hallux rigidus is osteoarthritis of the first metatarsophalangeal joint and is associated with restricted range of motion and pain (Fig. 70.16). This results from cartilage degeneration, altered joint mechanics, and osteophyte formation. Impingement of the dorsal osteophytes results in inflammation and pressure point pain.167 Athletic activities involving running have been associated with development of hallux rigidus.

FIGURE 70.16 Hallux rigidus. A: Anterior view. B: Medial view. Arthritis of the metatarsophalangeal joint reduces motion, especially in dorsiflexion. Push-off is painful.

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Symptoms and Signs Patients describe a dull, aching pain on the dorsal surface of the first metatarsophalangeal joint that occurs during weight-bearing activities involving the forefoot and often results in an antalgic gait. Unlike hallux valgus, pain from hallux rigidus is associated with or without wearing shoes. Neuropathic pain can result from first dorsal digital nerve entrapment. Physical examination reveals an osteophyte formation on the dorsal surface of the first metatarsophalangeal joint and extremely limited range of motion.

Diagnosis Radiographic imaging reveals degenerative changes of the first metatarsophalangeal joint. Early changes include dorsal and marginal osteophyte formation. Severe changes that can be visualized include joint space narrowing, sclerosis, joint irregularities, and sesamoid and cystic degeneration. Coughlin and Shurnas168 proposed a grade 0 to 4 classification system based on range of motion, physical exam findings, and radiographic results.

Treatment Conservative treatment includes rest, customized foot orthotics, and wearing low-heeled, rigid rocker bottom soled shoes with soft surfaces lining the dorsum of the foot. Corticosteroids can be injected in to the first metatarsal interspace lateral to the joint, along with local anesthetic application in the region of the first dorsal digital nerve.167 Several surgical treatments can be attempted to correct the condition. The least invasive, a cheilectomy, involves the excision of all irregular bony spurs contributing to decreased range of motion. This can provide significant pain relief and gain in function, although a successful outcome is inversely proportional to the degree of arthritic changes. A resection arthroplasty (Keller procedure), which involves excision of the base of the proximal phalanx, is usually reserved for patients with low functional demands.167 A proximal phalanx and metatarsal osteotomy can also be performed. Complications, such as flaccidity and motor weakness of the hallux, are quite high.167 Although a joint arthrodesis can provide analgesia, it results 3801

in loss of joint motion. Despite this, patients can continue to remain physically active.

INTRACTABLE KERATOSIS Etiology Intractable keratosis is characterized by hard callus formation that develops underneath the metatarsal heads due to plantar flexion.169 Callus formation results in point pressure on the plantar fat pad.

Symptoms and Signs Intractable keratosis presents as a painful discrete lesion that is aggravated by weight-bearing activities and causes an antalgic gait. Physical examination reveals a 1-cm focal, white-colored lesion with circumferential erythema found on the plantar aspect of the forefoot.170

Diagnosis Radiographic imaging should be performed to exclude other pathology, including fractures and metatarsal avascular necrosis.

Treatment Conservative treatment involves wearing shoes with wide toe boxes and placing a pad underneath the uninvolved metatarsal heads in order to offload weight from the involved metatarsal head. Pumice stones and prescription creams containing lactic acid can be used to reduce the mass of the keratosis and thereby provide symptomatic relief. Analgesic medications can provide minor relief. Corticosteroid injections are controversial as they can create fat-pad atrophy and further exacerbate the condition.171 Surgical options can include callus tissue reduction and core removal, a variety of distal metatarsal osteotomies, and segmental resection of the proximal metatarsal.170

SESAMOIDITIS Etiology and Pathophysiology Sesamoiditis refers to inflammation of the two sesamoid bones on the plantar of the first metatarsophalangeal joint. This state of inflammation 3802

can occur as a result of increased stress forces on the sesamoid bones from repetitive trauma due to increased activity, ill-fitting foot wear, anatomic variations, infection, osteoarthritis, or inflammatory arthropathies. Postural abnormalities may also contribute to this condition.

Symptoms and Signs Pain is localized on the plantar aspect of the foot and is aggravated by weight-bearing activities. Physical examination reveals pain with direct palpation of the sesamoid bone and on dorsiflexion of the metatarsophalangeal joint.172

Diagnosis Radiographic studies should be performed to exclude fractures and other anatomic abnormalities. If plain film radiographs are nondiagnostic, a bone scan, CT, or MRI can prove useful.172

Treatment The initial treatment includes reducing loading forces on the sesamoid bones, immobilization with rocker bottom shoes or orthoses, activity modification, and NSAIDs.172 If conservative management fails, then surgical options should be considered.172

GOUT Etiology Elevated systemic uric acid levels—due to increased uric acid production, decreased renal excretion of uric acid, or both—cause gout.173 When serum uric acid concentrations exceed 7.0 mg/dL, precipitation of uric acid crystal occurs.174 Gout typically manifests in men with a peak age of onset in the fifth decade of life and in women in the sixth decade of life.174

Symptoms and Signs The natural history of gout can be divided into three distinct stages: asymptomatic hyperuricemia, acute and intermittent gout, and chronic tophaceous gout.173 Asymptomatic hyperuricemia can last for 10 to 30 years before an acute gouty arthritis event occurs. This event is 3803

characterized by severe pain in conjunction with edema, erythema, and rubor of the affected joint, after which resolution occurs within 1 to 2 weeks. Gout typically involves only one joint in the early course of the disease, and it is usually the first metatarsophalangeal joint. The acute and intermittent phase involves asymptomatic periods interrupted by acute attacks. These intervals can vary from months to years, but over time, the frequency and duration of attacks and number of joints involved increases. Although it remains uncertain, the attacks may be associated with rapid fluctuations of serum uric acid levels. Chronic gouty arthritis typically develops after more than 10 years of acute intermittent gout. There are no pain-free intervals in this stage.

Diagnosis Patients report multiple painful, stiff, edematous joints, particularly in the toes, ankles, and knees. Although elevated serum uric acid levels (greater than 7.0 mg/dL) are commonly seen in gout, there may be periods of time when serum uric acid levels are normal.173 In addition to hyperuricemia, leukocytosis, elevated erythrocyte sedimentation rates, and elevated Creactive protein levels may be present in acute attacks. The criterion standard of diagnosis, however, remains aspiration and examination of synovial fluid from an actively affected joint. Under polarized microscopy, monosodium uric acid crystals are seen as negatively birefringent needlelike structures engulfed by polymorphonuclear neutrophils.

Treatment Treatment of acute gouty arthritis focuses on decreasing the inflammation within the joints.175 This is best accomplished through NSAIDs. In patients who cannot take NSAIDs, corticosteroids can be given via the oral, intravenous, or intra-articular routes. If taken within the first 12 hours of an acute gouty attack, oral colchicine can have an anti-inflammatory effect and can prevent uric acid crystal deposition. Although colchicine does not lower the uric acid levels, in low doses, it can be used to prevent or reduce the severity of future attacks. Patients, however, may not be able to tolerate the side effects of nausea, vomiting, and diarrhea. Chronic therapy to prevent recurrence of gouty arthritic attacks is aimed at 3804

normalizing serum uric acid levels. Uricosuric agents, such as probenecid, work by increasing uric acid secretion into the urine. Xanthine oxidase inhibitors, such as allopurinol, work by inhibiting uric acid synthesis. Surgical resection of large nodular deposits of uric acid crystals, also known as tophi, can offer improvement in terms of mechanical function.176

INTERDIGITAL (MORTON’S) NEUROMA Etiology An interdigital neuroma is characterized by a well-localized area of pain on the plantar aspect of the forefoot that radiates into the web space. It typically involves the third interspace of the foot. Although this condition is termed interdigital neuroma, it is not a true neuroma. The histopathologic changes include the degeneration of nerve fibers associated with deposition of amorphous eosinophilic material that is more congruent with neuropathy secondary to an entrapment phenomenon.177 What causes an interdigital neuroma is unclear, although it has been hypothesized that it arises from constant traction of nerve fibers against the transverse metatarsal ligament during dorsiflexion of the toes.178 Interdigital neuromas occur approximately 10 times more frequently in women than men. This may be explained by the state of continuous dorsiflexion of the feet when wearing high-heeled shoes.178

Symptoms and Signs Patients typically complain of localized pain in the region of the metatarsal head. The third interspace is more frequently involved than the second interspace, but it rarely involves the first or fourth interspace.179 The pain is aggravated by wearing tight-fitting shoes and walking and is alleviated by rest and removal of shoes. Upon palpation of the involved interspace, patients report a sharp pain that radiates into the toes. Often, a mass located in the interspace can be palpated. Palpating the affected interspace with one hand and squeezing the entire foot at the same time with the other hand, resulting in narrowing of the intermetatarsal space and compression of the mass can often reproduce symptoms. This can elicit an audible click, known as Mulder’s sign.170 The differential diagnosis of interdigital 3805

neuroma should include stress fracture, tendon sheath ganglion, foreignbody reaction, nerve sheath tumor, strain of the plantar capsule, and capsulitis or bursitis at the level of the plantar metatarsophalangeal joint.179 In many of these conditions, inflammation of the adjacent nerve also may be present, causing the neuritic sensation of an interdigital neuroma, thus complicating proper diagnosis. It is also important to distinguish interdigital pain from metatarsalgia, which gives rise to a host of other possible pathologies including avascular necrosis, synovial cysts, and tarsal tunnel compression.

Diagnosis Although interdigital neuromas are often diagnosed based solely on clinical findings, MRI, CT, and ultrasound have all been utilized for diagnostic purposes as well. MRI has emerged as the preferred imaging modality due to superior contrast resolution and precision. Interdigital neuromas are best visualized on short-axis (transverse) T1-weighted images through the metatarsal heads. Due to their highly vascular nature, intravenous contrast agents typically result in visual enhancement. They appear as bulbous masses arising between the metatarsal heads (Fig. 70.17).180 Although radiographs may reveal pathology at the metatarsophalangeal joint, they are not useful in the diagnosis of interdigital neuromas.

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FIGURE 70.17 Interdigital neuroma. Transverse T1-weighted (top) and contrast-enhanced fatsuppressed T1-weighted (bottom). Magnetic resonance images show the bulbous morphology of the perineural mass with plantar extension. The administration of contrast material reveals enhancement of the lesion.

Conservative management of interdigital neuromas includes wearing shoes with wider toe boxes, adequate cushioning, and heels no higher than 1 in. Neuroma pads—soft support inserts that are placed proximal to the affected metatarsal head—are designed to separate the metatarsal heads and prevent rubbing or irritating the affected neuroma when stepping down. Oral NSAIDs and corticosteroid injections into the affected interspace can be tried.178 However, corticosteroids can result in local fat atrophy and metatarsalgia. Phenol neurolysis of the common interdigital nerve has also been reported to be effective.181 When conservative management fails, surgical intervention may be indicated. This involves a dorsal incision in the midline of the affected interdigital space in order to release the transverse metatarsal ligament, as the nerve typically lies beneath this ligament. Postoperative recovery includes a compression dressing worn for several weeks after wound closure. Ambulation is permitted in a postoperative boot.182 It is important to note that patients may experience decreased sensation in the interdigital web space. 3807

HAMMERTOES Etiology Hammertoe deformities are primarily flexible or fixed plantarflexion deformities of the proximal interphalangeal (PIP) joint, with hyperextension of the metatarsophalangeal joint and extension deformities of the distal interphalangeal joint (Fig. 70.18).173,183 This results in a dorsal prominence on the PIP, which can cause pain secondary to compression and inflammation from footwear. Physical examination must include determining if the deformity is fixed or flexible. Other deformities may be present, such as hallux valgus or cavus foot deformities. Examination of the extensor surface of the PIP joint may reveal callus or ulcer formation. Intractable keratosis can develop underneath the metatarsal head of the involved toe.162

FIGURE 70.18 Hammertoe deformity, a typical small toe deformity, often causes corns and calluses with standard footwear. Extra deep shoes avoid these problems.

Diagnosis Radiographic imaging should include weight-bearing anteroposterior and lateral radiographs of the involved foot.

Treatment Conservative management involves the use of metatarsal pads and shoes with wide toe boxes. Surgical treatment involves metatarsophalangeal joint correction, but the type of surgery is influenced by whether the deformity is fixed or flexible. Fixed hammertoe deformities are corrected through resection arthroplasty of the PIP joint, with the aim of reducing soft tissue contraction forces through toe shortening. Additional procedures such as flexor/extensor tenotomies, metatarsophalangeal joint release, or arthroplasty may be necessary. Weil osteotomies, which primarily involve metatarsal shortening, have also been used to correct the deformity.184 3808

Flexible hammertoe deformities are surgically corrected with a Girdlestone flexor tendon transfer. This involves harvesting the long flexor tendon from the plantar aspect of the foot and surgically affixing this into the extensor hood. Thus, the tendon functions as both an extensor of the interphalangeal joints and a flexor the metatarsophalangeal joint.179 The major complication of Girdlestone flexor tendon transfer is a failure to identify a contracture of the flexor digitorum longus tendon during surgery, resulting in inadequate correction.183

CLAW TOE DEFORMITY Etiology Claw toe deformity results from dorsiflexion of the proximal phalanx on the lesser metatarsophalangeal joint and concurrent flexion of the PIP and distal interphalangeal joints (Fig. 70.19).183 Pain results from friction between the interphalangeal joints and the shoe. In addition, patients experience pain underneath the metatarsal heads from being in plantarflexion.179 As with hammertoes, claw toe deformities may be flexible or fixed. They typically involve all four of the lesser toes. The clinical evaluation is similar to that of hammertoe deformities, including inspection for possible callus and ulcer formation along the extensor surface of the PIP joints.

FIGURE 70.19 Claw toe deformity, a typical small toe deformity, often causes corns and calluses with standard footwear. Extra deep shoes avoid these problems.

Diagnosis Radiographic imaging should include weight-bearing anteroposterior and lateral radiographs of the involved foot.179

Treatment Conservative management includes wearing shoes that have increased 3809

depth to reduce pressure on the lesser toes and placement of arch supports underneath the metatarsal heads. Shoe inserts can be positioned proximal to the metatarsophalangeal joints in flexible deformities that are mild. The flexible deformity is corrected with a Girdlestone flexor tendon transfer. The fixed deformity requires a DuVries proximal phalangeal condylectomy in conjunction with the Girdlestone tendon transfer procedure.179 As with hammertoe surgical correction, the major complication is inadequate correction and subsequent recurrence of the deformity.183

HARD CORN (CLAVUS DURUM) Corns are painful, hyperkeratotic skin lesions located over bony prominences that result from excessive pressure on the skin. Histologic specimens reveal hyperplasia of the epidermis, especially proliferation of the stratum corneum.185 Hard corns are notable for their dry, horny appearance that develops over the dorsal and lateral surfaces of the fifth toe, on the lateral condyle of the proximal phalanx.

Treatment Conservative treatment is aimed at reducing pressure on the bony prominences by wearing shoes with large toe boxes. Surgical correction involves débridement of the lesion and, occasionally, necessitates removal of the distal portion of the proximal phalanx. The most common complication of the latter surgical procedure is excessive bone removal, resulting in a flaccid fifth toe.186

SOFT CORN (CLAVUS MOLLUM) Soft corns are macerated lesions that frequently occur in the fourth web space between the base of the proximal of the fourth toe and the medial condyle of the head of the proximal phalanx of the fifth toe.179 These typically develop as a result of small bony protrusion anomalies that cause pressure points, which can then result in ulceration.186

Treatment As with hard corns, management first focuses on reducing pressure on the 3810

bony prominences through utilization of footwear with large toe boxes. Other treatment modalities include the use of keratolytics such as salicylic acid.187 Surgical treatment involves removal of the bony protrusion.

INGROWN TOENAIL (ONYCHOCRYPTOSIS) An ingrown toenail is a painful condition resulting from nail plate penetration on the medial or lateral nail fold epithelium (Fig. 70.20). This typically involves the great toe. It is associated with trauma, tight-fitting footwear, improperly trimming the nails at the nail margins, and aberrant nail curvature.188

FIGURE 70.20 Ingrown toenail is often caused by improper nail cutting techniques or by wearing ill-fitting footwear that creates pressure against the lateral nail fold producing exquisite pain and tenderness.

Treatment If no infection is present, initial treatment includes elevation of the nail by placing cotton between the nail plate and the skin. This can be aided by daily foot soaks and removal of any pressure points on the nail. Additional treatment involves trimming an oblique portion of the affected nail toward the posterior nail fold under a digital block.188 The nail groove is then débrided and dressed. If infection or granulation occurs, treatment is focused on partial removal of the nail plate. This involves performing a digital nerve block, followed by a longitudinal incision from the base to the tip of the affected region of the nail plate, including the nail beneath the cuticle. The nail is then grasped with a hemostat and removed from the nail groove using a rocking motion. The nail groove is then débrided and 3811

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167. Beertema W, Draijer W, van Os J, et al. A retrospective analysis of surgical treatment in patients with symptomatic hallux rigidus: long-term follow-up. J Foot Ankle Surg 2006;45(4):244–251. 168. Coughlin M, Shurnas P. Hallux rigidus: demographics, etiology, and radiographic assessment. Foot Ankle Int 2003;24(10):731–743. 169. Kitaoka H, Patzer G. Chevron osteotomy of lesser metatarsals for intractable plantar callosities. J Bone Joint Surg 1998;80(3):516–518. 170. Coughlin M. Common causes of pain in the forefoot in adults. J Bone Joint Surg 2000;82(6):781–790. 171. Tsai W. Treatment of proximal plantar fasciitis with ultrasound-guided steroid injection. Arch Phys Med Rehabil 2000;81(10):1416–1421. 172. York PJ, Wydra FB, Hunt KJ. Injuries to the great toe. Curr Rev Musculoskelet Med 2017;10(1):104–112. 173. Eggebeen A. Gout: an update. Am Fam Physician 2007;76(6):801–808. 174. Ruddy S, Harris EJ, Harris C, et al, eds. Kelly’s Textbook of Rheumatology. 7th ed. Philadelphia: Elsevier Saunders; 2001. 175. Shekelle PG, Newberry SJ, FitzGerald JD, et al. Management of gout: a systematic review in support of an American College of Physicians clinical practice guideline. Ann Intern Med 2017;166(1):37–51. 176. Lee S, Sun I, Lu Y, et al. Surgical treatment of the chronic tophaceous deformity in upper extremities—the shaving technique. J Plast Reconstr Aesthet Surg 2009;62:669–674. 177. Graham C, Graham D. Morton’s neuroma: a microscopic evaluation. Foot Ankle 1984;5(150):150–153. 178. Hassouna H. Morton’s metatarsalgia: pathogenesis, aetiology and current management. Acta Orthop Belgica 2005;71(6):646–655. 179. Skinner H, ed. Current Diagnosis and Treatment in Orthopedics. 4th ed. Philadelphia: McGraw-Hill; 2006. 180. George VA, Khan AM, Hutchinson CE, et al. Morton’s neuroma: the role of MR scanning in diagnostic assistance. Foot 2005;15(1):14–16. 181. Magnan B, Marangon A, Frigo A, et al. Local phenol injection in the treatment of interdigital neuritis of the foot (Morton’s neuroma). Chir Organi Mov 2005;90(4):371–377. 182. Klenerman L. Morton’s neuroma. Curr Orthop 1997;11(1):15–18. 183. Kirchner J, Wagner E. Girdlestone-Taylor flexor extensor tendon transfer techniques. Foot Ankle Surg 2004;3(2):91–99. 184. Trnka H, Gebhard C, Muhlbauer M. The Weil osteotomy for treatment of dislocated lesser metatarsophalangeal joints: good outcome in 21 patients with 42 osteotomies. Acta Orthop Scand 2002;73(2):190–194. 185. Wolff K, ed. Fitzpatrick’s Dermatology in General Medicine. 7th ed. New York: McGrawHill; 2008. 186. Canale T, ed. Campbell’s Operative Orthopaedics. 10th ed. St. Louis, MO: Mosby; 2003. 187. Cordoro K, Ganz J. Training room management of medical conditions: sports dermatology. Clin Sports Med 2005;24(3):565–598. 188. Tintinalli J, ed. Tintinalli’s Emergency Medicine: A Comprehensive Study Guide. 6th ed. Philadelphia: McGraw-Hill; 2004.

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NECK AND LOW BACK PAIN CHAPTER 71 Neck Pain ANDREW J. ENGEL and NIKOLAI BOGDUK

Definition In its taxonomy, the International Association for the Study of Pain (IASP)1 construed neck pain to be pain arising from the cervical spine. It defined cervical spinal pain from a posterior perspective as pain anywhere in a region bounded superiorly by the superior nuchal line, laterally by the margins of the neck, and inferiorly by an imaginary transverse line through the T1 spinous process1 (Fig. 71.1). The definition allowed for the identification of upper and lower cervical spinal pain, for pain located in the respective halves of this region.

FIGURE 71.1 Neck pain is defined as pain perceived within a region bounded superiorly by the superior nuchal line, laterally by the margins of the neck, and inferiorly by an imaginary transverse line through the T1 spinous process.1

Neck pain was defined in this way primarily because patients with neck 3820

pain typically indicate the location of their pain as behind the cervical spine. A supplementary reason was to distinguish neck pain of spinal origin from pain arising from the viscera of the neck, which lie anterior to the cervical spine.1

Referred Pain Numerous experiments in human volunteers2–7 have shown that pain from various somatic structures, such as the posterior neck muscles, cervical synovial joints, and cervical intervertebral disks, can be referred to various extents in various directions, depending on the segmental location of the source of pain. This type of pain is known as somatic referred pain and is different and distinct from cervical radicular pain. It does not involve irritation of nerve roots. It arises because of convergence of primary afferents on common neurones in the spinal cord.1 Thus, pain that is mediated by a particular nerve, and relayed to a particular spinal cord segment, may be perceived in the territory subtended by other nerves that relay to that spinal cord segment. Characteristically, somatic referred pain is dull and aching in quality, in contrast to the lancinating quality of radicular pain. Furthermore, somatic referred pain tends to be sessile; it occupies a particular region and may expand slowly, in contrast to radicular pain which tends to shoot or travel in a linear pattern.1 From upper cervical segments (C1, C2, C3), pain can be referred into the occipital region, across the parietal region of the skull, and into the frontal region or orbit (Fig. 71.2). From lower cervical segments (C5, C6, C7), pain can be referred across the shoulder or shoulder girdle (see Fig. 71.2).

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FIGURE 71.2 Referred pain from the cervical spine. From upper cervical segments, pain can be referred into the occiput and into the head (inset). From lower cervical segments, pain can be referred into the region of the shoulder and shoulder girdle.

Older studies, using injections of hypertonic saline into the interspinous spaces of the neck, reported patterns of referred pain extending into the arm, forearm, and hand,2,4 but these observations have not been corroborated using modern techniques. Although some physicians have reported anecdotally that they have encountered such distant patterns of somatic referred pain, these patterns have not been formally documented in the modern literature. That literature indicates that the common patterns of somatic referred pain from the cervical spine are more proximal in distribution. Patterns of referred pain are not dependent on the structure that is the source of pain. The pattern is dictated by which segmental nerves innervate the source. Consequently, for example, the cervical zygapophysial joints5,6 and cervical intervertebral disks7 in the same vertebral segments have similar patterns of referred pain because they share a similar segmental nerve supply (Fig. 71.3).

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FIGURE 71.3 Patterns of referred pain from the cervical zygapophysial joints or the intervertebral disks at the segments indicated.

These patterns of referred pain, evoked by noxious stimuli in volunteers, have been corroborated and elaborated by studies of patients whose neck pain has been abolished temporarily by controlled diagnostic blocks of the cervical zygapophysial joints and lateral atlantoaxial joints.8 Pain from the C3–C4 segment may extend into the occipital region but largely tends to lie topographically over the levator scapulae muscle. Pain from C4–C5 tends to nestle into the angle between the neck and the top of the shoulder. Pain from the C5–C6 segments tends to radiate over the deltoid region of the shoulder. Pain from C6–C7 segments tends to spread more posteriorly, over the shoulder girdle, but there can be considerable overlap between the distributions of referred pain from C5–C6 and C6–C7. Pain from C1–C2 and C2–C3 structures radiates into the occipital region but can extend across or through the head into the forehead or orbit. Although there is considerable overlap between the pain patterns of C1–C2 and C2–C3, pain from C1–C2 tends to spread somewhat more rostrally across the vertex and into the forehead rather than across the parietal region and into the orbit.8

CERVICOGENIC HEADACHE In some patients with neck pain referred to the head, headache is their dominant complaint. Consequently, they seek the attention of neurologists 3823

or other specialists in headache. In those circles, this type of headache is referred to as cervicogenic headache, if and once the cervical origin of pain is established.9–11

Pursuing Diagnosis The rubric “neck pain” is not a diagnosis; it is simply a restatement of the patient’s presenting complaint. A diagnosis requires a statement of the source of pain, if not also its cause. However, because a diagnosis is not often possible, most practitioners avoid pursuing a diagnosis and manage neck pain as a symptom rather than a diagnosis. Neck pain does not include neurologic symptoms or signs. If a patient exhibits features of radiculopathy or myelopathy, those features take precedence. The pursuit of diagnosis converts from a pursuit of neck pain to a pursuit of the neurologic disorder. Traditional means of pursuing a diagnosis are history, examination, and imaging. To these have been added minimally invasive tests. These approaches or tools have different utility depending on the category of neck pain established by history. Very few causes of neck pain can be diagnosed from history alone, but history does provide cues that define different categories of neck pain. The five useful categories are trauma, acute, chronic, whiplash, and cervicogenic headache. These categories differ in terms of the nature, volume, and quality of evidence that apply to each, both for diagnosis and subsequent treatment. Although physical examination may provide an assessment of the patient’s disability to move his or her neck, it does not contribute to diagnosis. Features such as range of movement, aggravation of pain, and tenderness are nonspecific; they can be affected or produced by virtually any cause of neck pain. Moreover, most signs elicited by physical examination of the neck lack either reliability or validity or both.12 Therefore, they cannot be relied on to make a diagnosis. Medical imaging can detect fractures, tumors, and infections, but these are rare causes of neck pain. For most patients, imaging provides no diagnostic information. Medical imaging, therefore, has no role in the 3824

routine screening of patients with acute neck pain. In order to be efficient, and not wasteful, its use should be predicated by particular features in the patient’s history or presentation. Minimally invasive tests have no established or proven role in the investigation of acute neck pain. Their role lies in the pursuit of the causes of chronic neck pain.

TRAUMA Serious injuries to the neck can arise from motor vehicle accidents, falls, or a blow to the head. This etiology will be evident from the history. The lesions of concern are fractures to the cervical spine, particularly fractures that threaten the integrity of the spinal cord, for these may require specialist management by immobilization or urgent surgery. However, fractures are not common, even among patients with a history of significant injury. A review of studies in departments of emergency medicine found that only 3.5% ± 0.5% of patients suspected of possibly having a fracture proved to have a fracture on imaging.13 Studies looking for predictors of fractures have shown that the alerting features are loss of consciousness, neurologic signs, and immediate onset of pain.14 These features have been captured in the Canadian C-Spine Rules,15 which are validated guidelines for the use of imaging in the pursuit of fractures (Fig. 71.4). Given the low pretest likelihood of fractures, even in patients at risk, these rules serve to eliminate unnecessary imaging in patients in whom the likelihood of fractures is essentially zero and in whom any missed fractures are unlikely to be of practical consequence.

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FIGURE 71.4 The Canadian C-Spine Rules.1 MVC, motor vehicle collision.

ACUTE NECK PAIN Technically, the definition of acute neck pain is pain that has been present for less than 3 months.1 However, in practice, acute neck pain would be pain of recent onset, measured in hours or days. Whereas other considerations will apply later, the prime imperative of assessment of acute neck pain is the recognition of conditions that involve a serious cause of pain, or systemic conditions in which involvement of the neck is only part of the problem (Table 71.1). TABLE 71.1 A Synopsis of the Causes of Acute Neck Pain 3826

Uncommon or Rare Serious

Nonserious

Common

Fractures Tumors Discitis Septic arthritis Osteomyelitis Meningitis Epidural abscess Epidural hematoma Aneurysms Intracranial lesions Rheumatoid arthritis Ankylosing spondylitis Polymyalgia rheumatica Longus colli tendonitis Crystal arthropathies Neuromas

Unknown

Serious Conditions Serious causes of acute neck pain are rare. Two population studies of plain radiography of the cervical spine, each involving over 1,000 patients, both reported not detecting any serious disorder that was not otherwise suspected from the patient’s history.16,17 By inference, this zero prevalence of undiagnosed fractures, tumors, or infections has an upper 95% confidence limit of 0.4%. Thus, it can be deduced that serious causes of neck pain have a prevalence substantially less than 0.4%. This rarity argues against wanton application of medical imaging to screen for conditions that are extremely unlikely to be present. Screening for suspected fractures should be governed by the Canadian C-Spine Rules (see Fig. 71.4). For tumors and infections, no guidelines have been validated for the cervical spine, but in principle, those for the lumbar spine would seem applicable.18 For tumors, the indications for imaging would be a past history of cancer or persistence of pain and failure to improve on treatment. For infections, the indications would be a history of possible inoculation, an evident source for infection, immunosuppression, systemic features of infection, or failure to improve. Meningitis is readily suspected on clinical grounds (fever, neck stiffness, Kernig’s sign). Epidural hematoma is a serious condition because it threatens the spinal 3827

cord. Once neurologic signs appear, the window of opportunity for successful neurosurgical decompression is only a matter of hours.19 However, the initial presenting feature may simply be neck pain,20,21 but motor and sensory deficits develop usually within hours of the onset of pain.20,22–24 Patients presenting with neck pain should be warned to report immediately the onset of any new clinical features, at which time the instigation of investigations can be considered. Aneurysms most commonly present with headache, but neck pain alone can be the sentinel feature of dissections of the internal carotid artery, the vertebral artery, or the aorta.25–29 The alerting features to these conditions are a history of cardiovascular risk factors, direct trauma to the neck, and the onset of cerebrovascular features. A case report records two patients in whom neck pain was the presenting feature of intracranial lesions: one a subarachnoid hemorrhage and the other a glioblastoma multiforme.30 The mechanism of pain was neither determined nor discussed but possibly involves irritation of the dura mater of the posterior cranial fossa, which is innervated by cervical nerves. The rarity of such cases, however, excuses intracranial lesions from the differential diagnosis of acute neck pain in the first instance, but physicians should remain alert to this possibility in patients with persistent, unresponsive neck pain.

Inflammatory Disorders Neck pain can be, or can become, an additional feature for systemic inflammatory disorders such as rheumatoid arthritis, seronegative spondyloarthropathies, polymyalgia rheumatica, Reiter’s syndrome, and psoriatic arthritis. In such cases, the neck pain does not warrant pursuit of diagnosis, for the diagnosis is evident from the primary features of these conditions, such as widespread distribution of arthritis, arthralgia, or muscle pain. Longus colli tendonitis is a rare condition that involves inflammation and edema of the upper portion of the longus colli muscle. The presenting features are neck pain, limitation of neck movement, and difficulties swallowing.31 Medical imaging reveals edema in the prevertebral space and prevertebral muscles of the neck, and calcification can occur in the 3828

longus colli. Although alarming, the condition is self-limiting within about 2 weeks.31

Widespread Pain The neck can be one of several regions affected in widespread pain conditions such as fibromyalgia, but in such cases, the diagnosis is that of the widespread pain. A pursuit of the cause of the neck pain in particular is neither warranted nor required.

Rare Conditions Because the cervical spine contains many synovial joints, in principle, these could be affected by crystal arthropathies, which need to be considered in the differential diagnosis of neck pain. However, gout has a predilection for joints of the appendicular skeleton, and although it can affect the spine, it does so rarely.32 Other crystal arthropathies have not been reported affecting the cervical spine. Injuries to peripheral nerves of the shoulder girdle, such as the long thoracic nerve and the spinal accessory nerve, may not be readily apparent because they do not cause sensory problems, and patients may not be immediately aware of their motor deficits. Pain occurs not because of a cervical lesion but as a result of a neuroma developing on the proximal stump of the severed nerve and affecting deep sensory afferents.33 Because these afferents relay to cervical segments, the pain of the neuroma will be perceived as cervical pain.

Spurious Conditions Diffuse idiopathic skeletal hyperostosis, ossification of the posterior ligament, and Paget disease are conditions that can affect the neck, but there is no evidence that they cause neck pain. Paget disease has been expressly reported as not causing pain when it has affected the cervical spine.34 Although commonly invoked as a diagnosis, cervical spondylosis is no more than a radiographic change with age; it is no more frequent in patients with neck pain than in patients with no pain.35–37 Likewise, osteoarthritis of the cervical spine has no relationship to neck pain. If 3829

anything, the data show that patients with osteoarthritis of the cervical synovial joints are slightly less likely to have pain, although not significantly so statistically.37 A rubric commonly used for the diagnosis of neck pain is “soft tissue injury,” but this term means no more than neck pain in the absence of a fracture, without the nature of the “injury” and its location being specified. “Myofascial pain” is purportedly a diagnosis of neck pain when it affects the muscles of the neck. However, no signs for the diagnosis of this condition have been shown to be reliable,38 and none has been shown to be valid.

Unknown Because detectable causes of acute neck pain are rare, for most cases, the cause is unknown. For this reason, the IASP offered the rubric cervical spinal pain of unknown origin. However, although this term serves the strict requirements of taxonomy, it is unwieldy. No less wieldy is the term neck pain of unknown origin. For this reason, a term commonly used is idiopathic neck pain.

CHRONIC NECK PAIN The literature provides little evidence concerning the diagnosis of chronic neck pain. In contrast, there is an abundance of evidence concerning neck pain after whiplash, but it is not clear the extent to which the latter can be translated legitimately to chronic neck pain of spontaneous origin. Chronic neck pain amounts to neck pain that has persisted beyond 3 months.1 Commonly in practice, chronic neck pain is attributed to cervical spondylosis or cervical osteoarthritis, but as discussed earlier, these radiographic features have no statistically significant relationship to pain. By some practitioners, chronic neck pain is attributed to myofascial pain, but for this concept, there are no reliable or validated diagnostic criteria. To some extent, the guidelines for the pursuit of diagnosis of acute neck pain apply to chronic neck pain, but by the time neck pain has become chronic, many of the serious causes of neck pain will have declared themselves. However, some exceptions apply. Some tumors may be slow growing. Some spinal infections may remain 3830

cryptic for a long time. For the diagnosis of cervical spondylodiscitis, delays of 12 to 15 weeks have been reported.39 It is, therefore, appropriate to use cervical magnetic resonance imaging (MRI) to clear patients with chronic neck pain of cryptic lesions before pursuing other diagnostic tests. Other cryptic lesions include osteitis fibrosa cystica40 and other bone lesions. The reason for the lack of evidence on the diagnosis of chronic neck pain is that, apart from cryptic lesions, no feature on history, physical examination, or medical imaging has been shown to be diagnostic of any cause of chronic neck pain. It is for that reason that some physicians resort to minimally invasive tests for the diagnosis of chronic neck pain.

Cervical Disk Stimulation Cervical disk stimulation is a test for neck pain stemming from a cervical intervertebral disk. The test involves introducing spinal needles, along an anterolateral approach, into the disk suspected of being the source of pain and into adjacent disks that serve as controls41 (Fig. 71.5). Once the tip of the needle is placed at the center of the disk, a small volume of contrast medium, or normal saline, is injected into the disk in order to stress it (see Fig. 71.5). A positive response is one in which stimulation of the suspected disk reproduces the patient’s pain but stimulation of adjacent disks evokes no pain.41 However, caveats apply to the validity of cervical disk stimulation.

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FIGURE 71.5 Fluoroscopy images of stages in cervical disk stimulation. A: Anterior view of needles inserted into the C4, C5, and C6 intervertebral disks. B: Lateral view of needles inserted. C: Anterior view after injection of contrast medium into each of the intervertebral disks. D: Lateral view after injection of contrast medium. (Reproduced with permission from Bogduk N, ed. Practice Guidelines for Spinal Diagnostic and Treatment Procedures. 2nd ed. San Francisco, CA: International Spine Intervention Society; 2013.)

In the first instance, cervical disk stimulation can be false positive in patients whose neck pain stems from the cervical zygapophysial joints at the tested segment.42 In such patients, anesthetizing the zygapophysial joints relieves their pain completely. Because the innervation of the zygapophysial joints is topographically separate from that of the disk, local anesthetic blocks of the joints cannot anesthetize the disk. Therefore, the positive response to disk stimulation must be false either because disk stimulation also stresses the zygapophysial joints or because the tested segment is rendered hyperalgesic by the zygapophysial joint pain. Consequently, in order to be valid, cervical disk stimulation should only be performed in patients in whom cervical zygapophysial joint pain has been excluded.42 It has been conventional to perform cervical disk stimulation typically at segmental levels C4–C5, C5–C6, and C6–C7, on the grounds that the C5– C6 and C6–C7 disks are the most likely sources of cervical discogenic 3832

pain. However, this practice introduces another source of false-positive responses. A study showed that if all disks are tested, rather than just the usual three, there are often disks at other than accustomed levels that happen to be positive.43 Consequently, restricting the application of disk stimulation to just the lower three cervical disks generates both falsepositive and false-negative responses. If one of the three disks is positive to stimulation, the response will be false positive if there happens also to be a positive disk at a segment not tested. Conversely, testing just the lower three disks will be false negative if no disk at these levels is positive but a positive disk at higher levels remains untested. To avoid these problems, the standard of care has to be that all cervical disks must be tested.42

Medial Branch Blocks Cervical medial branch blocks are a test for pain stemming from a cervical zygapophysial joint. The test involves anesthetizing the medial branches that innervate the joint suspected of being the source of pain44 (Fig. 71.6). In order to be valid, the blocks must be controlled. Placebo-controlled blocks are the consummate standard, but an acceptable compromise is comparative local anesthetic blocks.44–46 On the occasion of the first block, the patient is randomized to receive either a short-acting (lidocaine) or a long-acting (bupivacaine) local anesthetic. If the response is positive, the block is repeated using the same or other agent.44–46 A positive result is defined as complete relief of the index pain on both occasions that the joint is anesthetized.44–46

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FIGURE 71.6 A lateral fluoroscopy view of a needle in position for the conduct of a C5 medial branch block. (Reproduced with permission from Bogduk N, ed. Practice Guidelines for Spinal Diagnostic and Treatment Procedures. 2nd ed. San Francisco, CA: International Spine Intervention Society; 2013.)

Prevalence No studies have provided data on the prevalence of either cervical discogenic pain or cervical zygapophysial joint pain in patients with chronic neck pain of spontaneous origin (i.e., idiopathic neck pain). The only data come from three studies conducted in pain clinics, on mixed samples of patients with neck pain with or without a history of minor trauma to the neck.47–49 Two of these studies reported only on the prevalence of cervical zygapophysial joint pain, which they found to be 36%47 and 60%.48 In the third study, the prevalence of zygapophysial joint pain was 45%, and the prevalence of discogenic pain was 13%.49 These data show that the cervical zygapophysial joints are the most common, detectable source of chronic neck pain, and that discogenic pain is substantially less common.

WHIPLASH Neck pain after whiplash can be distinguished from other categories of neck pain by the precipitating event: a read-end motor vehicle collision. This distinction is made because the motor vehicle accident constitutes circumstantial evidence that the patient possibly has an injury that could be the cause of their pain. For patients with idiopathic neck pain, no such 3834

etiology is available.

Etiology Studies of car crash dummies50 and of human volunteers51 have shown that, during a whiplash event, the cervical spine is initially compressed from below by a rising thorax. This causes a sigmoid deformation of the spine, during which the entire spine does not move outside the normal physiologic range of motion, but individual segments, typically C5–C6, undergo an abnormal posterior sagittal rotation. Later, the head catapults forward, and the cervical spine is passively flexed. During this phase, stresses are applied to the capsules of the zygapophysial joints, particularly those at C2–C3. The stresses are not large enough to tear the capsules but are nevertheless large in magnitude.52

Clinical Features The cardinal feature of a whiplash injury is neck pain. However, the prognosis is quite favorable. Some 60% of patients fully recover within 3 months, and 75% within a year (Fig. 71.7). Only about 25% of patients suffer disabling chronic pain, of whom a fifth are severely disabled.53

FIGURE 71.7 The recovery curve for whiplash. Most patients recover within 3 months or so, leaving a tail of about 25% with chronic neck pain. (Based on the data of Radanov BP, Sturzenegger M, Di Stefano G. Long-term outcome after whiplash injury: a 2-year follow-up considering features of injury mechanism and somatic, radiologic, and psychosocial findings. Medicine 1995;74:281–297.)

Mathematically, the recovery curve for whiplash (see Fig. 71.7) suggests that it is a composite of two populations, as shown in Figure 71.8. 3835

Group A are patients who recover rapidly regardless of treatment and respond well to reassurance, activation, and exercises. Group B are patients who do not recover and do not benefit even from tailored conservative care. These patients have greater pain, disability, and psychological distress at onset and exhibit cold hyperalgesia and mechanical hyperalgesia remote from the cervical spine.54 These differences suggest that the two groups suffer different injuries or injuries of different severity.

FIGURE 71.8 A graph showing how the recovery curve in Figure 71.7 can be resolved into two populations of patients: those who recover quickly (A) and those destined ab initio to have persistent disability (B).

For lack of reliability, validity, or both, no features on history or physical examination have been able to identify any source or cause of neck pain after whiplash. For patients with temporary pain, which recovers spontaneously, “muscle sprain” is the most plausible conjecture, but it has never been identified in patients in a valid manner. In case reports or small, descriptive series, lesion such as small fractures,55,56 aneurysms of the vertebral artery or internal carotid artery57–59 have been reported in individual patients but not in any substantial proportion of patients with either acute or chronic neck pain after whiplash. In clinical studies, the source of chronic neck pain after whiplash has been traced to the cervical zygapophysial joints in 54%60 and 60%61 of patients. Studies in laboratory animals have shown that the lesion responsible for chronic zygapophysial joint pain is a submaximal strain of the joint capsule.62 After such strains, the affected joint becomes a source 3836

of persistent nociceptive output which generates, in the dorsal root ganglion and central pain pathways, metabolic changes that are the hallmark of chronic pain.63–74

Diagnosis For acute neck pain after whiplash, pursuit of diagnosis is not warranted. The condition is self-evident from the presenting complaint and history of injury. Imaging is not indicated according to the Canadian C-Spine Rules15 (see Fig. 71.4). Multiple studies using MRI have not identified any lesions that might the cause of pain.75–80 For chronic neck pain after whiplash, the only investigation that has been shown to have utility are cervical medial branch blocks. With a prevalence of 54% to 60%, cervical zygapophysial joint pain is the single most common basis for chronic neck pain after whiplash.52,60,61 The joints most commonly responsible are those at C2–C3 and C5–C68 (Fig. 71.9).

FIGURE 71.9 The segmental location of painful zygapophysial joints in patients with chronic neck pain after whiplash, as determined by controlled, diagnostic, medial branch blocks. 8Asterisks indicate the segments most commonly responsible.

Most often, the neck pain arises from the joints at one or other of these segments. Patients with C2–C3 zygapophysial joint pain have upper cervical pain and headache. Those with C5–C6 pain have lower neck pain and referred pain into the shoulder region. In patients with unilateral pain, 3837

the ipsilateral joint is the cause. In patients with bilateral pain, both joints at the responsible segment are typically the source. Less frequently, the C6–C7 zygapophysial joint is the source of pain, either alone or in combination with the C5–C6 joint. Other combinations can occur, although far less frequently such as C2–C3 together with adjacent or remote joints and C5–C6 together with joints above.

CERVICOGENIC HEADACHE Differential Diagnosis By definition, cervicogenic headache is explicitly pain referred to the head from the cervical spine. That implies a source of pain in the cervical spine. The differential diagnosis encompasses other causes of headache that do not lie in the cervical spine but are nonetheless innervated by cervical spinal nerves. These include aneurysms of the vertebral artery or internal carotid artery and lesions in the posterior cranial fossa that irritate or stretch the dura mater, such as tumors, hemorrhage, and infection. These conditions would be distinguished from cervicogenic headache by the onset of neurologic features or features of infection.

Diagnosis A variety of causes of cervicogenic headache have been postulated and promoted,9–11 but few have satisfied the diagnostic criteria required by the International Headache Society.81 Those criteria allow for clinical diagnosis provided that the diagnostic tests used have proven reliability and validity (Table 71.2), but no clinical features have been shown to have these properties. Otherwise, the diagnostic criteria require relief of pain by controlled, diagnostic blocks. TABLE 71.2 Diagnostic Criteria for Cervicogenic Headache as Proposed by the International Headache Society81 Diagnostic Criteria A. Pain referred from a source in the neck and perceived in one or more regions of the head and/or face, fulfilling criteria C and D B. Clinical, laboratory, and/or imaging evidence of a disorder or lesion within the cervical spine or soft tissues of the neck known to be, or generally accepted as, a valid cause of headachea C. Evidence that the pain can be attributed to the neck disorder or lesion based on at least one of

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the following: 1. Demonstration of clinical signs that implicate a source of pain in the neckb 2. Abolition of headache following diagnostic blockade of a cervical structure or its nerve supply using placebo or other adequate controlsc D. Pain resolves within 3 mo after successful treatment of the causative disorder or lesion aTumors,

fractures, infections, and rheumatoid arthritis of the upper cervical spine have not been validated formally as causes of headache but are nevertheless accepted as valid causes when demonstrated to be so in individual cases. Cervical spondylosis and osteochondritis are not accepted as valid causes fulfilling criterion B. When myofascial tender spots are, the headache should be coded under 2. Tension-type headache. bClinical signs acceptable for criterion C1 must have demonstrated reliability and validity. The future task is the identification of such reliable and valid operational tests. Clinical features such as neck pain, focal neck tenderness, history of neck trauma, mechanical exacerbation of pain, unilaterality, coexisting shoulder pain, reduced range of motion in the neck, nuchal onset, nausea, vomiting, photophobia, etc., are not unique to cervicogenic headache. These may be features of cervicogenic headache, but they do not define relationship between the disorder and the source of the headache. c Abolition of headache means complete relief of headache, indicated by a score of zero on a Visual Analogue Scale (VAS). Nevertheless, acceptable as fulfilling criterion C2 is >90% reduction in pain to a level of 1 diagnosis. c Irritation from hardware. b

There are four studies that reported on the causes of FBS in individual series. Unfortunately, one is from 1981 and two from 2002. The most recent study was in 2010 but only looked at patients with prior fusion. It does not appear that there have been more recent descriptions despite FBS being fairly common. Because of the age of the data, some considerations are necessary. There has been much greater recognition of neuropathic pain and pain arising from the SIJ pain and FJs. Surgical techniques have improved. There is greater recognition of foraminal stenosis. It is too early to know all the causes in patients who have undergone total disk replacement. That said, the data we have is what we have to work with, coupled with experience. Burton et al.4 in 1981 reported an analysis of several hundred patients with FBS. About 58% had foraminal stenosis, 7% to 14% had central canal stenosis, 12% to 16% had recurrent (or residual) disk herniations, 6% to 16% had arachnoiditis, and 6% to 8% had epidural fibrosis. Other less common causes in their series included neuropathic pain, chronic mechanical pain, painful disk above a fusion, pseudarthrosis, foreign body, and surgery performed at the wrong level. They were unable to establish a diagnosis in less than 5% of their patients, even though their patients were evaluated early in the CT scan era and well before MRI scans. They did use discography. In 1981, surgeons were less aware of foraminal stenosis and discogenic pain.

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In a retrospective review of 181 patients with FBS seen at a tertiary care spine center, Waguespack et al.5 could make a diagnosis in 94% of patients. Slipman et al.6 also could make a diagnosis in about 89% of patients. Some patients had more than one primary diagnosis. DePalma et al.7 looked at the etiology of pain in patients who had lumbar fusions. The details are shown in Table 75.2 In the following section, I have used functional definitions of structural abnormalities that are a composite of those proposed by the North American Spine Society.33 The differential diagnoses of some of the more common causes of FBS along with some helpful symptoms, signs, radiologic findings, and response to injections are shown in Table 75.3. TABLE 75.3 Differential Diagnosis of Common Causes of Failed Back Surgery by Symptoms, Signs, Radiology, and Injections Diagnosis

Symptoms

Signs

Radiology

Injections

Lateral canal stenosis

Leg pain > LBP; relief with sitting LBP; ? worse with sitting

Loss of lumbar lordosis

MRI: foraminal stenosis

Restricted flexion in standing Hypoalgesia Allodynia

MRI: degenerated disk(s) No alternative diagnosis

Relief with transforaminal epidural No sustained relief

? Facet tenderness

Not specific

Variable

HNP on MRI

May have + provocative testing

Not helpful

Painful disk

Neuropathic pain Facet syndrome

Recurrent HNP

SI joint pain

Leg pain burning Dysesthesia Left or right LBP Vary with location; leg pain > LBP Gluteal pain with referral to leg and groin

+/− relief with sympathetic block Medial branch block relieves pain Epidural may provide temporary relief SI joint injection relieves pain

HNP, herniated nucleus pulposus; LBP, low back pain; MRI, magnetic resonance imaging; SI, sacroiliac; +/−, may be helpful.

FORAMINAL STENOSIS Foraminal stenosis was found in 15% and 35% of FBS patients in the studies of Waguespack et al.5 and Slipman et al.,6 half of what was seen 25 3993

years ago.4 The lower prevalence may be due to increased awareness of the problem, improved imaging studies, and/or better understanding of the need for meticulous decompression. Patients with foraminal stenosis have pain that is predominantly in the leg or buttock region, often in the distribution of a single dermatome. Pain is usually worsened by standing and walking and relieved by sitting. MRI or CT scan shows narrowing of the canal at the index level or an adjacent segment. There are no data regarding the utility of selective nerve root blocks in FBS. There are suggestions that when performed with excellent technique, they can provide some information, especially perhaps when there is no relief, which might suggest the targeted root was not the cause of pain.10 According to one systematic review, there is good evidence that lumbar selective nerve root blocks can aid with the identification of one or more symptomatic roots.9 There is moderate evidence that identifying or excluding a root as cause of pain improves surgical outcome.9 Other systematic reviews did not find the evidence convincing.11

PAINFUL DISK (DISCOGENIC PAIN) Pain that arises from within a disk is often referred to as discogenic pain. One or more painful disks was found to be the cause of FBS in 25% to 30% of patients.4–7 Painful disks can occur at the level of prior surgery, at an adjacent segment, or rarely at the index level despite prior posterolateral fusion.34,35 When there is a residual painful disk at the index surgical level, it is likely that it was not treated adequately by performing a fusion, especially an interbody fusion. When there is a painful disk at an adjacent segment, it was either present prior to surgery and not addressed or the disk degenerated after surgery.35 Risk factors for adjacent segment degeneration include body mass index >25 kg/m, preoperative disk degeneration, and superior FJ violation during surgery Although there is no totally consistent symptom complex for discogenic LBP, especially after surgery, the diagnosis is more likely when there is dominant midline LBP that might radiate to the left and right of the midline, the gluteal regions, and often to the leg in a nondermatomal fashion. Pain is usually worse sitting and during transition from sitting to standing. It may improve with standing or walking. Physical examination 3994

is not specific. There may be decreased flexion in standing due to pain. There may be tenderness over the spinous processes but not over the FJs. When the diagnosis of discogenic pain is suggested by history and examination, MRI shows a single degenerated disk, and other potential causes of chronic LBP have been excluded, it is likely that the diagnosis is correct.

DISK HERNIATION Recurrent or residual disk herniation was seen in 7% to 12% of patients with FBS.4–6 There are two common presentations of pain from a disk herniation: radicular and axial. The topography of the pain is primarily due to the location of the herniation. A posterolateral herniation is more likely to compress or irritate a nerve root and therefore present with predominant leg pain. A midline herniation, unless very large, does not compress neural elements and presents with predominant LBP. A disk that is degenerated and herniated can cause both leg pain and LBP. In the presence of epidural or perineural fibrosis, a disk herniation may cause more leg pain than expected than if there were no fibrosis. Diagnosis of recurrent or residual disk herniation is inferred from the history and physical examination and confirmed by MRI.

FACET JOINT PAIN The FJs were the cause of pain in 3% to 18% of patients with FBS.6,7,36,37 FJ injury may occur during surgery because of progressive degeneration of the motion segment at the surgical level or degeneration due to the mechanical stresses of fusion at an adjacent segment. There has been increased interest in the role of FJs since the introduction of total disk arthroplasty (TDR). Van Ooij et al.38 reported that FJ arthrosis was responsible for clinical failure in 11 of 27 patients. Shim et al. reported radiologic degradation of the facets in 32% to 36% of patients after TDR.38,39 There are no reports of definitively correlated symptoms and signs of FJ pain in patients with FBS. Based on best evidence and clinical expertise, it is reasonable to perform medial branch blocks on most FBS patients as part of the routine evaluation when back pain (vs. leg pain) predominates 3995

unless there is another obvious cause for the problem.36,40 Features of the history that increase the likelihood of FJ pain being present are age greater than 65 years, absence of midline pain, and improvement in pain by lying supine. Other features are pain is not worse with forward flexion including sitting, not worse when rising from sitting to standing, and not worse with coughing. Features from the examination are tenderness to palpation over the FJs or transverse processes. The diagnosis of FJ pain is made when there is excellent relief of the target pain on two occasions after medial branch block.36

SACROILIAC JOINT PAIN There is consistent evidence that the SIJ can be a cause of pain in at least 2% to 3% in patients with FBS and may be as high as 42% in patients who have had fusion to the sacrum.5–7,41–43 The SIJ can become painful due to transfer of stress after fusion or might have been present before surgery but not recognized.44,45 Again, there are no specific signs or symptoms specific for SIJ pain, but there are clues to the diagnosis. Virtually all patients have pain distal to the posterior iliac crest and lateral to the midline spine. Some patients will point directly over the SIJ when asked to show where the pain is centered. Pain is frequently referred to the groin, thigh, calf, and occasionally the foot—patterns that might otherwise suggest radiculopathy or even hip joint pathology. Pain may increase with single-leg weight bearing. Most often, there is tenderness directly over the SIJ. Plain radiographs, MRI, and CT are not definitive. The confirmation of SIJ pain requires relief of the target pain after fluoroscopically guided local anesthetic SIJ injection.

SPINAL STENOSIS AND AXIAL LOW BACK PAIN The classic symptom of central spinal stenosis is leg pain with walking (neurogenic claudication) or standing. In addition, many if not most patients with spinal stenosis also report LBP.46–48 Anecdotally and experientially, there are patients with spinal stenosis with predominant LBP, especially in the gluteal region. Pain is worse with standing or walking, and there is complete or near-complete relief of pain sitting. This symptom complex is quite the opposite of discogenic pain but similar to FJ 3996

pain. Patients usually experience at least temporary relief of pain after epidural steroid injection and no relief after medial branch block, again just the opposite of FJ pain. The patients with FBS and predominant LBP might have spinal stenosis at the index level or an adjacent segment that developed after surgery or was not addressed at surgery.

NEUROPATHIC PAIN Neuropathic pain is pain due to injury or physiologic dysfunction of the peripheral or central nervous system (CNS). Neuropathic pain was the predominant problem in 10% to 13% of FBS patients.4–6 It is likely that there is increased attention being paid to neuropathic pain as better treatments have become available. There are several potential mechanisms for neuropathic pain after spine surgery. A nerve root could have been damaged prior to surgery due to either sudden injury (acute disk herniation) or prolonged compression from foraminal stenosis or disk herniation. In the latter two examples, radicular type pain continues despite technically successful surgery. Alternatively, a nerve could be damaged during the surgery itself, which is sometimes referred to as a battered nerve. There can be peripheral nerve injuries such as cluneal neuroma due to nerve injury at an iliac crest donor site. Meralgia paresthetica can also be seen.28,49 Neural injury or dysfunction can be responsible for both amplification and persistence of pain. Neuropathic pain of spinal origin usually presents with a predominance of leg pain in one or two adjacent dermatomes or along the path of a peripheral nerve. In classic presentations, the pain is described as burning, dysesthetic, or electrical, but in neuropathic disorders after spine surgery, pain is more frequently described as aching and stabbing. Pain may be constant or intermittent. It is often precipitated or aggravated by simple activities because the damaged nerves are hyperexcitable and respond abnormally to even minor mechanical changes. In pure and uncomplicated neuropathic pain, there is no evidence of nerve root compression on imaging studies. It is important to distinguish neuropathic pain from what I call neurogenic pain. Neurogenic pain implies that a nerve is being compressed or irritated rather than its being 3997

permanently damaged. To further complicate matters, some patients have both neuropathic pain plus ongoing neural compression (neurogenic), which is referred to as a mixed pain syndrome. Neuropathic pain can also be due to physiologic dysfunction in the peripheral nervous system or CNS without obvious structural nerve damage. Because of prolonged or repeated chemical or mechanical damage to afferent nerves, these nociceptors may become sensitized and hyperexcitable (peripheral sensitization). There is lowering of their activation thresholds and subsequent increased responsiveness to all stimuli. In this physiologically altered setting, innocuous stimuli may be perceived as painful (allodynia), minimally noxious stimuli may be perceived as very painful (hyperalgesia), and there can be stimulusindependent pain as well. A similar sensitization can develop in the CNS because of “constant bombardment” by painful afferent stimuli (central sensitization). In patients with persistent axial LBP (rather than the more typical neuropathic extremity pain) despite perfect surgery and no other explanation for pain, it has been proposed that the back pain represents central sensitization and neuropathic pain.50,51

EPIDURAL FIBROSIS Epidural fibrosis has been reported to occur in 16% of patients with FBS when assessed by MRI and 83% when assessed by epiduroscopy.52 Some believe epidural fibrosis is a frequent cause of pain after back surgery, but others have found no relation between amount or location of scar and pain or disability.52–54 Most spine surgeons feel that most often fibrosis is an incidental finding that does not in and of itself causes pain but perhaps has the potential to make other problems such as radiculopathy due to disk herniation or spinal stenosis worse.53 That said, it is true that some patients with FBS and fibrosis do improve after lysis of adhesions, but this is not proof that the scar itself was the cause.55 Most authors feel that further research is necessary before epidural lysis becomes standard practice.

DECONDITIONING Deconditioning has been considered to be at least partially responsible for 3998

the persistent pain and pain-related impairment and disability in many patients with chronic LBP and FBS. I view three models for this so-called deconditioning syndrome. The pure physical deconditioning model holds that loss of muscle strength and endurance is responsible for reduced activity, impairment, and disability.56 The cognitive-behavioral model emphasizes the fear-avoidance paradigm, which holds that some patients with chronic LBP avoid activities out of pain-related catastrophic thinking and fear.56 They believe that attempts to increase their function will result in increased pain and progressive structural damage, and, as a result, they markedly curtail their activity. A third model is a combination of the two in which patients have both the maladaptive fear avoidance and true physical deconditioning. As a result of the fear-avoidant decreased activity, there is disuse (perhaps better termed underuse) with progressive loss of muscle strength and endurance.56–60 In patients with chronic LBP and deconditioning, the paraspinal musculature is most affected.57 There is MRI, CT scan, and ultrasound evidence that after spine surgery, many patients have decreased crosssectional area (CSA) of their lumbar muscles.58 Motosuneya et al.59 looked at the changes in muscle CSA after five different types of spine surgery and surprisingly found some loss of muscle strength even in those patients who had anterior spine surgery. They opined that rigid fixation and resultant protection of the paraspinal muscles was at least partly responsible.59 There is consistent evidence that posterior spine surgery (and possibly anterior as well) can cause loss of muscle density, histologic changes, and probably decreased strength. There is a trend in the evidence that suggests a correlation between greater muscle changes and LBP after surgery. Nearly all investigators agree there is good evidence that exercise is effective in reducing impairment and disability, but the mechanisms are not straightforward. Most likely, the deconditioning syndrome has both physical and psychological components. There can be loss of muscle volume and strength from the surgery itself and disuse. There might be a psychological component due to fear avoidance.

Psychological Factors in Failed Back Surgery 3999

(“Right Patient”) It has been well documented and fully accepted that many patients with chronic LBP have a psychological condition.13,14 It is no wonder then that presurgical psychological testing can predict the outcome of spine surgery quite well.13,61 It is also of note that spine surgeons and other spine specialists do not do well in the identification of psychological distress.15 In patients with chronic LBP, the most common psychological illnesses are depression, anxiety disorder, and substance abuse disorder, and so, it is logical that many of these same factors are present in patients with sufficient structural abnormalities to potentially warrant surgery.14 Most often, it appears that these psychological illnesses develop because of the injury.62 Although rarely the only cause of pain, psychological factors can make pain and function worse. Although preoperative depression correlates with postoperative symptoms, the literature suggests that the early psychological response is a very important predictor of longer term outcome.21,22 This might be particularly relevant to management of FBS and warrants special attention to depressive illness and fear avoidance. For example, Adogwa et al.63 showed that patient outcome for revision surgery for spinal stenosis, adjacent segment degeneration, and pseudoarthrosis correlated best with preoperative Zung Depression Scale score. In a different very useful framework, the fear-avoidance model is important for patients with FBS. Preoperative fear avoidance does not appear to be a significant risk factor of FBS, but its early appearance after surgery appears to be predictive of eventual poor outcome.22,23,64 Fear avoidance, in the postoperative setting, is the avoidance of movements or activities due to fears of ruining the surgery, causing more pain, and/or reinjury. Fear avoidance can lead to inactivity and then disuse and deconditioning, which might worsen any disability. In turn, increased pain and depressive mood disorder might follow. Archer and associates22 prospectively studied fear avoidance and other psychological factors before and after spine surgery. In their series, fear avoidance 6 weeks after surgery was predictive of level of pain, physical health, and disability at 6 months. In addition, preoperative depression 4000

predicted similar poor results. Catastrophic thinking, again in this context, is an exaggerated negative interpretation of the meaning of the pain.65 Patients dwell on the most negative conceivable aspects and feel helpless and hopeless. Such thinking can be present in the postoperative period and appears to correlate to some degree with fear avoidance. Yet, another model revolves around dysfunctional childhood and with what is now termed adverse childhood events. Such patients might be at higher risk for chronic pain, impairment, disability, and FBS.8,66 Identified disruptions include childhood physical or sexual abuse; abandonment; or parents who had addictive disease, chronic pain syndromes, or severe psychological illness, among others. It is also important to recognize that some of the psychological problems that can arise after surgery might be due to the psychological trauma of surgery itself (posttraumatic stress disorder [PTSD]) or the fear of making things worse afterward (fear avoidance and catastrophizing).67,68 Hart et al.67 reported a 22% prevalence of PTSD after spine surgery. This postoperative psychological distress was correlated with poorer outcome. The same authors also reported that preoperative psychiatric diagnosis was the strongest predictor of PTSD and seemed to be a stronger predictor of worse outcome than preoperative mental health.68

Establishing the Diagnosis ROLE OF THE HISTORY The history is the most important part of the evaluation of a patient with FBS. When possible, preoperative notes and imaging studies should be part of the history. The history provides the information necessary to order and interpret other diagnostic elements. The most important elements of the history include a thorough description of the current pain, a comparison of the pain before and after surgery, the time course of the reappearance of the pain, and the response of the pain to specific activities. It is also very valuable to analyze whether the type of surgery performed was appropriate for the preoperative symptoms and condition. The history 4001

should lead to a limited differential diagnosis, suggest the emphasis for the physical examination, and provide guidelines for selecting appropriate imaging studies and diagnostic injections. It is important to remember there may be more than one diagnosis present.

Preoperative Versus Current Pain Pain that is essentially the same before and after surgery in terms of severity, location, quality, and response to mechanical maneuvers suggests that the original problem was not corrected. There may have been an error in diagnosis, an error selecting the correct surgery, or an incomplete surgery. On the other hand, when symptoms have changed significantly, it is most likely that there is new pathology, either a complication of surgery, technical failure, or progression of the underlying disease.

Location of Pain (Especially Low Back Pain Versus Leg Pain) It is useful to divide FBS patients into those with predominantly LBP and those with predominantly leg pain. In general, when LBP is greater than leg pain, the most common causes are discogenic pain at the level of the index surgery or at adjacent levels, FJ pain, SIJ pain, or instability. If fusion was attempted, there may be a pseudarthrosis, although pseudarthrosis itself can be an incidental finding rather than the cause of pain. When leg pain predominates, the more common causes include residual foraminal stenosis; recurrent or residual disk herniation; neuropathic pain; and also SIJ dysfunction, hip disease, or peripheral nerve injury or entrapment.

Response to Mechanical Changes There are no studies that document the changes in pain in response to common activities in patients with FBS. Therefore, these correlations are extrapolated from studies in patients with chronic LBP and no prior surgery. These responses to biomechanical stresses are clues but obviously cannot be considered definitive. Response to Sitting

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LBP or leg pain that increases with sitting and with flexion in standing is more likely due to one or more painful disks or instability Leg pain that improves with sitting is usually due to spinal stenosis. Transition from Sitting to Standing LBP that worsens during the transition from sit to stand suggests disk pain or SIJ and speaks against FJ pain.14 LBP that increases with standing suggests posterior element pathology such as FJ pain. Leg pain that increases with standing or walking suggests spinal stenosis.

Quality of Pain The word the patient uses to describe the pain is occasionally helpful. Burning, electric shock-like pain, dysesthesia, or superficial (skin) tenderness to light touch (allodynia) suggests neuropathic pain. However, neuropathic pain after spine surgery may not fit these classical descriptors. Screening tests for neuropathic pain, although useful before surgery, are not as helpful after spine surgery.51

TIME COURSE OF APPEARANCE OF PAIN Preoperative Low Back Pain or Leg Pain Never Improves or Early Onset of Old Symptoms When LBP never improves or recurs within days to a month or so after surgery, it is most likely that the symptomatic structural pathology was not adequately addressed by surgery, there was a complication such as wrong level surgery or the wrong procedure for this particular patient was done. Partial pain relief implies correction of only part of the structural problem. This outcome falls in the category of residual pathology, and the differential diagnosis has already been outlined.

New Leg Pain Soon after Surgery The early appearance of new leg pain suggests direct neural injury during surgery, misplacement of a pedicle screw, or, less commonly, deep venous thrombosis.49

Pain Improves but Recurs 1 to 6 Months after Surgery 4003

Pain that improved initially but recurred in 1 to 6 months may be due to residual, recurrent, or new pathology. If pain location and description resemble preoperative symptoms, residual, or recurrent pathology is likely. Pain that has new characteristics is more likely due to new pathology. There may be recurrent disk herniation, failure (loosening of pedicle screws) of internal fixation, instability, and late infection.

Pain Improves but Recurs and Is Different Pain that recurs late and has a different location or quality compared to the preoperative pain is more likely due to new pathology, which can occur at the index level or adjacent segment. Adjacent segment problems include painful degenerated disk, herniation, stenosis, or facet dysfunction. In addition, SIJ problems occur, especially if there is fusion to L5 or the sacrum.

ROLE OF RADIOLOGIC EVALUATION OF FAILED BACK SURGERY The radiologic evaluation is important. The choice of the type of imaging is determined by the surgery performed and clues from the history and physical examination, which usually allow for a reasonable differential diagnosis. The best information will be obtained if the clinician consults with the radiologist regarding the suspected diagnosis, type of prior surgery, and current symptoms. The radiologist can then follow along with the testing in real time, which should yield the best information. Radiologic examination should include plain x-rays and MRI scan.8,25,69,70 CT is important if there is suspicion that the problem involves the bony structures, nonunion of fusion or location, or fracture of internal fixation screws, or if the patient is very claustrophobic.8,24,69 There are only rare indications for nuclear imaging studies (infection, possible malignancy, possible rheumatologic illness), myelography (pseudomeningocele), or CT myelography. Standard radiographs with standing flexion and extension lateral views and anteroposterior (AP) view are very important and are too frequently not performed.8 These standard films are used to evaluate whether the desired segment(s) were addressed as an assessment of the alignment in 4004

multiple planes, extent of disk space narrowing if any, spondylolisthesis, and when fusion has been attempted, pseudarthrosis, or broken or misplaced internal fixation devices.8,24 There are several excellent reviews of postoperative imaging that demonstrate the normal findings based on type of surgery as well as findings that indicate a structural problem.25,69,70 MRI is usually the optimal exam for most FBS patients. It is important that the radiologist knows this is a patient with FBS so the proper imaging sequences are obtained. MRI is excellent for the diagnosis of spinal stenosis, disk herniation, disk degeneration, and infection. It will show if decompression was adequate to decompress the nerve root. Arachnoiditis can easily be detected with MRI but is less valuable when there are certain types of instrumentation.

ROLE OF DIAGNOSTIC INJECTIONS Anesthetic Injections There are little data on the utility of diagnostic spinal injections in patients with FBS.9,36 Anesthetic injections are the standard for the diagnosis of FJ and SIJ pain.36,71,72 A transforaminal injection (TFI) is sometimes used to determine if a nerve that appears compressed on MRI or CT scan is in fact the pain generator.73,74 A positive TFI may be defined as relief of the target pain after anesthetizing a specific spinal nerve.

Provocation Disk Injections (Discography) Discography had been used extensively in the evaluation of patients with chronic LBP and FBS who were suspected of having discogenic pain. However, discography has fallen into disfavor because of data that suggests injection into a disk can result in long-term degeneration.12 That said, it might play a very limited role in patients with FBS when definitive diagnosis is elusive, pain is refractory, and surgery is being considered.7,75

Treatments There is a spectrum of treatments for FBS that ranges from manual therapy, exercise, and medication through interventional pain treatments and repeat surgery.76 The treatment of each patient should be based on the 4005

cause of the pain and then the best available published evidence integrated with the physician’s clinical expertise and each patient’s values and circumstances. It must be recognized that just as pain management is not necessarily a failure of spine surgery, neither is corrective spine surgery a failure of pain management.

NONSPECIFIC TREATMENTS Rehabilitation and Exercise Rehabilitation is usually the first line of treatment for patients with FBS. The premise is that many patients are weak and deconditioned and exercise therapy will help overcome these factors.60 In addition, there is evidence that exercise therapy helps patients overcome their fear avoidance, which leads to improvement in many domains, physical and psychological.66 Several studies have looked at the response to exercise and rehabilitation in patients with FBS.77–79 Timm77 compared five types of treatment for FBS: high-tech exercise, low-tech exercise, modalities, manipulation, and control group with no treatment. Both active forms of exercise were better than control, passive modalities and manipulation. Brox et al.78 reported outcomes in patients treated for FBS after discectomy. The program was 25 hours per week for 3 weeks and included cognitive-behavioral therapy and lectures. At 1 year, LBP (0 to 100) improved from 65 to 51 and ODI improved from 45 to 32. Miller et al.79 compared the outcomes of chronic LBP and FBS patients in an interdisciplinary functional restoration program. Both groups did well with significant decreases in pain and disability. The chronic LBP patients without prior surgery had greater reductions in pain and disability, but the FBS patients were significantly more improved in strength and endurance measures, activities of daily living, and fear of exercise after the program. Karahan et al.80 compared isokinetic, lumbar stabilization, home exercises, and no treatment in a single-blind randomized trial of patients with FBS. They used both psychological and physical outcome measures. The isokinetic and lumbar stabilization groups had equivalent clinical and statistical improvement, both better than home exercise. All exercise groups did better than control. 4006

Medications The use of medications for patients with FBS is based on clinical experience, expert opinion, case series, and extrapolation from studies on patients with chronic LBP and other pain states rather than proof of efficacy in FBS.81 Medications might play an adjunctive role while a patient is in rehabilitation, but in some patients, medication becomes a long-term treatment. Acetaminophen (APAP), although commonly used, has been shown to be no more effective than placebo in acute LBP.82,83 There are no studies of APAP in chronic LBP or FBS. Risk of liver disease is significant at doses above 3 g per day. There is little to recommend APAP in patients with FBS. Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed for acute LBP. However, the data are mixed regarding efficacy. Newer trials report no advantage over placebo in chronic LBP.81,84 NSAIDs have side effects that can be very serious, including myocardial infarction, gastrointestinal hemorrhage, and renal and liver toxicity, among others. Although the risk of major cardiovascular event is not high, it is important. Of note is that recent studies suggest that cardiac events can occur in the first week of use with a second peak before 30 days.85 It is prudent to avoid NSAIDs in the elderly and patients with underlying medical problems, especially cardiac, who are at greatest risk of serious adverse events. For most patients skeletal muscle relaxants do not provide much benefit for chronic LBP.84 The antiseizure medications such as gabapentin, pregabalin, and topiramate might offer some benefit, although good data are lacking. Neither tricyclic nor selective serotonin uptake inhibitors are effective for chronic LBP.84 Duloxetine has been shown to be useful in some patients with chronic LBP but does not seem to have been studied in patients with FBS. Opioid analgesics have become the most controversial medications for the treatment of pain not related to malignancy and are discussed in detail elsewhere. The most recent guideline of the American College of Physicians (ACP) states that pharmacologic therapies should be considered 4007

in patients who have not responded to nonpharmacologic therapies. They suggest NSAIDs and tramadol as first-line therapies, and tramadol or duloxetine as second-line therapies.84 Paradoxically, this is the recommendation even though NSAIDs have little value and potentially serious adverse events. The guideline goes on to state, Clinicians should only consider opioids as an option in patients who have failed the aforementioned treatments and only if the potential benefits outweigh the risks for individual patients and after a discussion of known risks and realistic benefits with patients (grade: weak recommendation, moderate-quality evidence).

SOME OF THE SPECIFIC TREATMENTS FOR SPECIFIC DISORDERS Discogenic Pain Discogenic pain can occur at the index level of prior surgery or adjacent segment. In the setting of FBS, rehabilitation and fusion surgery have been compared. For patients with mild to moderate pain after discectomy, a 3week interdisciplinary functional rehabilitation program was equal to fusion surgery.78

Facet Joint Pain Klessinger36 studied the efficacy of radiofrequency neurotomy (RFN) in 120 patients who had undergone microsurgical lumbar disk surgery and had residual axial LBP. There were 34 who had a positive response to diagnostic medial branch blocks and then were treated with RFN. Twenty patients (58.8%) achieved at least 50% reduction in pain for a minimum of 6 months. Good results have been seen in patients with chronic LBP of FJ origin as well.86 Successful RFN relieves pain to a meaningful degree for about 9 to 12 months. When pain recurs, RFN can be repeated. Repeat RFN is usually successful unless there has been disease progression or technical failure.87

Sacroiliac Joint Pain There do not appear to be studies of nonsurgical therapies for the treatment of SIJ pain after lumbar surgery.41 The noninterventional options that have 4008

been reported in SIJ pain without fusion include medications (topical and oral), physical therapy, support belts, and manual therapy. If response is poor, SIJ corticosteroid injection can be considered the next step. The duration of relief after steroid injection varies greatly. Some patients achieve long-lasting relief after one to three injections, but others require several injections each year.88 For patients who do not respond to these treatments, SIJ RFN can be effective in well-selected patients and sustained for 12 months in some.89–91 Finally, for patients with severe and refractory pain, SIJ fusion has been reported to be helpful.92

Spinal Stenosis As previously noted, spinal stenosis may involve the central canal or foramen or both. Foraminal stenosis is more common than central stenosis in patients with FBS. Central stenosis can be treated initially with rehabilitation and epidural corticosteroid injections. Patients who fail medical treatment and rehabilitation usually do well with surgery.93–96 The same paradigm seems appropriate for foraminal stenosis. If stenosis is severe and extensive decompression is needed, fusion may be required. For mixed pain syndromes, if decompression is not sufficient, medications and/or spinal cord stimulation (SCS) may be useful.

Neuropathic Pain Neuropathic pain is best treated sequentially with medication trial first and perhaps SCS if medications prove ineffective. If there is limited success, SCS is often useful.97 SCS is discussed in detail elsewhere. Newer 10-kHz high-frequency SCS appears to improve efficacy and even provide improvement in the LBP component. There are case series regarding the treatment of cluneal nerve injuries with injections of corticosteroids and sometimes with alcohol.98

Lysis of Adhesions As noted earlier, most patients develop fibrosis after back surgery, and there is debate about its significance. In one theory, the fibrosis is responsible for the pain, and therefore, lysis of the adhesions will result in improvement. There are several studies and reviews that present evidence 4009

of effectiveness in a small number of well-selected patients.76,99,100

Psychological Interventions Psychological illness, just like structural problems, is treated according to its severity and type with a detailed discussion elsewhere in this book. Depression, anxiety disorder, substance abuse disorder, and PTSD might best be treated with some combination of individual psychotherapy, group therapy, and, when necessary, medications. In addition, time-limited cognitive-behavioral therapy can be useful for reducing catastrophic thinking with its maladaptive interpretation of pain, increasing function, insomnia, and other stress-related problems. Indirect forms of cognitive-behavioral treatments—physical rehabilitation, for example—can be useful for fear avoidance and even catastrophic thinking. Physical rehabilitation can provide both of strength and body mechanics training and at the same time help patients overcome some of the fear avoidance, catastrophic thinking, and even depression.66,101 Mindfulness training, also known as mindfulness-based stress reduction (MBSR), has been evaluated in a randomized controlled but short-term study in patients with FBS.102 One group received usual care plus MBSR weekly for 8 weeks, and the other usual care alone. The MBSR group had clinically and significantly greater improvement than the control group in level of pain, pain acceptance, function, and sleep quality. Results were clinically and statistically significant. In a systematic review, Reiner et al.103 found evidence that MBSR reduced pain intensity in patients with chronic pain. Schütze and associates104 showed in a small study that the combination of MBSR and physical therapy produced meaningful improvements in pain catastrophizing, physical function, and depression.

Reoperation The role of reoperation is complex and depends on the structural cause of the FBS, levels of pain, and disability and psychological status. If there is an anatomical abnormality that corresponds to the patient’s pain, and the patient has failed all reasonable conservative care, surgery might be a viable option. Surgery is not likely to benefit neuropathic pain but might 4010

be beneficial for radicular pain. Brox et al.78 showed that reoperation after failure of discectomy was not better than aggressive conservative care consisting of an inpatient program for several weeks. Therefore, it appears reasonable to offer rehabilitation before contemplating surgery, although the magnitude of the conservative care used by Brox et al.78 is rarely available to most patients. Indications for surgery can include recurrent disk herniation, residual spinal stenosis, pseudarthrosis, progressive deformity, and severe adjacent segment disease.93–96 References 1. Lattig F, Fekete T, O’Riordan D, et al. A comparison of patient and surgeon preoperative expectations of spinal surgery. Spine 2013;38:1040–1048. 2. Mancuso C, Duculan R, Stal M, et al. Patients’ expectations of lumbar spine surgery. Eur Spine J 2015;24:2362–2369. 3. Mancuso C, Duculan R, Cammisa F, et al. Fulfillment of patients’ expectations of lumbar and cervical spine surgery. Spine J 2016;16:1167–1174. 4. Burton C, Kirkaldy-Willis W, Yong-Hing K, et al. Causes of failure of surgery on the lumbar spine. Clin Orthop 1981;157:191–199. 5. Waguespack A, Schofferman J, Slosar P, et al. Etiology of long-term failures of lumbar spine surgery. Pain Med 2002;3:18–22. 6. Slipman CW, Shin CH, Patel RK, et al. Etiologies of failed back surgery syndrome. Pain Med 2002;3:200–214. 7. DePalma M, Ketchum J, Saullo T. Etiology of chronic low back pain inpatients having undergone lumbar fusion. Pain Med 2011;12:732–739. 8. Kizilkilic O, Yalcin O, Sen O, et al. The role of standing flexion-extension radiographs for spondylolisthesis following single level disk surgery. Neurol Res 2007;29:540–543. 9. Cohen SP, Hurley RW. The ability of diagnostic spinal injections to predict surgical outcomes. Anesth Analg 2007;105:1756–1775. 10. Yeom JS, Lee JW, Park K, et al. Value of diagnostic lumbar selective nerve root block: a prospective controlled study. AJNR Am J Neuroradiol 2008;29:1017–1023. 11. Datta S, Manchikanti L, Falco FJ, et al. Diagnostic utility of selective nerve root blocks in the diagnosis of lumbosacral radicular pain: systematic review and update of current evidence. Pain Physician 2013;16:SE97–SE124. 12. Cuellar J, Stauff M, Herzog R, et al. Does provocative discography cause clinically important injury to the lumbar intervertebral disc? A 10-year matched cohort study. Spine J 2016;16:273–280. 13. Block AR, Ohnmeiss DD, Guyer RD, et al. The use of presurgical psychological screening to predict the outcome of spine surgery. Spine J 2001;1:274–282. 14. Dersh J, Gatchel R, Mayer T, et al. Prevalence of psychiatric disorders in patients with chronic disabling occupational spinal disorders. Spine 2006;31:56–62. 15. Daubs M, Patel A, Willick S, et al. Clinical impression versus standardized questionnaire: the spinal surgeon’s ability to assess psychological distress. J Bone Joint Surg Am 2010;92:2878– 2883. 16. Crombez G, Vlaeyen J, Heuts P, et al. Pain-related fear is more disabling than pain itself:

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CHAPTER 76 Psychological Screening of Candidates for Spine Surgery or Placement of Implanted Devices ROBERT EDWARDS and ROBERT N. JAMISON

Introduction Chronic pain, generally defined as pain persisting for more than 3 months, or past the normal healing time, affects nearly 100 million adults in the United States.1 It is estimated that 25 million adults report suffering with daily pain at any one time, and pain as a symptom accounts for 50 million primary care office visits.2 Patients with persistent pain often report depression, anxiety, irritability, sexual dysfunction, and decreased energy.3 Family roles are altered and worries about financial limitations and the consequences of a restricted lifestyle are common.4 Chronic pain is one of the major reasons to seek health care and can impose a tremendous burden on the quality of life of those affected by this condition.5 According to the Global Burden of Disease Initiative of the World Health Organization, chronic pain is ranked first in associated disability and overall burden.6 It has been determined that chronic pain adversely affects individuals at a higher frequency than depression, substance abuse, arthritis, and Alzheimer disease.7,8 Despite multiple medical interventions and numerous treatment efforts, the incidence of chronic pain continues to rise and represents one of the costliest health care conditions in the United States.9 In fact, chronic pain imposes the greatest economic burden of any health condition10,11 and affects more people than diabetes, heart disease, and cancer combined.9 Persistent back pain in particular is one of the principal drivers of these costs, both in the United States12 and internationally,13 with indirect costs (e.g., lost or reduced work productivity) accounting for more than half of 4017

this economic burden.14 Although there are many accepted and recommended treatments for chronic pain, the efficacy of these treatments is limited, and many individuals receiving treatments for their pain continue with disabling pain despite these therapies. The Agency for Healthcare Research and Quality (AHRQ) listed 20 common treatments for persons with chronic pain.15 They reported that the long-term effect sizes for most medical interventions for pain, including back surgery and implanted devices, tend to be small. The AHRQ article recommended that selection of therapies that have the lowest cost and lowest chance for harm be considered first because there was no clear comparative advantage for most treatments compared to another.16 The AHRQ also set as a priority the identification of those chronic pain patients who would most likely benefit from specific treatments for chronic pain.15 Studies suggest that most patients with chronic pain present with some psychiatric symptoms. Close to 50% of patients with chronic pain have a comorbid psychiatric condition, and 35% of patients with chronic back and neck pain have a comorbid depression or anxiety disorder.17 Many chronic pain patients have a history of physical or sexual abuse, or a past history of a mood disorder.18 In surveys of chronic pain clinic populations, between 50% and 70% of patients have significant psychopathology, making psychiatric comorbidity the most prevalent comorbidity in patients with chronic noncancer pain.19 In addition, the presence of a long-lasting pain syndrome is a leading risk factor for suicide.20 Psychological assessment is designed to identify problematic emotional reactions, maladaptive thinking and behavior, and social problems that contribute to pain and disability. When psychosocial issues are identified, treatment can be tailored to address these challenges in the patient’s life, thereby improving the likelihood and speed of recovery and prevention of ongoing or more severe problems. (4) When various first-line treatment options such as trials of medication and physical therapy fail or are ineffective, spinal surgery, spinal cord stimulation (SCS), or placement of an intrathecal drug delivery system (IDDS) are considered as treatment options, especially for those with severe intractable pain. The purpose of this chapter is to review the major psychosocial 4018

variables that have been shown to be associated with poor outcome from surgery or an implanted device. We provide a brief critical review of factors that contribute to poor outcome from surgery, SCS, or an IDDS, present accepted strategies for assessing those psychological and social factors that predict outcome from surgery and implantable devices for pain and offer recommendations for future evaluation procedures in order to improve outcomes.

SPINAL SURGERY Lumbar surgery with or without bone grafts and with or without implanted hardware can be controversial when employed for treating chronic pain alone. Radiologic studies have shown that 80% of asymptomatic individuals have evidence of degenerative disk disease or a bulging or herniated disk,21 conditions often considered an indication for surgery. Yet, no clear indicators currently exist to determine which patients with low back pain would benefit from surgery.22 In the United States, rates of spine surgery for back and leg pain have been steadily increasing, and there is a wide variation of the frequency of back surgery from one region of the country to the next.23 Outcome trials of surgery for individuals with chronic low back pain have indicated success rates that range between 41% and 57%.24 A number of controlled trials, however, have indicated that surgery is no better than physical therapy and multidisciplinary rehabilitation.25–29 A troublesome component of back surgery is postsurgical complications and increased pain. Rates of complications and reoperations after spine surgery have ranged from 5% to 16%.24 Deyo and Mirza,30 found that 2 years after surgery, there was no significant difference between back pain patients of similar diagnosis who were treated surgically or nonsurgically. Turner et al.,31 reviewing all published research on spinal fusion, found that approximately 65% to 75% of all patients achieved satisfactory clinical outcomes. In these studies, poorer outcome was associated with a number of factors, including greater numbers of fused levels and the use of instrumentation. Similarly, Hoffman and colleagues,32 in a literature review on laminectomy and discectomy, found that the mean success rate of these procedures for relief of spine pain was 67%. The popular media have highlighted these and 4019

similar results, which appear to provide support for declarations about treatments for back pain such as that of a recent issue of Consumer Reports (June 2017) that stated “conventional approaches don’t always work and can cause other serious problems.” Failed spine surgery can significantly impact the patient, the physician, the employer, and the third-party payer. The patient often continues to remain disabled, with perhaps even greater pain, increased medication dependence, and more emotional difficulty than prior to the surgery. The pain may be so great, or the surgery so unsuccessful, that reoperation is required, as is the case in an estimated 10% of those who undergo laminectomy and discectomy,32 and 23% of those who undergo spinal fusion.31 The patient after failed surgery places many demands on the health care system, often requiring increasing medications and multiple additional treatments. Patients often feel frustrated and discouraged. The physician may become angry with the patient for not responding to treatment and the employer can be concerned about his or her obligation to pay compensation to a permanently disabled worker. Given that spine surgery can be effective yet the implications of failed spine surgeries can be so profound, it becomes critical to determine factors that may lead to poor results from such procedures. Improper pre- and postoperative information and treatments may also worsen surgical results. A growing body of research indicates that psychosocial factors are among the most significant influences on spine surgery results. For example, DeBerard et al.33 compared the outcomes of spinal fusion in patients who had been recommended for a preoperative psychological evaluation (based on surgeon recognition of the presence of psychosocial concerns) versus those who were not recommended for such evaluations. Those recommended for a psychological evaluation did less well after surgery, suggesting that even the surgeons’ perception of psychological issues was predictive of outcome. In another study, DeBerard and colleagues34 demonstrated that those who were identified with more negative affect (high psych) before back surgery had more repeat surgeries, had greater disability, had higher medical expenses, and had a higher incidence of disability after surgery than those with less emotional distress. Thus, presurgical evaluation and careful patient selection can be extremely 4020

important in helping to identify those individuals who might benefit the most from lumbar surgery.

SPINAL CORD STIMULATION AND INTRATHECAL DRUG DELIVERY SYSTEMS SCS with implantable or externalized systems has been available since the 1960s.35 The theoretical basis of the efficacy of SCS is based on Melzack and Wall’s36 gate control theory that proposes that stimulation of large nerve fibers overrides the transmission of small nerve fibers that transmit pain. SCS is expected to reduce, not eliminate pain by blocking the conduction of primary nerve pathways.37 It seems to be most successful in relieving pain in the limbs (e.g., the leg or arm), although more recently, neurostimulation devices have been developed that target axial back pain.38,39 Throughout the years, there have been improvements in SCS systems allowing for better coverage of painful areas with multiple channels, higher frequency stimulation, burst technology, electrode surfaces with increased number of contacts, and leads that are shaped to provide varying degrees of coverage.40 Spinal cord stimulators have reported success rates ranging from 20% to 70%.41 They have been found to be efficacious for neuropathic pain42 and radiculopathy.43 There has been a rapid increase in the number of implanted spinal cord stimulators, and some econometric analyses have indicated that SCS may be a costeffective treatment option, particularly for patients with persistent neuropathic pain syndromes and complex regional pain syndrome.44 Spinal infusion of analgesics, with use of an IDDS has been utilized since the 1980s.45 Spinally administered analgesics had initially been used for treatment of cancer pain46 and with the subsequent development of implantable components for continuous intrathecal infusions became an acceptable method to treat patients with intractable spasticity as well as pain.47 This technology consists of implanting a drug delivery device designed for long-term continuous infusion of medication. The drug delivery system consists of a collapsible drug reservoir into which the drug is injected and, powered by a battery and computer chip, allows for variable infusion rates and bolus injections through a catheter anchored in the back with the tip of the catheter positioned within the thecal sac to 4021

deliver drug to the cerebrospinal fluid (CSF).48 Such infusions for cancer pain have good success rates (defined as a reduction of pain by one-third), ranging from 60% to 90%.49 Collectively, intrathecal infusion devices have provided pain relief in noncancer pain patients who had failed more conservative therapies50 and patients with an IDDS have demonstrated a reduction in side effects from oral medications, decreased need for oral analgesia, and improvement in their physical assessment.51 The data indicate variable success rates for noncancer pain ranging from 25% to 70%.52 Although outcome studies report that SCS and/or an IDDS are efficacious in treating chronic pain, decisions for implantation have historically been based on clinical judgment of the implanting physician.49 Recent empirical work, though, has begun to investigate the clinical characteristics that are associated with outcomes for implantable devices. A study by Hassenbusch and colleagues53 compared SCS with intrathecal infusions by measuring postoperative verbal numeric scores and activity levels. The findings of this study and others suggest that IDDS were useful in reducing bilateral or axial pain (e.g., pain just in the low back), whereas SCS is better for unilateral radicular symptoms (e.g., pain down one leg stemming from nerve damage in the back).50 In general, patients considered for an implantable device often are not seen as poor candidates for spinal surgery, either due to previous failed surgery or lack of clear pathology accounting for the pain, and have failed to respond to conservative approaches and long-term use of oral opioids. Implantation of these devices, however, is not without risks. Reports of infection or intrathecal granulomas causing neurologic injury are documented,54 and the safety of these devices for use with chronic noncancer pain patients is an important consideration. The risks associated with SCS include possible nerve injury, spinal cord puncture, bleeding, and infection. Similar risks also exist for IDDS including discomfort at the implantation site as well as possible disconnections, kinking, catheter migration, and inflammatory masses (granulomas) that build up at the tip of the catheter. Risks also include increased depression if the device becomes ineffective in reducing pain.48 Because of the risks associated with implantation of these devices, as well as their substantial costs, there 4022

has been a good deal of emphasis on patient selection. As noted earlier, some studies have focused on identifying pain phenotypes that are most responsive to implantable therapies48,53; other areas of investigation include evaluation of psychosocial factors that might predict success or failure of stimulators or IDDS. Thus, a careful evaluation of each candidate for surgery or for an implantable device is judged to be important, and in clinical practice, a psychological evaluation is often a recommended or mandatory part of the evaluation process for patients being considered for implantable pain-management devices.

AFFECTIVE DISORDERS AS PREDICTORS OF OUTCOME Many chronic pain patients experience some level of depression. For up to 85%, the intensity of this emotional experience is sufficient to meet the diagnostic criteria for clinical depression.17 Depressive symptoms include depressed mood, diminished interest in almost all activities, weight loss or gain, insomnia or hypersomnia, agitation or psychomotor retardation, fatigue or energy loss, feelings of worthlessness or guilt, impaired concentration, and recurrent thoughts of death unrelated to other comorbidities.55 Several studies have assessed depression using different instruments and found that it can be predictive of greater disability and poor outcomes of spinal surgery.56 Kjelby-Wendt et al.57 examining discectomy results found that patient satisfaction with surgery was strongly related to elevated scores on the Beck Depression Inventory (BDI)—in fact, elevated scores were found in 55% of dissatisfied patients but in only 18% of satisfied patients. Schade et al.58 found that depression, as assessed on a simple Likert-type scale, had strong negative correlations with return to work and overall recovery. Trief et al.59 found that high scores on the Zung depression inventory were associated with little reduction in back pain and elevated work disability after spine surgery. Finally, DeBerard et al.34 found that depression was strongly related to total medical costs in workers’ compensation patients undergoing spinal fusion. Patients with chronic pain and a comorbid psychiatric disorder are more likely to report greater pain intensity, more pain-related disability, and a 4023

larger affective component to their pain than those without psychiatric comorbidity.60,61 Patients with chronic pain and psychopathology, especially those with chronic low back pain, also typically have poorer pain and disability outcomes with treatment.62–64 There is a significantly poorer return-to-work rate 1 year after injury among patients with chronic pain and anxiety and/or depression compared with those without any psychopathology.65 Thus, psychiatric comorbidity, primarily major depression and anxiety disorders, is associated with greater levels of chronic pain, more disability, and a worse response to treatment. Given the significant interpatient variability in treatment outcomes, it would be of tremendous value, from both a societal and patient perspective, to identify in advance who is most and least likely to benefit from surgery or an implanted device. In general, some risk factors have been identified that correlate with greater risk for pain or poor outcomes from treatment for pain. These include variables such as pain chronicity, psychological distress, a history of abuse or trauma, poor social support, and significant cognitive deficits.65 In particular, psychopathology and/or extreme emotionality have been seen as contraindications for certain therapies.66 Outcome studies highlight the poor response of patients with psychiatric comorbidity to many treatments.67,68 For example, spinal pain patients with both anxiety and depression have a 62% worse return-towork rate than those with no psychopathology.69 Epidemiologic research suggests a bidirectional association between back pain and emotional distress; pain increases symptoms of depression and individuals with a preexisting depressive disorder have a disproportionately high risk for developing spinal pain.70 Similarly, cognitive processes such as maladaptive beliefs and pessimistic expectations are associated with a greater likelihood of developing chronic pain and with poorer functional outcomes among chronic low back pain patients.71 There is also evidence of a genetic predisposition toward increased depression and anxiety among persons with low back pain based on twin studies.72 Numerous factors are likely to play a role in shaping outcomes following surgical interventions or placement of an implanted device in patients with chronic back pain. However, there does not seem to be a consensus on what factors are the strongest and most consistently 4024

predictive of outcomes, and there is no universally accepted standard approach for screening surgical candidates or individuals considered for an implanted device. Nonetheless, a presurgical psychological evaluation is often recommended based on research demonstrating the predictive value of spine presurgical psychological evaluations.73 A recent systematic review was carried out of the current literature, using critical appraisal and strategies to limit bias, to determine the strength of the evidence for the assumption that careful screening will help to predict pain-related and functional outcomes from lumbar surgery or SCS.74 Collectively, a statistically significant relationship was found between psychological factors and treatment outcome (e.g., high preimplant levels of distress were prospectively associated with less SCSrelated pain relief) in 92% of the studies reviewed. In particular, presurgical somatization, depression, anxiety, and poor coping were most useful in helping to predict poor response (i.e., less treatment-related benefit) to lumbar surgery and SCS. Older age and longer pain duration were also predictive of poorer outcome in some studies, whereas pretreatment physical findings, activity interference, and pain intensity were minimally predictive. Interestingly, several studies have confirmed that younger patients treated earlier in the course of their pain condition derive the most benefit from SCS,75 which might suggest that using SCS as a “last resort” could be a suboptimal management strategy. A review of psychosocial characteristics as predictors of outcomes following SCS suggests that depression is most robustly linked to poor SCS outcomes.76 Indeed, Sparkes and colleagues76 cite multiple welldesigned studies suggesting that higher levels of preimplantation depressive symptoms impact negatively on the efficacy of SCS treatment. Trief and colleagues59 found that patients with elevated state anxiety scores on the State Trait Anxiety Inventory (STAI) achieved less pain relief and lower return to work rates after surgery than did patients with lower anxiety. One particularly troublesome type of anxiety centers on the belief that increasing function and activity may increase the likelihood of reinjury. This type of fear measure has been assessed by several questionnaires including the Tampa Scale for Kinesiophobia.77 Den Boer et al.78 found that elevated scores on the Tampa scale were associated with 4025

delayed return to work after lumbar disk surgery. One plausible explanation for this result is that patients with a heightened fear of movement might be less likely to engage in aggressive postoperative rehabilitation. Kiecolt-Glaser et al.79 suggest that anxiety may increase postoperative pain and such increased noxious sensations could then downregulate immune function, further compromising the surgery healing process.

SOMATIZATION Estimated rates of chronic pain patients with somatization (sometimes known as hypochondriasis) vary, ranging from 1% to 12%, even though unexplained symptoms are a common problem in medical settings.80,81 The classical concept of somatization that implies that there is no pathophysiologic basis for physical complaints is quite problematic to apply to patients with chronic pain. This is because the majority of patients with chronic pain have some underlying physical condition that is at least partially responsible for their pain. The pain symptoms due to a physical or somatic cause (such as degenerative disk disease in the lumbar spine) may then be amplified by psychiatric factors, such as depression, anxiety, pain catastrophizing, fear of movement, and/or poor coping.82 Areas in the brain which process pain and mood together (such as the prefrontal and anterior cingulate cortices, and insula, commonly termed the medial pain system) may be the underlying brain substrates by which pain signals coming from the spinal cord are then amplified and perceived as heightened pain sensations. Hence, it is more appropriate to think of somatization as a process of amplification of bodily signals centered in the brain. There may or may not be a physical basis in the body for the abnormal physical sensations.83 The “somatoform pain disorders” fall within the “Somatization Disorders” classification in Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) and are meant to capture this concept of amplification of bodily perceptions, which is made worse by concomitant depression. The two diagnoses most commonly used with chronic pain patients are Pain disorders associated with psychological factors and a general medical condition, and Pain disorders associated with psychological factors. For patients with a strong 4026

component of heightened awareness of pain, the evidence is strong that repeated invasive procedures and implanted devices almost uniformly are unsuccessful.61,74 Education about the nature of the problem and helping patients understand the risk associated with repeated treatments is also important. Providers should resist a dualistic model that postulates that pain is either all physical or all mental in origin. This model alienates patients who may feel blamed for their pain and is not consistent with modern models of pain causation. Multiple lines of evidence suggest that pain is a product of efferent as well as afferent activity in the nervous system. We know that tissue damage and nociception are not necessary or sufficient for pain and the relationship between pain and nociception is highly complex. We are only beginning to understand the complexities of the relationship between pain and suffering, which appears to be a central phenomenon.84

PAIN SENSITIVITY Recent studies have also suggested that quantitative sensory testing (QST) may be a useful adjunct to psychological evaluation in the assessment of patients under consideration for spinal surgery or for placement of an implantable device. QST involves the administration of standardized noxious stimuli under highly controlled conditions; often, parameters such as pain threshold and tolerance in response to a variety of stimulus modalities are measured as indices of pain sensitivity. Our group recently reported that high levels of pain sensitivity may be associated with elevated risk for pain medication misuse85 and individual differences in QST responses may be useful as prognostic indicators in a variety of settings. For example, among neuropathic pain patients undergoing SCS, the degree of pretrial mechanical allodynia was inversely associated with the amount of pain relief reported by patients.86 That is, the most mechanosensitive patients reported the least SCS-related analgesic benefit. Functional neuroimaging studies have revealed that SCS functions in part by activating cortical pain-modulatory circuitry,87 and it may be that the most preoperatively pain-sensitive individuals are those whose painmodulatory systems are the most difficult to engage. Patients with chronic 4027

low back pain exhibit generalized patterns of hypersensitivity to pain that are consistent with central sensitization-like processes,88–90 indicating that heightened pain sensitivity in the central nervous system may represent an important pain mechanism in patients with chronic back pain. Assessment of pain sensitivity is potentially useful in several surgical contexts. First, there is some evidence that a higher degree of preoperative pain sensitivity is associated with poorer pain and disability outcomes following spinal surgery.91–93 Such findings are consistent with data from other surgical procedures indicating that preoperative sensory phenotyping with QST can provide valuable prognostic data.94,95 Second, assessment of sensory responses to provocative tests such as discography, which involves injection of radiographic dye into the nucleus pulposus of a putatively disrupted disk, can be illuminating. The injection, performed under fluoroscopy and combined with postdiscogram CT, gives evidence of the presence and extent of disk disruption. Interestingly, the injection of a disrupted disk has been demonstrated to act as a stimulus that provokes pain, often with a pattern and intensity similar to the patient’s normally occurring pain. For example, Vanharanta et al.96 found that injection of moderately to severely disrupted disks provoked pain that was similar or an exact reproduction of normally occurring pain in approximately 65% of cases. On the other hand, injection into normal-appearing disks provoked exact or similar reproduction of pain in only 18% of cases. Even stronger results along the same lines were obtained by Walsh et al.97 Thus, discography may provide a laboratory method for administering controlled stimulation of the disk in order to assess whether certain patients with low back pain display heightened pain sensitivity.

ANGER Anger is a common and prominent emotion in patients with chronic pain. Patients with low back pain, in particular, may experience and express anger about past medical care; about unfair treatment by employers, friends, and family; and about the physical and functional limitations that are endemic to low back pain.98 A study by Fernandez and Milburn99 demonstrates just how frequently patients experience this emotion. These researchers asked chronic pain patients to endorse the intensity of 10 4028

different emotions they were experiencing and found that anger was given the highest ratings of all emotions assessed.99 High levels of anger have also been associated with postoperative complications and elevated levels of postoperative pain for spinal surgeries as well as other procedures.100 There are numerous reasons why anger may have a negative impact on pain-related outcomes. First, anger may lead to maladaptive lifestyle changes, such as poor health habits, lack of physical exercise, or excessive use of drugs or alcohol. Such poor health behavior profiles may impair the benefits of physical interventions and have a negative impact on the patient’s commitment to postoperative rehabilitation. Second, anger can lead to the desire for vindication or revenge, and certainly, this can influence treatment results.101,102 Similarly, DeGood and Kiernan103 have found chronic pain patients who are angry and blame their employer for their injuries report high levels of emotional distress and have poorer response to treatment. Third, anger has been shown to have an adverse effect on many health conditions, such as cardiovascular disease, headaches, asthma, and many others, which may in turn exacerbate the negative effects of pain.104 Final, anger appears to directly impact physiologic pain perception by increasing muscle tension near the site of the injury, activating neural circuits underlying regulation of pain, and interfering with the analgesic effects of endogenous opioids.105,106

Cognitive Factors A growing body of research is examining the ways in which patients’ thoughts and beliefs concerning their pain, independent of personality or emotional factors, can strongly affect treatment outcome.95 Such cognitions and coping strategies have been demonstrated to influence the level of pain experienced by the patient, level of functional ability, and adjustment to the pain and efforts to overcome it.95 For example, catastrophizing is a pain-specific psychosocial construct composed of negative cognitive and emotional processes such as helplessness, pessimism, rumination about pain-related symptoms, and magnification of pain reports.70,107 Overall, higher catastrophizing has been shown to be a risk factor for the development of long-term pain and for negative sequelae 4029

of pain such as worsening physical disability, higher health care costs, and the amplification of pain sensitivity among patients with low back pain and joint pain. Retrospective survey studies in patients with musculoskeletal pain have indicated that catastrophizing often emerges as one of the most important pretreatment variables predicting surgical outcomes108,109 and a risk factor that impairs the effectiveness of painrelieving interventions. Fortunately, catastrophizing is a modifiable risk factor that can be ameliorated with a variety of nonpharmacologic treatments, from physical therapy to meditation.60,70,107 As such, it should be assessed as part of any psychosocial screening.

COPING STRATEGIES Coping strategies may be defined as specific thoughts and behaviors individuals use to manage their pain or their emotional reactions to pain.110 For example, “active” pain coping generally includes engaging in positive thinking, making encouraging self-statements, distracting one’s attention from pain, undertaking as much physical activity as possible within pacing guidelines, or using physical pain-reducing techniques such as relaxation exercises and stretching. Facilitating such coping strategies seems to be an important part of many nonpharmacologic treatments for chronic pain. One recent prospective study of multidisciplinary treatment revealed that patients who entered treatment with stronger personal beliefs in their ability to control pain, and those who increased their use of positive self-statements and cognitive reinterpretation of pain showed the most substantial decreases in pain-related interference at 6 months and 18 months posttreatment.111 Coping strategies may affect the patient’s level of attentiveness to pain, the ability to persist in the face of pain, and the extent to which the patient feels entitled to be taken care of as a result of the pain. There are a number of questionnaires available to assess painrelated coping strategies, including the Vanderbilt Pain Management Inventory (PMI).112 However, the largest body of research on coping in chronic pain (and the only research directly applied to surgical screening) has used the Coping Strategies Questionnaire (CSQ).113 Gross114 administered the CSQ preoperatively to 50 lumbar laminectomy candidates. Patients who obtained good results from surgery indicated on 4030

the CSQ that they felt better able to control the pain and also indicated they were more self-reliant. Other coping strategies assessed by the CSQ, such as hoping and praying and catastrophizing, were associated with poor surgical outcomes. These results are consistent with several other studies demonstrating that more passive coping strategies and perceived lack of pain control tend to be associated with greater pain levels, higher opioid consumption, greater levels of depression, and poorer treatment outcome.107,115 Recent research by den Boer et al.78,116 provides further support for the strong influence of coping strategies on surgical outcome. In this study, patients undergoing spine surgery for lumbar radicular syndrome were examined. “Passive pain coping” was assessed preoperatively using the Pain-Coping Inventory. Results indicated that passive pain coping, along with negative surgical outcome expectancy, predicted more severe disability and reduced work capacity at 6 months after surgery. Taken together with the just-cited study by Gross,114 these results demonstrate that the effectiveness of surgery may be partially mediated by the manner in which the patient thinks about the experience of pain and the strategies he or she has available to cope with the pain.

Behavioral Factors All the psychosocial factors discussed up to this point are components of a patient’s internal milieu: thoughts, feelings, and personality. Factors external to the patient can also exert profound influences upon recovery from spine surgery. Especially powerful in this regard are the responses of others to the patient’s pain. Pain behavior almost always occurs in a social context, communicating to observers that the patient is in distress. Observers, in turn, may react to such behavior with attempts to relieve the patient’s pain, help him or her to avoid further problems, or be supportive of limitations in activity. Employers, and even the insurance system, may also inadvertently support pain behaviors through provision of disability benefits or time off of work. Unfortunately, such solicitous responses from others, although well intentioned, may serve to reinforce or reward pain behaviors, increasing the likelihood that patients will continue to show and experience pain.117,118 Moreover, the patients’ individual attachment style 4031

is an important predictor of outcomes; individuals with anxious or insecure attachment styles are at elevated risk for poorer mental and physical health and for less treatment-related improvement.119 These social factors are especially important in the occupational setting. Anema and colleagues120 compared return-to-work rates in injured workers across numerous countries and found that differences in job characteristics and social disability systems were more important than medical interventions, patient, and injury-related factors in predicting occupational outcomes. In addition, these same home- and work-related social forces contribute to shaping important outcomes after spine surgery, as patients with minimal social and occupational support have more postoperative complications, pain, and disability following a variety of operative procedures.121–123

EARLY-LIFE TRAUMA AND ABUSE Strong prospective links have been observed between early traumatic experiences and the subsequent development of chronic pain.95,124 Childhood physical, sexual, and psychological abuse are reported to be risk factors for the adult development of musculoskeletal pain conditions.125 In adulthood, posttraumatic stress disorder (PTSD) has been identified as a risk factor for chronic pain, for the transition from acute to chronic pain, and for elevated severity of pain and disability in abuse victims.126–128 Overall, a disproportionately high number of chronic back pain patients have been the victims of abuse or abandonment as either adults or as children. In one study, more than half of the patients with chronic refractory low back pain evaluated at a multidisciplinary pain clinic had a history of at least one form of such childhood psychological trauma.129 These figures are substantially higher than the base rate in the US population. At present, the treatment implications for patients are unknown. Whereas some studies130 find less positive outcomes following spine surgery among patients with a significant history of childhood abuse, others have not confirmed this finding, highlighting the need for additional research.129

SUBSTANCE ABUSE Excessive use and abuse of opioid medications and alcohol appear to be 4032

red flags for poor surgical outcome.131,132 To the extent that patients depend on such substances, their responsibility for pain relief and improvements in functional ability through participation in postoperative rehabilitation may be diminished.133 Many chronic pain patients use excessive amounts of opioids. For example, Polatin and colleagues134 found that 19% of spine pain patients entering a work-hardening program had a history of substance use disorder, and even higher rates were reported in other studies. Unfortunately, there is little research addressing the relationship of substance use disorder and spine surgery outcome, although the results suggest that there is a higher incidence of spine surgery failures among those who continually abuse prescription medication and alcohol.135 The medical literature is clearer in demonstrating a relationship between poor surgical outcomes and smoking cigarettes.136

COMPONENTS OF PSYCHOLOGICAL EVALUATIONS Generally speaking, a goal of lumbar surgery and an implanted device for pain is to reduce pain. There are other potential positive outcomes from surgery or placement of an implanted device for pain including (1) relying less on prescription medication, (2) improving activities of daily living, and (3) returning individuals to productive lifestyles. A psychological evaluation is designed to help identify patients at risk for poor outcome and to prepare the patient so that they can achieve maximum benefit from surgery or implanted device.137 Regarding implanted devices, Medicare and many health insurance companies in the United States require implant candidates to have a psychological evaluation. As part of the evaluation, patients need to be informed of the risks as well as possible benefits from surgery or placement of an implanted device and to address realistic expectations. For SCS and IDDS, patients undergo a trial designed to determine the likely efficacy of a permanent implant. For SCS, the trial consists of temporary placement of a stimulator lead for 4 to 10 days and a successful trial, often required by Medicare and third-party payers, includes self-reported pain reduction by 50% and overall patient satisfaction. For IDDS patients, the trial is often conducted during a brief inpatient stay. It is important to remind patients with an IDDS that they 4033

would need to return periodically to refill their drug delivery system and for SCS patients that their time using the device directly affects battery longevity. Showing prospective implant patients a model of the device so that they can hold it and understand how it works can be important. Open discussion of any concerns about having a device implanted can also be useful. For some SCS patients, there may be some loss of normal sensation and having future magnetic resonance imaging (MRI) studies may be contradicted with some systems. For any device, future revisions or explants may be necessary in the event of infection, failed batteries, or any severe complication. Psychological evaluations should include the assessment of sensory, affective, cognitive, and behavioral components of the pain experience, expectations of benefit of an implanted device, and identification of personality and psychosocial factors that can influence treatment outcome.137 Table 76.1 presents the major categories that should be addressed during a psychological interview. The sensory experience is usually best understood through description of the severity, location, and temporal characteristics of chronic pain. Distressing emotional qualities of the experience of pain as well as preexisting emotional dispositions need to be understood, as fear138 and depression17 are powerful determinants of the response and emotional reactions to pain, related disability, and overall care. Patterns of thinking may exacerbate and maintain dysfunctional pain as well as facilitate coping that enhance adjustment during painful flareups. There is variability in the extent to which chronic pain interferes with activities of daily living or contributes to substantial functional impairment. Clinicians have long relied on careful appraisal of nonverbal behavior in the course of physical examinations and through observation of patients outside the examining situation, for example, when engaged in spontaneous behavior elsewhere in clinics or in everyday situations. Selfreport can also be useful in assessing nonverbal behavior by focusing on overt activity rather than subjective experience, for example, functional capacity or competence and disability in different situations. Finally, family socialization and important life experiences influence both effective and ineffective patterns of attempts to cope with pain. History gathering typically is the primary source of this information. Ethnic and cultural 4034

variation and family histories of managing pain and illness may be of importance. For example, when significant others in a patient’s family have had a history of recurrent, persistent, or particularly severe pain, there is a disposition to similar patterns in the patient themselves.139 TABLE 76.1 Categories to Be Addressed during a Psychological Interview 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

Pain description Aggravating and minimizing factors Past and current treatments, including medication use Daily activities: content and level Relevant medical history Development, education, and employment history Compensation status, engagement in litigation History of drug or alcohol abuse History of psychiatric disturbance Current emotional status Financial and social support Perceived directions for treatment

Of comparable importance are current social contexts. Patients experiencing social distress (e.g., with employers, family members or others) either directly related to painful episodes (reduced employment, isolation from the community) or unrelated to painful episodes (e.g., financial distress, difficult relationships) are likely to increase demands on the health care system. Furthermore, the presence of a supportive social environment is associated with lower levels of pain and less physical disability following surgical intervention.140 Although clinicians must be aware of the objectives of referral sources, patients similarly are typically carefully attuned to the expectations and goals of referral agencies and those engaged in the assessment. Patients frustrated with lack of success in treating pain or provision of financial and other support when unable to earn a livelihood bring different concerns to the assessment than patients who are not worried by such situations and expect the assessment will lead to effective care. Long histories of inadequate care or denial of care are more likely to lead to hostile behavior.

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VALIDATED PSYCHOLOGICAL MEASURES A psychological evaluation should include valid and reliable assessments of subjective pain intensity, mood and personality, activity interference, pain beliefs, and coping (Table 76.2). The following categories include some popular assessment tools used to measure these constructs. TABLE 76.2 Assessment Categories and Frequently Used Psychometric Measures 1. Pain intensity Numerical rating scales (NRS) Visual analogue scales (VAS) Verbal rating scales (VRS) Pain drawings (PD) 2. Mood and personality Minnesota Multiphasic Personality Inventory (MMPI) Symptom Checklist 90 (SCL-90) Beck Depression Inventory (BDI) Hospital Anxiety and Depression Scale (HADS) 3. Functional capacity Short-Form Health Survey (SF-36) Multidimensional Pain Inventory (MPI) Pain Disability Index (PDI) Oswestry Disability Index (ODI) Roland-Morris Questionnaire (RMQ) Waddell Disability Instrument Functional Rating Scale Back Pain Function Scale 4. Pain beliefs and coping Coping Strategies Questionnaire (CSQ) Pain Management Inventory (PMI) Pain Self-Efficacy Questionnaire (PSEQ) Survey of Pain Attitudes (SOPA) Inventory of Negative Thoughts in Response to Pain (INTRP) Chronic Pain Self-Efficacy Scale (CPSS) Pain Catastrophizing Scale (PCS) 5. Medication monitoring and adverse effects Screener and Opioid Assessment for Pain Patients (SOAPP-R) Current Opioid Misuse Measure (COMM) Opioid Compliance Checklist (OCC) Opioid Risk Testing (ORT) Side Effects Checklist (SEC)

Pain Intensity Measures Because one of the obvious primary goals of surgery or placement of an 4036

implanted device for chronic pain is to decrease the intensity of the pain, it is important to monitor pain intensity for a period before surgery or a device trial and after treatment. There are a number of ways to measure pain intensity, including numerical pain ratings, visual analogue scales, verbal rating scales, pain drawings, and a combination of standardized questionnaires. Pain intensity rating methods have evolved from designs originally developed by Budzynski141 and Melzack.142 Studies have shown that self-monitored pain intensity ratings are both reliable and valid.143 The daily monitoring of multiple measures of pain intensity over a 1- to 2week period before considering a trial of SCS or IDDS has a number of benefits. First, more information is obtained than can be gained from a single index of perceived pain intensity. More specifically, averaging multiple measures of pain intensity over time increases the reliability and validity of the assessment and is preferable to a single rating of pain intensity.141 Second, in the case of a trial of SCS or IDDS, average pain intensity ratings can serve as a baseline to help establish whether continued treatment is needed after an appropriate trial period. Baseline measures are essential to making judgments about the overall impact of treatment for pain. Numerical pain ratings often involve the patient’s rating of his or her pain on a scale of 0 to 10 or 0 to 100. Ideally, the external validity of the measure is improved by descriptive anchors that help the patient understand the meaning of each numerical value (e.g., 1 to 2, pain can be ignored at times; 3 to 4, pain is present but does not interfere with activity; 5 to 6, the pain is very noticeable and begins to limit function; 7 to 8, pain is quite severe and performing average daily activities is impaired; 9 to 10, pain is as worse as it can be and all activity is significantly impaired). Another popular means of measuring pain intensity is the visual analog scale (VAS), which uses a straight line with extreme limits of pain at either end.143 Some clinics employ electronic pain ratings available on a laptop computer, cell phone, or Internet Web site that can be used at home on a daily basis to get multiple time-stamped assessments of pain in the patient’s natural environment.144,145 There are a number of verbal rating scales,143 that consist of phrases chosen by the patients—as few as four or as many as 15, often ranked in 4037

order of severity from “no pain” to “excruciating pain”—to describe the intensity of their pain. Other verbal scales can be used to describe the quality of pain, for example, piercing, stabbing, shooting, burning, throbbing.146 Among the self-report measures, numerical rating scales are most popular among professionals. However, there is no evidence to suggest that VAS or verbal rating scales are any less sensitive to treatment effects. All these types of measures have been shown to be acceptable in the quantification of clinical pain.143,147

Mood and Personality Patients with chronic pain often report depression, anxiety, irritability, a history of physical or sexual abuse, or a past history of a mood disorder.148,149 Patients with chronic low back pain with evidence of a personality disorder or high ratings of depression and neuroticism respond more favorably to conservative management rather than surgery or placement of an implanted device.150–152 Mental health professionals continue to debate the best way to measure psychopathology and/or emotional distress in chronic pain patients. Although most measures are helpful in ruling out severe psychiatric disturbance, unfortunately, no measure can boast perfect validity in predicting treatment outcome.153 The measures commonly used to evaluate personality and emotional distress include the Minnesota Multiphasic Personality Inventory-2 (MMPI-2),154 the Symptom Checklist 90 (SCL-90-R),155 the BDI,156 the Hospital Anxiety and Depression Scale (HADS),157 and others. The MMPI and its successor, the MMPI-2, had been the instruments traditionally used in assessing chronic pain patients and to predict outcome following spine surgery and SCS.154,158 This measure consists of 567 true/false items and yields a distinct profile for each pain patient. Studies have shown that these profiles can predict return-to-work in males as well as response to surgical treatment.159 Although this test was widely used to measure psychopathology, the profiles obtained for chronic pain patients could be misinterpreted because of the physical symptoms frequently reported by these patients.160 Patients also reported disliking the test’s emphasis on psychopathology that seemed to be unrelated to their pain problem. 4038

The SCL-90 is a 90-item checklist with a 5-point scale that offers a global index score as well as nine subscale scores as a general assessment of emotional distress and has been used to evaluation outcomes from surgery161 and SCS.162 This self-report instrument offers easy inspection of individual items that may pertain specifically to persons with chronic pain. However, its disadvantages include the high correlation between subscales and the absence of validity scales to detect subtle inconsistencies in responses.163 The BDI assesses depressive symptoms in chronic pain patients. This 21-item self-report questionnaire measures the severity of depression and is commonly used to evaluate the outcome of treatment. It is easy to administer and score, although one limitation is the potential for misinterpretation of an elevated depression score as a result of the frequent endorsement of somatic items by chronic pain patients, for example, fatigue, sleep disturbances, and loss of sexual interest. The BDI has been used to predict outcome of lumbar disk surgery,164 surgical management of spinal stenosis,165 and benefit of peripheral nerve stimulation.166 The Center for Epidemiologic Studies Depression (CES-D) scale is an additional tool for assessment of depressive symptoms in pain patients.167 The HADS is a 14-item scale designed to assess the presence and severity of anxious and depressive symptoms. Seven items assess anxiety, and seven items measure depression, each coded from 0 to 3. The HADS has been used extensively in clinics and has adequate reliability (Cronbach’s α = .83) and validity, with optimal balance between sensitivity and specificity. It has been translated into many languages and is widely used around the world in clinical and research settings.168

Functional Capacity and Activity Interference Measures Some clinicians consider pain reduction meaningless unless accompanied by a noticeable change in function. Thus, some reliable measurement of functional capacity is often desirable before the onset of therapy. Research has shown that physical impairment, defined as an objective medical condition such as an amputation, is not very predictive of disability, which is an inability to work because of a medical impairment. Rather, beliefs about an injury predict disability and physical performance after surgery 4039

better than pain ratings or a physical impairment.169,170 Measures that can be used to assess activity level and function include the Short-Form Health Survey (SF-36),171 the West Haven-Yale Multidimensional Pain Inventory (WHYMPI, mostly known now as the MPI),172 and the Pain Disability Index (PDI).173 It is preferable to consider functional measures that are specific to the chronic pain condition being assessed, for example, back pain patients will have different activity limitations than someone with upper extremity pain. The SF-36, which was initially developed from the Medical Outcomes Study to survey health status, includes eight scales that measure (1) limitations in physical activities due to health problems, (2) limitations in social activities due to physical and emotional problems, (3) limitations in usual role activities due to physical health problems, (4) bodily pain, (5) general mental health, (6) limitations in usual role activities due to emotional problems, (7) vitality (energy and fatigue), and (8) general health perceptions.171 Although the SF-36 is a popular measure, pain patients tend to score very low (severe limitations) such that modest improvements can go undetected. An expanded measure known as the Treatment Outcomes of Pain System (TOPS),174 that incorporates the SF36, has been modified specifically for patients with pain to improve sensitivity and reliability of measurement of treatment outcome. The MPI is a 56-item measure made up of 7-point rating scales. The subscales assess activity interference, perceived support, pain severity, negative mood, and perceived control. The advantage of this self-report instrument is that it was created specifically for chronic pain patients and can be useful in classifying those patients into three types: dysfunctional, interpersonally distressed, and adaptive copers.175 Strong evidence supports the presence of these three types in the assessment of chronic pain patients.176 Other popular functional measures include the Oswestry Disability Questionnaire,177 the Roland-Morris Functional Disability Scale,177 the Waddell Disability Instrument,178 the Functional Rating Scale,179 and the Back Pain Functional Scale.180

Pain Beliefs 4040

Pain perception, beliefs about pain, and approaches to self-managing pain are important in predicting the outcome of treatment and are particularly relevant as predictors for implantable devices. Unrealistic or negative thoughts about an ongoing pain problem may contribute to increased pain and emotional distress, decreased functioning, a greater reliance on medication, and poor outcome from surgery.181 Certain chronic pain patients are prone to maladaptive beliefs about their condition that may not be compatible with the physical nature of their pain.182 Patients with adequate psychological functioning exhibit a greater tendency to ignore their pain, use coping self-statements, remain active, and use less medication after joint replacement surgery.183 Because efficacy expectations have been shown to influence the efforts patients will make to manage their pain, measures of self-efficacy or perceived control are useful in assessing a patient’s attitude after surgery.184 Several self-report measures assess coping and pain attitudes. The most popular tests used to measure maladaptive beliefs include the CSQ,113 the PMI,185 the Pain Self-Efficacy Questionnaire (PSEQ),186 the Survey of Pain Attitudes (SOPA),187 and the Inventory of Negative Thoughts in Response to Pain (INTRP).188 Other instruments include the Pain Beliefs and Perceptions Inventory (PBPI),189 and the Chronic Pain Self-Efficacy Scale (CPSS).190 Finally, the Pain Catastrophizing Scale (PCS)191 is a well-validated, widely used, self-report measure of catastrophic thinking associated with pain. The construct of catastrophizing incorporates magnification of pain-related symptoms, rumination about pain, feelings of helplessness, and pessimism about painrelated outcomes. Assessment of catastrophizing is important when evaluating candidacy for an implanted device because it adversely affects outcome and is a strong predictor for continued disability following surgery.192 Individuals rate the extent to which they experience the thought or feeling described by each item when they are in pain; scores on this 13item measure can range from 0 to 52 (each item is scored 0 = not at all to 4 = all the time). The PCS has good psychometric properties in pain patients and controls.193 In recent studies of chronic pain patients, Cronbach’s α for the PCS has been reported as above 0.9, indicating very high levels of internal item consistency.194 Distraction has been useful in reducing 4041

catastrophizing,195 as is even a brief course of cognitive behavioral therapy.196 It is suspected that patients who have unrealistic beliefs and expectations about their condition are also poor candidates for pain treatment.197 Patients who have a high catastrophizing score, who endorse passive coping on the PMI, who demonstrate low self-efficacy regarding their ability to manage their pain on the PSEQ, who describe themselves as disabled by their pain on the SOPA, and who report frequent negative thoughts about their pain on the INTRP are at greatest risk for poor treatment outcome following placement of an implanted device.

ELECTRONIC PAIN ASSESSMENT PROGRAMS There has been recent interest in implementing electronic pain assessment programs in clinic settings to assess and monitor persons with chronic pain prior to surgery or a trial of an implanted device.198,199 Evidence exists of the benefits of such programs in assessing risk of poor outcomes, to reduce personnel time, and to document change along the continuum of pain care.200 Preliminary studies suggest that a Web-based secure electronic assessment program outweighs the benefits of a paper questionnaire.201 In a study designed to determine the impact of an electronic pain evaluation program, chart reviews were conducted between pain patients who completed an electronic pain assessment program (N = 89) and controls who represented standard care (N = 120).202 Chart review findings suggested that posted reports on the patient medical record from an electronic assessment increased the presence of key pain assessment information that were not found when incorporating notes from a traditional paper-and-pencil questionnaire. In particular, information on past treatments; adverse effects; psychological symptoms of depression, anxiety, and irritability; mental health treatment; past history of smoking; litigation; and substance abuse were documented more frequently (P < .001).200 It is thought that a detailed evaluation would be beneficial when determining benefit from an implanted device or spinal surgery. In a second related study by Butler and colleagues,202 two groups of chronic pain patients (treatment as usual = 75, electronic pain assessment = 72) were interviewed after completing their initial clinic visit and completed 4042

mailed questionnaires 3 months later. Results from this study showed that those subjects who had completed the electronic pain assessment program reported more discussion about legal issues, substance use history, and medication safety compared with those patients who were not given the electronic assessment program (P < .05). Satisfaction questionnaire responses supported both provider and patient perceived benefit of using the electronic pain assessment program. Overall, results indicate that use of a comprehensive electronic pain assessment program improves documentation of chart elements in clinic notes and can be associated with increased discussion of key, pain-relevant topics during the clinical visit and in assessing patients considered for surgery or an implanted device.

Conclusion A growing body of research reviewed in this chapter indicates that psychosocial factors can strongly influence spine surgery outcome and long-term benefit from an implanted device. These results suggest that a comprehensive psychological screening should be included as a component of the diagnostic process in many spine surgery candidates and patients considered for placement of an implanted device for pain. Table 76.3 provides a set of general referral guidelines that a physician can keep in mind when considering the need for a psychological assessment.203 When the provider judges that a patient displays four or more of these points (listed in Table 76.3), a referral for a comprehensive psychological screening should be initiated. Such a referral is especially critical if there is a planned surgery that will be exploratory and highly invasive, for example, involving multiple levels and instrumentation, or involves a reoperation, or when placement of an implanted device is being considered for a condition that is complex and particularly protracted. TABLE 76.3 Referral Guidelines for Presurgical Psychological Screening203 Excessive pain behavior Symptoms inconsistent with identified pathology High levels of depression or anxiety Sleep disturbance: insomnia or hypersomnia Excessively high or low expectations about surgical outcome

4043

A high degree of pain-related catastrophizing Limited pain coping skills High levels of social/interpersonal conflict Negative attitude toward work or employer Emotional lability or mood swings Inability to work or greatly decreased functional ability (37 kg: 2,250 mg/d PO divided bid to tid

Diflunisal

Dolobid

8–12

98–99

1,500 mg

Salsalate

Generic only

1

90–95

3g

3

99

3,200 mg

300 mg

Propionic Acid Derivatives Fenoprofen Nalfon

Flurbiprofen

Ansaid

4.7– 5.7

>99

Ibuprofen

Advil, Caldolor, Motrin

2–4

90–99

Ketoprofen

Orudis

1.1–4

99

300 mg

Naproxen

Naprosyn

15

>99

1,250 mg (1,000 mg)

Naproxen sodium

Aleve, Anaprox

15

>99

1,100–1,375 mg (1,100 mg)

Oxaprozin

Daypro

54.9

>99.5

1,200 mg (1,200 mg)

Fenamates Meclofenamate

Meclomen

2–3

99

400 mg

Diclofenac sodium

Zorvolex, Dyloject

2

>99

105 mg PO; 150 mg IV

Tolmetin

Tolectin

5

99

1,800 mg (30

4071

2,400 mg PO; 3,200 mg IV (6 mo–11 y: 40 mg/kg/d)

500– 750 mg PO bid 1,500 mg PO bid

N/A

300– 600 mg PO tid to qid 50–100 mg PO bid to tid 400 mg PO q4– 6h; 400– 800 mg IV q6h

N/A

50 mg PO q6– 8h 250– 500 mg PO q12h bid 275– 550 mg PO q12h 1,200 mg PO qd 50–100 mg PO q4–6h 18–35 mg PO tid; 37.5 mg IV q6h 200–

N/A

N/A

6 mo–11 y: 5–10 mg/kg PO q6–8h, 10 mg/kg IV q4–6h; 12+ y: 400 mg PO/IV q4–6h N/A

≥2 y: 10–20 mg/kg/d PO divided q8– 12h ≥2 y: 11–22 mg/kg/d PO divided q8– 12h 10–20 mg/kg PO qd

N/A

N/A

≥2 y: 15–30

Ketorolac

Toradol

2.5–5

99

Mefenamic acid

Ponstel

2

90

mg/kg/d)

600 mg PO tid

mg/kg/d divided tid to qid ≥6 mo: 0.5 mg/kg IM/IV q6h for up to 72 h

40 mg PO, 120 mg IM/IV (120 mg IM, 60 mg IV) 1,000 mg

30 mg IM/IV q6h, 10 mg PO q4–6h 250 mg PO q6h up to 7 d 7.5–15 mg PO qd 20 mg PO qd 1,000– 2,000 mg divided qd to bid

60+ kg: 7.5 mg PO qd

(≥6 y only) 20–30 kg: 400 mg PO qd; 31–45 kg: 600 mg PO qd; 46– 60 kg: 800 mg PO qd; >60 kg: 1,000 mg PO qd 1–2 mg/kg/d PO divided bid to qid

≥14 y: 250 mg PO q6h for up to 7 d

Enolic Acid Derivatives (Oxicams) Meloxicam Mobic 15–20

>99

15 mg (7.5 mg)

Piroxicam

Feldene

30–86

99

20 mg

Nabumetone

Relafen

23

>99

2,000 mg

Acetic Acid Derivatives Etodolac Lodine

7.3

>99

1,000 mg (20–30 kg: 400 mg/d, 31–45 kg: 600 mg/d, 46–60 kg: 800 mg/d, >60 kg: 1,000 mg/d)

200– 400 mg PO q6– 8h

Indomethacin

Indocin

4.5

97

25–50 mg PO tid

Sulindac

Clinoril

7.8

93

200 mg (4 mg/kg/d up to 150–200 mg/d) 400 mg

150– 200 mg PO bid up to 7– 14 d

N/A

COX-2 Selective NSAID (Coxib) Celecoxib Celebrex 11

97

400 mg

100–

(≥2 y only)

4072

N/A N/A

200 mg PO qd to bid

10–25 kg: 50 mg PO bid; >25 kg: 100 mg PO bid

bid, twice a day; COX, cyclooxygenase; IM, intramuscular; IV, intravenous; N/A, not available; NSAID, nonsteroidal anti-inflammatory drug; PO, by mouth; q12h, every 12 hours; q4–6h, every 4 to 6 hours; q4h, every 4 hours; q6–8h, every 6 to 8 hours; q6h, every 6 hours; q8–12h, every 8 to 12 hours; qd, every day; qid, four times a day; tid, three times a day.

Mechanism of Action PROSTAGLANDIN SYNTHESIS AND PHARMACOLOGY NSAIDs act by inhibiting prostaglandin synthesis in vivo. Prostaglandins (PGs) are derived from arachidonic acid and other polyunsaturated fatty acids; the 20-carbon polyunsaturated essential fatty acid (arachidonic acid) is the major source in mammalian tissues. PGs derived from arachidonic acid contain two double bonds. These are PGE2, thromboxane and prostacyclin. Analogous compounds synthesized from icosatrienoic (linoleic) and eicosapentaenoic acids contain one fewer or one more double bond in the side chains (PGE1, PGE3, respectively).2 The PGs, thromboxanes, hydroxy acids, and leukotrienes, which retain the 20carbon unsaturated fatty acid backbone, are collectively known as eicosanoids.3 Their release, usually as a result of trauma, is the major stimulus for eicosanoid production as PGs cannot be stored and are released as soon as they are synthesized.4 Cell membrane disruption causes phospholipid release which is converted to arachidonic acid by the action of phospholipase A2 (PLA2). Arachidonic acid then acts as a substrate for the COX enzyme.

CENTRAL SITES OF ACTION PGs also are involved in the pyretic response. After injection of pyrogens, cerebrospinal fluid (CSF) PG levels rise. That effect can be prevented by pretreatment with aspirin alluding to the central sites of action.5 Acetaminophen (paracetamol) is analgesic and antipyretic but lacks clinically useful peripheral anti-inflammatory activity. Acetaminophen blocks PG synthetase within the blood–brain barrier; the same effect is not 4073

seen in the periphery. Therefore, it is not an NSAID per se, although it is commonly used for many of the same indications as NSAIDs. Acetaminophen is discussed in more detail later in the chapter.

PERIPHERAL SITES OF ACTION Prostanoids do not generally activate nociceptors directly; they sensitize them to mechanical stimuli and chemical mediators of nociception such as bradykinin.6 PGE2 is the predominant eicosanoid released from endothelial cells of small blood vessels7 and is a key mediator of both peripheral and central pain sensitization.3 Because it is the prostanoid most associated with inflammatory responses, the formation of PGE2 at inflammatory sites is often considered an indicator of local COX activity, and suppression of PGE2 is an indicator of a reduced inflammatory process.8 The production of PGE2 is slow in onset and of long duration in response to inflammation.9

COX-1 AND COX-2 SELECTIVITY COX is encoded by two genes.10 Although the isomerization of PGH2 into PGE2 has been well characterized biochemically and pharmacologically, the enzyme responsible, PGE synthase (PGES), was only recently purified and cloned.11,12 The existence of more than one COX isoform, and specifically one that is positively regulated by cytokines and negatively regulated by glucocorticoids, was long suspected. In the early 1990s, an inducible COX isoenzyme was cloned.13 The recognition of two COX isoforms, then designated COX-1 and COX-2, generated intense efforts to characterize the relative contribution of each isoform to prostanoid production in specific situations (Fig. 78.1).

4074

FIGURE 78.1 Simplified arachidonic acid pathway differentiating COX-1 and COX-2 effects.

COX-1 and COX-2 are membrane-associated enzymes with a 60% amino acid sequence homology.14 In spite of their structural similarity, the two COX isoforms have different gene expression profiles, distinct kinetic properties, and different interactions with PLA2s and synthases.15 COX-1 is expressed constitutively and produces prostanoids that fine-tune physiologic processes requiring instantaneous or continuous regulation (e.g., hemostasis).14 COX-2 expression is usually low but can be induced by numerous factors including neurotransmitters, growth factors, proinflammatory cytokines, lipopolysaccharide, calcium, phorbol esters, and small peptide hormones.16 However, there are exceptions to the original constitutive versus inducible theory of COX expression. COX-1 expression can be induced in some stress conditions, such as nerve injury, and many tissues, including the central nervous system (CNS) and the kidney, constitutively express COX-2.16 In the spinal cord, there are detectable basal levels of both COX-1 and COX-2. That might enable immediate reactions to transmitter release that results in prostanoid production.17 A third isoform designated COX-3 that was identified in dogs is formed as a splice variant of COX-1.18 Because canine COX-3 can 4075

be inhibited by therapeutic concentrations of acetaminophen, initial reports postulated that COX-3 inhibition was the mechanism of action of acetaminophen, However, this does not appear to be true; more recent evidence indicates that COX-3 is not expressed in humans.19

Induction of COX-2 The original hypothesis formulated by John Vane in his Nobel prize– winning work on the mechanism of action of NSAIDs was that these compounds inhibited prostanoid production in the periphery preventing a sensitizing action of PGE2 on the peripheral terminals of sensory fibers.20 Peripheral inflammation induces an increase in COX-221 and PGES expression in the CNS. The pro-inflammatory cytokine interleukin 1β (ILIβ) is upregulated at the site of inflammation and plays a major role in inducing COX-2 in local inflammatory cells by activating the transcription factor nuclear factor kappa B (NF-κB).22 IL-1β is also responsible for the induction of COX-2 in the CNS in response to peripheral inflammation. However, this is not the consequence either of neural activity arising from the sensory fibers innervating the inflamed tissue or of systemic IL-1β in the plasma. Rather, peripheral inflammation produces some other signal molecule that enters the circulation, crosses the blood-brain barrier, and acts to elevate IL-1β, leading to COX-2 expression in neurons and nonneuronal cells in many different areas of the spinal cord.3,23 An elevation of COX-2 also occurs at many levels in the brain and spinal cord, mainly in the endothelial cells of the brain vasculature.24 Thus, there appear to be two forms of input from peripheral inflamed tissue to the CNS. The first is mediated by electrical activity in sensitized nerve fibers innervating the inflamed area, which signals the location of the inflamed tissue as well as the onset, duration, and nature of any stimuli applied to this tissue.21 This input is sensitive to peripherally acting COX-2 inhibitors (and to neural blockade with local anesthetics, e.g., epidural anesthesia).25 The second is a humoral signal originating from the inflamed tissue, which acts to produce a widespread induction of COX-2 in the CNS. Regional anesthesia does not affect this23,26; it only is blocked by centrally acting COX-2 inhibitors.23,25 One implication of this is that patients who receive neuraxial anesthesia for surgery may require a centrally acting COX-2 4076

inhibitor to optimally reduce postoperative pain and the postoperative stress response.25 Therefore, the permeability of the blood–brain barrier to both nonselective and COX-2 selective NSAIDs is important.27,28 Inhibitors of COX-2 that better penetrate the blood–brain barrier might represent more efficient analgesics and could also act to reduce many of the more diffuse aspects of inflammatory pain, such as generalized aches and pains, depression, and loss of appetite, which are key aspects in determining the “quality of life” response to treatment.29 The main process by which a drug passes from the circulation into the CNS is passive diffusion. Lipophilicity and ionization are critical determinants of this transfer.30 The CSF represents a convenient sampling point for drugs that enter the CNS; however, there are very few NSAIDs for which the CSF pharmacokinetics has been defined.31 The high lipid solubility of indomethacin allows it to rapidly cross into the CSF and equilibrate with the free plasma concentration.32 Similar results are seen with ketoprofen.33

Pharmacokinetics NSAIDs are weak acids with pKa values typically lower than 5. Because weak acids will be 99% ionized 2 pH units above their pKa, these antiinflammatory agents are present in the body mostly in the ionized form. Although NSAIDs differ in their individual pharmacokinetic properties, some general factors affecting NSAID pharmacokinetics can enable clinicians to select among the different agents available.

ABSORPTION Oral Most NSAIDs are rapidly absorbed following oral administration, with peak plasma concentrations generally reached within 2 to 3 hours, although slow-release dosage forms have been developed to maintain active plasma levels for prolonged times. Factors affecting gastric emptying may profoundly affect the time course of the clinical effect of an NSAID. The extent of drug absorption from the gastrointestinal (GI) tract is more important than the rate.34 Rectal and topical administration minimize GI side effects that are common with these agents. In general, 4077

the rate and extent of NSAID absorption is comparable for the rectal and oral routes.35

Injectables Intravenous (IV) and intramuscular (IM) NSAIDs forms are available in several countries. Ketorolac is the only parenteral NSAID available in the United States. Parecoxib, an injectable analog of the COX-2 selective NSAID valdecoxib, was under study, but those trials ceased when valdecoxib was withdrawn from the market. Parenteral administration may be advantageous in renal colic due to a more rapid onset than oral administration but has demonstrated no advantage over oral forms for any other indication.36 Several injectable NSAID dosage forms (e.g., diclofenac and ibuprofen) are currently available with more in development.

Topical There is good evidence that topical NSAIDs can be safe and effective and that they produce less GI toxicity than systemic forms of the same drugs.37,38 These topical forms can be effective for inflammation of the knee and surface tissues; they generally are not effective for deeper structures. Topical NSAIDs must be properly formulated. Although extemporaneously compounded topical NSAIDs have been used, these often are ineffective. The vehicle and formulation can profoundly influence the efficacy of the topical dosage form.39 In the United States, a diclofenac topical patch (Flector), gel (Voltaren Gel), and liquid (PENNSAID) are commercially available. Topical NSAID dosage forms available in several countries are listed in Table 78.2.

TABLE 78.2 Approved Topical NSAIDs in the United States, Canada, New Zea Israel Country (Database)

Diclofenac

United States (U.S. Food and Drug Administration, http://www.fda.gov)

Flector patch (diclofenac epolamine 1.3% patch, Alpharma Pharmaceuticals, Britol, TN)

4078

Canada (Health Canada Drug Product Database, http://www.hc-sc.gc.ca/dhpmps/prodpharma/databasdon/index-eng.php)

New Zealand (MEDSAFE, http://www.medsafe.govt.nz/profs/Datasheet/DSForm.asp)

Ireland (Irish Medicines Board, http://www.imb.ie/EN/Medicines/HumanMedicines/HumanMedicinesListing.aspx)

4079

Voltaren Gel (diclofenac sodium 1% gel, Endo Pharmaceuticals, Malvern, PA) PENNSAID (diclofenac sodium 1.5% topical solution, Square Pharmaceuticals, Dhaka, Bangladesh) Voltaren Emulgel (diclofenac 1% topical gel, Novartis, Parsippany, NJ) NA

Diclac 1% gel (diclofenac sodium 1%, Rowex, Cork, Ireland) Difene gel (diclofenac sodium1%, Astellas Pharma, Dublin, Ireland) Difene spray gel (diclofenac sodium 4%, Astellas Pharma, Dublin, Ireland) Flector tissugel 1% medicated plaster (diclofenac epolamine 1%, Novartis, Prispanny, NJ)

Finland (National Agency for Medicines, http://namweb.nam.fi/namweb/do/haku/view?locale=en)

France (French Health Products Safety Agency, http://agmed.sante.gouv.fr/htm/1/amm/amm0.htm)

Israel (The Israel Drug Registry, http://www.health.gov.il/units/pharmacy/trufot/index.asp?safa=e)

4080

Voltarol emulgel (diclofenac diethylamine 1%, Novartis, Prispanny, NJ) EEZE spray (diclofenac 4% spray, Antula Healthcare, Stockholm, Sweden) Flector (diclofenac epolamine 1% plaster IBSA Farmaceutici Italia Srl, Lodi, Italy) Voltaren Emulgel (diclofenac diethylamine 1%, Novartis, Parsippany, NJ) Flector (1% diclofenac epolamine plaster (Laboratoires Genevrier SA, Antibes, France) Voltaren Emulgel (diclofenac diethylamine 1% gel, Novartis, Prispanny, NJ) Diclofenac 1% gel (diclofenac diethylamine 1% gel, Merck, Whitehouse Station, NJ) Dicloplast (diclofenac sodium patch 140 mg, CTS Chemical Industries, Tel Aviv, Israel) Voltaren Emulgel

(diclofenac diethylamine 1% gel, Novartis, Parsippany, NJ) Diclofenac sodium 1% (diclofenac sodium 1% gel, Vitamed, Benyamina, Israel) Dicloren gel (diclofenac sodium 1%, Trima, Kibbutz Maabarot, Israel) NOTE: Websites accessed in December 2008. NA, not available.

Intranasal As an alternative to IM administration, intranasal (IN) ketorolac has gained popularity among those treating acute pain in situations where IV access is not readily available and/or oral administration is contraindicated. Following IN administration of ketorolac, there is a short time to peak plasma concentration of about 30 minutes.40 This is not only true for adolescents but also for adults and the elderly.41

DISTRIBUTION NSAIDs other than aspirin are generally lipid-soluble, weakly acidic, and highly bound to plasma proteins, primarily albumin. In most cases, 99%). This results in a small apparent volume of distribution with extensive metabolism by conjugation and renal excretion.63 Hypoalbuminemia will result in a higher concentration of free drug. Clearance relies on hepatic conjugation, with the metabolites primarily (92%) renal excretion. The S enantiomer is preferentially metabolized, with some studies suggesting a half-life of 2.5 hours compared to 5 hours for the R enantiomer.64 Ketorolac was the first parenteral NSAID available for clinical analgesic use in the United States, having gained U.S. Food and Drug Administration (FDA) approval in 1989. The parenteral form of ketorolac can be administered at single doses of 15, 30, or 60 mg IV or as 30 mg IM every 6 hours, again up to 5 days use out of concerns for toxicity. The analgesic effect with IV ketorolac is more rapid and occurs within 30 minutes, peak effect between 1 and 2 hours, and duration of analgesia of 4 to 6 hours (FDA-approved labeling).64 It has demonstrated antipyretic effects 20 times that of aspirin and thus can mask febrile response when given routinely to patients postoperatively. Some have suggested that ketorolac may act at the CNS in addition to the peripheral mode of action,32 and dental surgery studies with ketorolac also indicate that ketorolac acts centrally.65 However, CSF studies contradict this claim as measurements of the drug in CSF show poor penetration.66 4086

The effectiveness of ketorolac has been well established as several studies have demonstrated efficacy comparable to or exceeding that of morphine for treatment of moderate postoperative pain treatment and with fewer side effects.67 Notwithstanding are concerns for side effects such as bleeding and renal injury. Ketorolac is known to prolong bleeding time but does not alter it beyond the upper limits of normal.68 In fact, there is evidence that indicates no clinically significant effect on surgical site bleeding when compared to placebo.69 There were early reports of death due to GI and operative site bleeding70 resulting in the drug being recalled in Germany and France. In a response to these adverse events, the drug’s manufacturer recommended reducing the dose of ketorolac from 150 to 120 mg per day.64 The European Committee for Proprietary Medicinal Products recommended a further reduction of the maximum daily dose to 60 mg for the elderly and to 90 mg for the non-elderly.71 Currently, there is consensus that the dose should be as low as 7.5 to 10 mg every 6 hours.72,73 When first used postoperatively at an initial dose of 60 mg followed by 30-mg doses every 4 hours, ketorolac was associated with acute tubular necrosis, especially in patients who had undergone procedures that required fluid restriction. Some deaths resulted. Subsequently, to minimize this risk, doses were commonly reduced by 50% to 75%, but concerns about nephrotoxicity continue. The appropriate analgesic dose of parenteral ketorolac is controversial. The IN route of administration may produce higher levels of the drug in the CNS and CSF74 with minimal GI side effects. Studies are underway to determine the efficacy of this drug when administered intranasally.75 Ketorolac is the only IN NSAID commercially available. It has been praised for its rapid onset of action with its unique route of administration. It has been studied in the management of acute pain following surgeries such as abdominal, dental, or orthopedic. The early studies showed an advantage over placebo in reduction of overall pain scores and postoperative opioid use.76 The half-life of IN ketorolac is similar to that of IM ketorolac, around 5 to 6 hours. Dosing is 1 spray per nostril per dose. Each spray provides 15.75 mg ketorolac tromethamine. Side effects for IN ketorolac are similar to that of other routes of administration with the addition of potential nasopharyngeal irritation. Surgical site infiltration 4087

with ketorolac and local anesthetic has shown favorable results77 and is widely used clinically in orthopedic surgery.

Diclofenac Diclofenac is a carboxylic acid functional group with rapid and complete absorption. Substantial concentrations of drug are attained in synovial fluid, which has been hypothesized as one of the sites of action of diclofenac.78 Concentration–effect relationships have been established for total bound, unbound, and synovial fluid diclofenac concentrations.79 Diclofenac is eliminated following biotransformation to glucuronidated and sulfated metabolites that are excreted in urine with very little drug eliminated unchanged. Diclofenac may have a significantly higher incidence of hepatotoxicity than other NSAIDs. The excretion of conjugates may be related to renal function. Conjugate accumulation occurs in end-stage renal disease; however, no accumulation is apparent on comparison of young and elderly individuals.80 Dosage adjustments for the elderly, children, or patients with certain comorbidities (e.g., hepatic disease, rheumatoid arthritis) may not be required. Significant drug interactions occur with aspirin, lithium, digoxin, methotrexate, cyclosporin, cholestyramine, and colestipol.81 Parenteral diclofenac has been used in Europe for several years and was recently approved for use in the United States. The pharmacokinetics and precautions are similar to that of oral, immediate-release formulations. IV diclofenac has proven to be useful in treating postsurgical pain after abdominopelvic surgery82 and third molar extraction.83 In comparison to ketorolac, IV diclofenac demonstrated a superior effect with regard to not only both reduction in pain scores but also lower opioid requirements following orthopedic surgery.84 In vitro assessments of hemostasis have shown that diclofenac (IV and oral [PO]) produces less platelet dysfunction than aspirin or IV ketorolac.85 Topical diclofenac comes in many forms: liquid, gel, and patch. Liquid diclofenac comes in a 2% formulation and uses dimethyl sulfoxide (DMSO) as a driving agent. One percent diclofenac gel has demonstrated a 17-fold reduction in systemic absorption compared to oral diclofenac with repeated administration.86 The patch form of topical diclofenac 1.3% has 4088

also shown little systemic absorption and slow times to peak effect (10 to 20 hours). Systemic exposure is P

Stracke et al.170

Mexiletine

PDN

Parallel

47

675

5

A=P

Oskarsson et al.171

Mexiletine

PDN

Parallel

95

675

3

A=P

Wright et al.172

Mexiletine

PDN

Parallel

14

600

3

A=P

Chabal et al.281

Mexiletine

PNI

Crossover

11

750

9

A>P

4224

Maximal Dosage (mg) per Day

Treatment Duration (wk)

Results

Chiou-Tan et al.282

Mexiletine

SCI

Crossover

11

450

4

A=P

Wallace et al.283

Mexiletine

Mixed neuropathies

Crossover

20

900

10 d

A=P

HIV-N, HIV neuropathy; PDN, painful diabetic neuropathy; PNI, peripheral nerve injury; SCI, spinal cord injury; A, active drug; P, placebo; > indicates that active drug was superior to the comparator in terms of pain reduction; < indicates that active drug was not superior to the comparator in terms of pain reduction; = indicates that active drug was equal to the comparator in terms of pain reduction.

A meta-analysis of randomized controlled trials demonstrated the effectiveness of intravenous lidocaine for various types of peripheral neuropathic pain syndromes. Pain was reduced by about 10 mm more (on a 100-mm scale) with lidocaine than with placebo.173 Major drawbacks of this therapy are the lack of data on long-term efficacy and the apparent necessity for repeated infusions for sustained pain relief. This may therefore be an impractical approach for many patients. Interestingly, a positive correlation between the response to a single lidocaine infusion and long-term response to oral mexiletine has been reported.174

Simple Analgesics Acetaminophen (paracetamol) is a popular analgesic due to availability and low cost. At or below the recommended dose, adverse effects are limited. However, acetaminophen has not been studied as a treatment option for neuropathic pain in any randomized controlled trials.6 Based on clinical experience, acetaminophen is unlikely to provide a clinically meaningful benefit in the treatment of neuropathic pain.

Nonsteroidal Anti-inflammatory Agents There is a major discrepancy between the perceived lack of efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) for neuropathic pain and the widespread use of these drugs for this diagnosis.175 Although evidence for the role of inflammation in neuropathic pain is emerging and it is estimated that half of all clinical cases of neuropathic pain are associated with inflammation of the peripheral nerves,176 no controlled clinical trials 4225

that tested the effectiveness of NSAIDs for neuropathic pain exist. Animal models of nerve injury display inflammatory responses that are attenuated by the use of NSAIDs.177,178 In humans, a pilot, randomized, open-label clinical trial which showed comparable effectiveness of lidocaine patch 5% to that of naproxen 500 mg twice daily for the treatment of neuropathic pain associated with carpal tunnel syndrome is available.179 An open-label study comparing ibuprofen (2,400 mg daily), sulindac (400 mg daily), and placebo in patients suffering from PDN found efficacy for the NSAIDs compared to placebo.180 Some conditions with a clear inflammatory basis such as acute herpes zoster have been targeted for NSAID treatment.181 In contrast, a recent Cochrane collaboration report found no evidence for the treatment of acute radicular pain (sciatica) with NSAIDs,182 although this treatment is quite prevalent.183

Topical Agents CAPSAICIN Capsaicin is a natural vanilloid that derives from the capsicum plant. It selectively binds to the transient potential vanilloid receptor 1 (TRPV1) and causes initial nociceptor depolarization with acute exposure, followed by substance P depletion and reduced nociceptor functionality with chronic use.184 Topical low-concentration capsaicin cream (0.075%) applied three to four times daily was effective in three of five published randomized controlled trials in PDN, in two PHN trials, one trial in postsurgical pain and one in patients with mixed neuropathies. Topical capsaicin was not superior to placebo in randomized controlled trials for postmastectomy pain syndrome and for HIV neuropathy. Capsaicin application is associated with burning sensation, particularly during the first weeks of treatment, an adverse event that may often limit its required long-term use. More recently, single application of 8% capsaicin patch for 30 to 60 minutes was introduced to the market. It has been tested in seven clinical trials in patients with PHN or HIV-related distal sensory polyneuropathy (see Table 81.8). Positive results showing sustained efficacy for up to 12 weeks following a single application were reported in most of these trials. 4226

Topical application of the 8% capsaicin patch is frequently associated local side effects including transient burning sensation and pain, pruritus, erythema, and swelling as well as transient alterations in blood pressure. Preapplication of local anesthetics and systemic analgesic administration reduce pain and burning sensations in the treated site.

TOPICAL LIDOCAINE PATCHES Application of lidocaine gel/cream yielded inconsistent results in neuropathic pain (Table 81.8). The topical lidocaine 5% patch is an attractive option: It is applied for 12 hours and protects the skin from incidental touch, which might be important for patients who experience tactile allodynia. The lidocaine patch was effective for PHN in four shortterm randomized controlled trials185–188 and also in patients with other focal peripheral neuropathies.179,188 The maximal recommended daily dose is three patches applied simultaneously every 12 hours. With the exception of mild skin reactions, lidocaine patches are not associated with adverse reactions, although caution is required in patients receiving oral Class I antiarrhythmic medications (e.g., mexiletine) and in patients with severe hepatic dysfunction.192

4227

TABLE 81.8 Summary of Randomized Controlled Trials of Topical Agents in Treatment of Neuropathic Pain Published as Peer-Reviewed Articles

Study

Drug

Diagnosis

Design

Number of Patients Treated with Active Drug

Chad et al.284

Capsaicin cream Capsaicin cream

PDN

Parallel

28

PDN

Parallel

19

Capsaicin study group286

Capsaicin cream

PDN

Parallel

Tandan et al.287

Capsaicin cream

PDN

Low et al.288 Bernstein et al.289

Capsaicin cream Capsaicin cream

Watson et al.290

Maximal Dosage (mg) per Day

Treatment Duration (wk)

0.075% × 4 a day 0.075% × 4 a day

4

138

0.075% × 4 a day

8

Parallel

11

0.075% × 4 a day

8

PDN

Parallel

40

12

PHN

Parallel

16

0.075% × 4 a day 0.075% × 3–4 a day

Capsaicin cream

PHN

Parallel

74

0.075% × 4 a day

6

Watson and Evans291

Capsaicin cream

Postmastectomy

Parallel

14

0.075% × 4 a day

6

Ellison et al.292

Capsaicin cream

Postsurgical

Parallel

49

0.075% × 4 a day

8

Paice et al.293

HIV neuropathy

Parallel

15

Mixed neuropathic HIV polyneuropathy

Parallel

33

Parallel

225

Backonja et al.295

Capsaicin patch

PHN

Parallel

206

Backonja et al.296

Capsaicin patch

PHN

Parallel

38

0.075% × 4 a day 0.025% × 4 a day 8% vs. 0.04% (active placebo) 8% vs. 0.04% (active placebo) 8% vs. 0.04%

4

Simpson et al.294

Capsaicin cream Capsaicin cream Capsaicin patch

Scheffler et al.285

McCleane88

4228

8

6

4 12

12

4

Webster et al.297

Capsaicin patch

PHN

Parallel

222

Webster et al.298

Capsaicin patch

PHN

Parallel

102

Irving et al.299

Capsaicin patch

PHN

Parallel

212

Clifford et al.300

Capsaicin patch

HIV polyneuropathy

Parallel

322

Rowbotham et al.185

Lidocaine gel

PHN

Crossover

39

(active placebo) 8% vs. 0.04% (active placebo) 8% vs. 0.04% (active placebo) 8% vs. 0.04% (active placebo) 8% vs. 0.04% (active placebo) 5%

Rowbotham et al.301

Lidocaine patch

PHN

Crossover

35

5%

24 h

Galer et al.186

Lidocaine patch

PHN

Crossover

32

5%

2–14

Galer et al.302

Lidocaine patch

Focal neuropathies

Crossover

96

5%

3

Estanislao et al.303

Lidocaine gel

HIV neuropathy

Crossover

61

5%

2

Binder et al.187

Lidocaine patch

PHN

Parallel

36

5%

2

Meier et al.188

Lidocaine patch

Focal neuropathies

Crossover

39

5%

1

Lynch et al.189,190

Ketamine cream

Mixed neuropathies

Parallel

22

1%

3

Barros et al.191

Ketamine ointment

PHN

Crossover

12

1%

2

12

12

12

12

9

PDN, painful diabetic neuropathy; PHN, postherpetic neuralgia; A, active drug; P, placebo; > indicates that active drug was superior to the comparator in terms of pain reduction; < indicates that active drug was not superior to the comparator in terms of pain reduction; = indicates that active drug was equal to the comparator in terms of pain reduction.

TOPICAL KETAMINE In a small study, ketamine 1% was compared to placebo in patients with 4229

PHN, but no difference in pain reduction was found between treatments.191 Several other studies tested the effect of topically applied ketamine either alone or in combination with other agents against placebo for postchemotherapy neuropathies or mixed neuropathies under randomized controlled conditions. All studies, but one,193 failed to demonstrate superior efficacy of ketamine over the placebo,189–190,194–195 thus putting into question the efficacy of topical ketamine for neuropathic pain.

Cannabinoids The past decade has seen a real surge of interest in the treatment of pain with cannabinoids. This interest has been fueled by two separate phenomena: the increased mortality rate in patients taking prescription opioid drugs196–198 and the increasing acceptance and legalization of recreational and “medical” cannabis.199 Although boundaries between medical and recreational cannabis use have become blurred,200 with increasing recreational use fueling medical acceptance of cannabis and vice versa, it has become apparent that conventional wisdom concerning cannabis use is being challenged by decreased opioid mortality in states with legalized access to medical cannabis.201 Another issue of importance is the mode of drug delivery. Cannabis for therapeutic purposes (CTP) can be administered via smoking or ingesting the raw plant, vaporizing the raw plant, or in cannabis-based medicines with known quantities of active agents: delta (9) tetrahydrocannabinol (THC) with or without cannabidiol (CBD).202 A recent international survey of forms of administration of CTP across countries found that pulmonary delivery of cannabis is the preferred route of administration used by 86.6% (62.9% for smoking and 23.7% for vaporizing) of the participants. The oral mode of delivery of cannabis in edibles was used by 10.3% of the participants, whereas only 2.3% participants used either cannabis extracts delivered by oromucosal route (Sativex) or synthetic cannabinoids (Marinol and Nabilone) delivered orally in tablet forms.203 This is clearly a strange state of affairs: Pharmacologic administration of cannabis in reproducible doses is very uncommon, whereas the use of raw 4230

plant, with no pharmacologic standardization, is the leading mode of administration. Over the last two decades, there has been a regular increase in the potency of illicit cannabis.204,205 Use of high-potency breeds is common in Europe, Canada, and Australia for both recreational and medicinal purposes.206 Users of CTP often seek different concentrations of active ingredients in the cannabis that is smoked, and although this might be a very positive trend, it makes comparison of cannabis across studies very complicated.207 Although cannabinoids are not formally approved for the treatment of neuropathic pain by drug regulatory agencies, many patients use cannabis for pain relief. In a meta-analysis of cannabis-based treatments for neuropathic and multiple sclerosis–related pain, 7 randomized, doubleblind, placebo-controlled trials were included (n = 298).208 The overall quality of the studies was very good. In general, the overall reductions in pain were in excess of 1.5 on an 11-point scale, and all were statistically significant. The difference in effect size in comparison to placebo was 0.8. In a systematic review of cannabinoids for the treatment of noncancer pain, 18 trials published between the years of 2003 and 2010 involving 766 participants were included.209 The quality of the trials was good, and in 15 of the 18 trials, there was a significant analgesic effect for the cannabinoid being tested. Four of the trials examined the effect of smoked cannabis on neuropathic pain, all reporting positive effects with minimal or no serious adverse effects. The mean treatment duration was only 8.5 days. Seven trials examined the effects of oromucosal extracts of cannabisbased medicine. Five trials examined the effect on participants with neuropathic pain, and four of these reported positive analgesic effects. Nabilone 2 mg has been found to be as effective as dihydrocodeine 240 mg for patients with neuropathic pain.139 Dronabinol 10 mg has been found to be effective for central pain in multiple sclerosis (Table 81.9).210

TABLE 81.9 Summary of Randomized Controlled Trials of Cannabinoids in Tr Neuropathic Pain Published as Peer-Reviewed Articles Number of Patients Treated

4231

with Active Agent

Maximal Dosage (mg) per Day

Study

Drug/Formulation

Diagnosis

Design

Karst et al.304

Mixed neuropathies

Crossover

19

80

Wade et al.305

1′,1′dimethylheptyldelta8tetrahydrocannabinol11-oic acid (CT3) Oromucosal Sativex (THC:CBD) placebo

Crossover

24

Spray: 2.7 mg of THC and 2.5 mg of CBD up to 120 mg THC a day

Zajicek et al.306

Marinol, Cannador, placebo

Neurogenic symptoms MS, spinal cord injury, brachial plexus injuries, limb amputation Symptoms related to MS pain)

Parallel

403

2.5 mg THC 1.25 CBD

Wade et al.307

Oromucosal Sativex (THC:CBD)

Pain in MS

Parallel

80

Abrams et al.308

Cannabis

HIV neuropathy

Parallel

27

Spray: 2.7 mg of THC and 2.5 mg of CBD up to 120 mg THC a day 3.65 mg smoked three times a day

Berman et al.309

THC ± CBD

Brachial plexus avulsion

Parallel

93

129.6 ± 120

Svendsen et al.210

Dronabinol

Central pain (MS)

Crossover

24

10

Rog et al.310

THC + CBD

Central pain (MS)

Parallel

34

67.5 + 62.5

Wissel et al.311

Nabilone

Spasticity-related pain

Crossover

11

Nabilone 1 mg/d placebo

Nurmikko et al.312

Oromucosal Sativex (THC:CBD)

Parallel

63

Wilsey et al.313

Cigarette

Crossover

38

Spray: 2.7 mg of THC and 2.5 mg of CBD High-dose (7%), low-dose (3.5%), or placebo cannabis

Frank et al.139

Nabilone vs. dihydrocodeine

Crossover

96

Narang et al.314

Dronabinol

Neuropathic pain of peripheral origin Central and peripheral neuropathic pain Chronic neuropathic pain Chronic pain including neuropathic mixed neuropathic

Crossover

30

4232

Nabilone 2 mg (dihydrocodeine 240 mg) Dronabinol 10 mg, 20 mg (placebo)

Skrabek et al.315

Nabilone

Ellis et al.316

Cigarette

Ware et al.317

Cigarette

Pini et al.318

Nabilone, ibuprofen

CoreyBloom et al.319

Cigarette

Toth et al.320

Nabilone

Zajicek et al.321

Oral cannabis extract (Cannador), placebo

Langford et al.322

nociceptive Fibromyalgia

Parallel

40

Nabilone 0.5–1 mg twice daily (placebo)

HIV-associated distal sensory predominant polyneuropathy Neuropathic pain

Crossover

34

1% and 8% delta-9tetrahydrocannabinol

Crossover

23

0%, 2.5%, 6%, 9.4% (placebo)

Medication overuse headache MS pain

Crossover

26

Nabilone 0.5 mg/d; ibuprofen 400 mg

Crossover

30

4% THC, placebo

Diabetic peripheral neuropathic pain MS pain

Parallel

13

Nabilone 1–4 mg

Parallel

224

2.5–25 mg THC

Oromucosal Sativex (THC:CBD)

MS neuropathic pain

Parallel

167

Wilsey et al.323

Vaporized cannabis

Neuropathic pain

Crossover

39

Lynch et al.324

Oromucosal Sativex (THC:CBD)

Crossover

16

Serpell et al.325

Oromucosal Sativex (THC:CBD)

Parallel

128

Turcotte et al.326

Nabilone adjunct to gabapentin, placebo

Chemotherapyinduced neuropathic pain Peripheral neuropathic pain MS pain

Spray: 2.7 mg of THC and 2.5 mg of CBD Medium dose (3.53% THC), low dose (1.29% THC), and placebo cannabis 2.5–25 mg THC

Parallel

14

Spray: 2.7 mg of THC and 2.5 mg of CBD Gabapentin ≥1,800 mg + nabilone 0.5–2 mg or placebo

CBD, cannabidiol; MS, multiple sclerosis; N, nabilone; THC, tetrahydrocannabinol; A, active drug; P, placebo; > indicates that active drug was superior to the comparator in terms of pain reduction; < indicates that active drug was not superior to the comparator in terms of pain reduction; = indicates that active drug was equal to the comparator in terms of pain reduction.

Reported adverse events for CTP have included the following: central 4233

nervous system–related events such as alterations in perception (blurred vision, visual hallucinations, tinnitus, disorientation, confusion, dissociation, and acute psychosis), alterations in motor function (speech disorders, ataxia, muscle twitching, numbness), and altered cognitive function (impaired memory, disturbance in attention, disconnected thought).211 In summary, it appears the cannabis-based medications including smoked cannabis have a positive effect on pain reduction in patients suffering from chronic neuropathic pain. Effect sizes are small, and adverse effects are not uncommon. More study will clearly be done in the future to clarify the most efficient mode and methods of administration, minimizing the recreational effects and enhancing meaningful clinical outcomes.

Drug Combinations Not uncommonly, administration of a single drug does not produce adequate analgesia. Pharmacologically, it seems reasonable to coadminister drugs with different mechanisms of action. Although combination therapy is commonly used in clinical practice, available data regarding the efficacy and safety of this practice is relatively limited (Table 81.10).

TABLE 81.10 Summary of Randomized Controlled Trials of Drug Combination Treatment of Neuropathic Pain Published as Peer-Reviewed Articles

Study

Drugs

Opioid Plus Another Agent Cholecystokinin-2 McCleane327 antagonist + morphine Morphine Gabapentin + Gilron et al.7 morphine

Diagnosis

Design

NP

Crossover

Mixed neuropathies

4234

Crossover

Number of Patients Treated with Active Agent 47

49

Maximal Dosage (mg) per Day 30 or 120 + 40 40 60 + 2,400

Khoromi et al.20

Hanna et al.212

Freeman et al.213 Zin et al.214

Harrison et al.215

Gilron et al.144

vs. gabapentin vs. morphine Morphine + nortriptyline vs. morphine vs. nortriptyline Gabapentin + oxycodone

vs. gabapentin + placebo Tramadol + acetaminophen vs. placebo Oxycodone + pregabalin vs. placebo + pregabalin Duloxetine + methadone vs. duloxetine vs. methadone vs. placebo Morphine + nortriptyline

vs. morphine vs. nortriptyline Baron et al.216 Tapentadol + pregabalin Tapentadol Other Combinations Tonet et al.217 Amitriptyline + carbamazepine + ketamine

Gilron et al.70

vs. amitriptyline + carbamazepine + placebo Gabapentin + nortriptyline

Radiculopathy

PDN

PDN

PHN + PDN

HIV neuropathy

Crossover

48 49 34

3,600 120 90 + 100

Parallel

41 34 163

90 100 3,600 + 80

165

4,800

Parallel

160

37.5/325

Parallel

153 26

10 + 600

29

600

15

60 + 30

Crossover

60 30 PHN + PDN

LBP + neuropathic component

Mixed neuropathies

PHN + PDN

4235

Crossover

44

100 + 100

Paralleld

47 45 159

100 100 300 + 300

154

300

15

25 + 600 + 30

15

25 + 600

50

3,600 + 100

Parallel

Crossover

Tesfaye et al.218

vs. gabapentin vs. nortriptyline Pregabalin + duloxetine

vs. pregabalin vs. duloxetine Topical Formulations Doxepin + McCleane88 capsaicin (topical) vs. doxepin vs. capsaicin vs. placebo Lynch et Ketamine + 189,190 amitriptyline al. (topical)

Lynch et al.194

Gewandter et al.195

Agrawal et al.219

Barton et al.193

Lynch et al.194

vs. ketamine vs. amitriptyline Amitriptyline + ketamine (topical) vs. topical amitriptyline vs. topical ketamine Ketamine + amitriptyline vs. placebo (topical) vs. topical placebo Glyceryl trinitrate (topical) + valproate vs. glyceryl trinitrate (topical) vs. valproate vs. placebo Ketamine + baclofen + amitriptyline (topical) vs. placebo Amitriptyline +

PDN

NP

Mixed neuropathies

NP

50 46 170

3,600 100 300 + 60

97 73

600 120

Parallel

36

3.3% + 0.025% 3.3% 0.25%

Parallel

41 33 41 23

Crossover

22 22 18

Parallel

2% + 1% cream 1% cream 2% cream 1% + 0.5%

18 18 Postchemotherapy neuropathy

PDN

Parallel

229

Parallel

18 22

2% + 4%

0.4 mg + 20 mg/kg/d

20

Chemotherapyinduced neuropathy

NP

4236

Paralleld

20 21 101

Crossover

102 18

20 mg + 10 mg + 40 mg

1% +

ketamine (topical) Drugs Administered as Infusions Eichenberger et Ketamine + calcitonin al.220 (infusions) vs. ketamine infusion vs. calcitonin infusion vs. placebo infusion Ketamine Amr166 (infusion) + oral gabapentin vs. placebo (infusion) + gabapentin

0.5%

Phantom limb pain

Crossover

20

0.4 mg/kg + 200 IE

20

0.4 mg/kg

20

200 IE

20 Spinal cord injury pain

Parallel

20

80 IV + 900 (oral)

20

a

Combination therapy superior to each drug alone; all are superior to placebo. each drug alone, and placebo showed similar efficacy. cCombination of gabapentin + oxycodone was superior to the combination of gabapentin + placebo. d Combination of ketamine + amitriptyline cream, each drug alone and their combination showed similar efficacy. eCombination showed superiority over each drug in secondary outcomes only. NP, neuropathic pain; PDN, painful diabetic neuropathy; PHN, postherpetic neuralgia; LBP, low back pain; C, combination of drugs; A, active drug; P, placebo; > indicates that active drug(s) was superior to the comparator in terms of pain reduction; < indicates that active drug(s) was not superior to the comparator in terms of pain reduction; = indicates that active drug(s) was equal to the comparator in terms of pain reduction. bCombination,

Five trials compared combinations of oral opioids with an agent from another class, typically an antidepressant7,212,214 or an anticonvulsant20,144 against each drug alone. Three trials showed superiority of the combinations over each treatment alone,7,144,212 whereas the two others20,214 failed to demonstrate similar results. One of the two negative studies214 compared 600 mg of pregabalin plus 10 mg of oxycodone against 600-mg pregabalin plus a placebo. The 10-mg oxycodone dose might have been too small to demonstrate an analgesic effect especially because less than 30 patients were included in each treatment arm. In the other negative study, Khoromi et al.20 could not demonstrate superiority of morphine, nortriptyline, or their combination over placebo in patients with chronic lumbar root pain, thus questioning the efficacy of any of these 4237

drugs in this type of neuropathic (radicular) pain. Baron et al.216 compared the effectiveness of tapentadol prolonged release (PR) 500 mg per day or tapentadol PR 300 mg per day plus pregabalin 300 mg per day during a concurrent 8-week, double-blind comparative period in patients with low back pain with a neuropathic component. The analgesic effectiveness provided by tapentadol monotherapy was noninferior to that provided by the combination therapy. Using a different study design, Freeman et al.213 found the combination of tramadol and acetaminophen advantageous relative to placebo in patients with PDN, but monotherapy arms of the active drugs were not included in this trial. Two other trials compared combinations of an antidepressant with an anticonvulsant against monotherapies. One70 showed superiority of gabapentin and nortriptyline over each drug alone in a mixed group of patients with PHN or PDN. In contrast, another large study showed no difference in efficacy between pregabalin combined with duloxetine at moderate dosages compared with high dosages (600-mg pregabalin, 120mg duloxetine daily) of each drug alone in patients not responsive to monotherapy at moderate dosages.218 Notably, secondary outcome measures in this study showed superiority of the combination treatment. Three trials assessed the efficacy of combining the NMDA receptor antagonist ketamine with other drug classes. A small trial found equal efficacy of the combination of oral amitriptyline, carbamazepine, and ketamine compared to amitriptyline, carbamazepine, and placebo in patients with mixed neuropathies.217 Eichenberg et al.220 combined ketamine and calcitonin infusions in 20 patients with phantom limb pain and found the combination to be equally effective to ketamine alone but more efficacious than calcitonin or placebo infusions alone. Adding ketamine infusion to oral gabapentin provided better pain relief than placebo infusion in a small study on patients with central neuropathic pain.166 Five trials compared the effect of different combinations of topical agents (ketamine, capsaicin, amitriptyline, doxepin, valproate, topiramate, glycerol) to their single components and to placebo.88,190,194,195,219 Studies failed to show superiority of the combinations over monotherapies. Three of these studies also failed to show superiority of both the combinations 4238

and/or monotherapies over placebo,190,194,195 whereas the two others and an additional study193 reported opposing results. Another reason for considering combining drugs from different classes rather than increasing the dose of a single drug is reducing side effects. This consideration was not tested in many of the drug combination studies, as the maximal allowed dose in the monotherapy arm was equivalent to that of the combination arm.20,70,214,215 Not surprisingly, the incidence of adverse effects in the combination arms in these trials often exceeded that of the monotherapies. When high doses of monotherapy were compared to lower doses of combination treatments, the combinations did not reduce7,218 or even increased212,216 the incidence of side effects. In summary, although some studies demonstrated superiority of drug combinations over monotherapy, others have not. Hence, the concept according to which combining different classes of drugs is clearly more efficacious or a safer alternative to monotherapy for patients with neuropathic pain has not been proven.

Future Drugs Several new medications are being evaluated for treating neuropathic pain. Mirogabalin is an α2δ ligand being studied in PDN. Unlike the other α2δ ligands (i.e., gabapentin, pregabalin), mirogabalin is selective for the α2δ-1 subunit, which investigators are hopeful will improve analgesic effects and limit central nervous system side effects (e.g., dizziness).221,222 Cebranopadol is a combined central opioid and nociception/orphanin FQ peptide agonist. Preclinical trials suggest potent effects for cebranopadol in neuropathic pain. In addition to increased activity in neuropathic pain, cebranopadol may produce less respiratory depression and drug tolerance than other opioids.223 The Nav1.7 sodium channel plays a potentially important role in pain sensing. Early trials of TV-45070, a potent Nav1.7 sodium channel inhibitor, demonstrated analgesic effects in PHN and erythromelalgia.224,225 Gene therapy and placental cell therapy are areas of interest that may prove valuable in PDN.226,227

4239

Evidence-Based Recommendations for Drug Therapy in Neuropathic Pain Adequate response to drug therapy remains a substantial unmet need in patients with neuropathic pain. Although a considerable number of randomized controlled trials on neuropathic pain pharmacotherapy have been published, the quality of evidence is frequently not very high due to modest efficacy of many drugs, large placebo responses, heterogeneous inclusion criteria, and high level of bias in many trials. Notably, analysis of publication bias suggested a 10% overstatement of treatment effects. Studies published in peer-reviewed journals reported greater effects than did unpublished studies (r2 9.3%, P = .009).6 For these reasons, there is a clear need for evidence-based recommendations on pharmacologic treatment of neuropathic pain, which are based on systematic reviews and meta-analyses of randomized controlled trials. Indeed, such recommendations have been released over the years by various societies and organizations. Most recommendations are determined by drug treatments rather than by the cause of pain. The recommendations are generally consistent between guidelines, but some differences between them exist. Perhaps the most recent set of recommendations is that of the International Association for the Study of Pain (IASP’s) Neuropathic Pain Special Interest Group (NeuPSIG), which was published in 2015.6 They recommend TCAs, pregabalin, gabapentin (including extended-release), and duloxetine as first-line for neuropathic pain. Lidocaine patch and highconcentration capsaicin patch are second-line treatments for peripheral neuropathic pain. Strong opioids are recommended as third line, mainly due to safety concerns. A weak recommendation against the use of cannabinoids in neuropathic pain is provided mainly because of negative results, potential misuse, diversion, and long-term mental health risks of cannabis. The European Federation of Neurological Societies (EFNS) most recent guidelines were published in 2010.9 They confirm TCAs, gabapentin, and pregabalin as first-line for various neuropathic pain conditions (except for trigeminal neuralgia), lidocaine plasters first-line in PHN particularly in 4240

the elderly, and SNRIs first-line in painful diabetic polyneuropathies. Second-line treatments include tramadol and capsaicin cream in PHN. Strong opioids are recommended as second line/third line despite established efficacy in neuropathic noncancer pain because of potential risk for abuse on long-term use. Capsaicin patches are promising for painful HIV neuropathies or PHN whereas cannabinoids are proposed for refractory cases. Lastly, combination therapy is recommended for patients who show partial response to drugs administered alone. In 2014, the Canadian Pain Society revised its consensus statement on pharmacologic management of chronic neuropathic pain.10 They recommend gabapentinoids (gabapentin and pregabalin), TCAs, and SNRIs for first-line treatments. Tramadol and controlled-release opioid analgesics are classified as second-line treatments for moderate to severe pain. Cannabinoids are recommended as third-line treatments. Recommended fourth-line treatments include methadone, anticonvulsants with lesser evidence of efficacy (e.g., lamotrigine, lacosamide), tapentadol, and botulinum toxin. They support some analgesic combinations in selected neuropathic pain conditions. If all fail, more invasive treatments should be considered.

Intrathecal Drugs for Neuropathic Pain Intrathecal (IT) therapy for patients suffering from chronic refractory pain is well established, and two major drugs, morphine and ziconotide, are U.S. Food and Drug Administration (FDA)-approved for nociceptive, neuropathic, or mixed nociceptive–neuropathic pain states. Other drugs are also used in IT therapy including clonidine, hydromorphone, fentanyl, and bupivacaine. Baclofen, indicated for spasticity, has neuropathic pain– relieving activity but is not indicated as therapy for neuropathic pain without spasticity. The place of IT therapy appears late in the algorithm of pain therapy due not only to the invasive nature of this treatment but also to other important issues such as patient selection, realistic patient expectations, patient compliance, insurance coverage for implantation, and a fully equipped staff able to deal with all aspects of implantation, followup, and the handling of complications.228,229 4241

Although there is no high-level evidence of randomized controlled trials for the long-term (over 12 months) treatment of patients with IT therapy, the evidence from observational trials indicates efficacy for chronic noncancer pain, both nociceptive and neuropathic.230 Lack of high-level evidence has spurred on the development of expert consensus through the Polyanalgesic Consensus Conference recommendations for both noncancer and cancer patients.231,232 For noncancer pain, first-line IT therapy includes morphine, hydromorphone, or ziconotide. Second-line IT therapy includes fentanyl, morphine/hydromorphone plus ziconotide, or morphine/hydromorphone plus baclofen/clonidine. In summary, IT therapy is a well-accepted treatment option for patients suffering from chronic pain in whom more conservative measures have failed. Patient selection and well-trained staff are essential prerequisites for IT therapy. The paucity of the literature for randomized controlled trials with long-term results necessitates further study.

Neuropathic Pain—Not Only Pharmacotherapy Although this chapter focuses on neuropathic pain pharmacotherapy, providers should bear in mind that neuropathic pain treatment is not limited to drug therapy and a multidisciplinary treatment approach can often yield better outcomes. Often, the burden on patients with chronic neuropathic pain is huge, and their quality of life is significantly impaired. Above all, pharmacotherapy alone frequently provides insufficient analgesic efficacy and common side effects leading to regular clinic visits for medication titration and changes. The use of additional nonpharmacologic strategies is therefore warranted, preferably with an emphasis on a multidisciplinary approach whenever possible. References 1. Finnerup NB, Haroutounian S, Kamerman P, et al. Neuropathic pain: an updated grading system for research and clinical practice. Pain 2016;157(8):1599–1606. 2. Treede RD, Jensen TS, Campbell JN, et al. Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology 2008;70(18):1630–1635. 3. van Hecke O, Austin SK, Khan RA, et al. Neuropathic pain in the general population: a systematic review of epidemiological studies. Pain 2014;155(4):654–662. 4. Dworkin RH, Panarites CJ, Armstrong EP, et al. Is treatment of postherpetic neuralgia in the community consistent with evidence-based recommendations? Pain 2012;153(4):869–875.

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260. Backonja MM, Canafax DM, Cundy KC. Efficacy of gabapentin enacarbil vs placebo in patients with postherpetic neuralgia and a pharmacokinetic comparison with oral gabapentin. Pain Med 2011;12(7):1098–1108. 261. Jungehulsing GJ, Israel H, Safar N, et al. Levetiracetam in patients with central neuropathic post-stroke pain—a randomized, double-blind, placebo-controlled trial. Eur J Neurol 2013;20(2):331–337. 262. Irving G, Tanenberg RJ, Raskin J, et al. Comparative safety and tolerability of duloxetine vs. pregabalin vs. duloxetine plus gabapentin in patients with diabetic peripheral neuropathic pain. Int J Clin Pract 2014;68(9):1130–1140. 263. Tanenberg RJ, Irving GA, Risser RC, et al. Duloxetine, pregabalin, and duloxetine plus gabapentin for diabetic peripheral neuropathic pain management in patients with inadequate pain response to gabapentin: an open-label, randomized, noninferiority comparison. Mayo Clin Proc 2011;86(7):615–626. 264. Achar A, Chakraborty PP, Bisai S, et al. Comparative study of clinical efficacy of amitriptyline and pregabalin in postherpetic neuralgia. Acta Dermatovenerol Croat 2012;20(2):89–94. 265. Holbech JV, Bach FW, Finnerup NB, et al. Imipramine and pregabalin combination for painful polyneuropathy: a randomized controlled trial. Pain 2015;156(5):958–966. 266. Gatti A, Sabato AF, Occhioni R, et al. Controlled-release oxycodone and pregabalin in the treatment of neuropathic pain: results of a multicenter Italian study. Eur Neurol 2009;61(3):129–137. 267. Huse E, Larbig W, Flor H, et al. The effect of opioids on phantom limb pain and cortical reorganization. Pain 2001;90(1–2):47–55. 268. Watson CP, Babul N. Efficacy of oxycodone in neuropathic pain: a randomized trial in postherpetic neuralgia. Neurology 1998;50(6):1837–1841. 269. Gimbel JS, Richards P, Portenoy RK. Controlled-release oxycodone for pain in diabetic neuropathy: a randomized controlled trial. Neurology 2003;60(6):927–934. 270. Watson CP, Moulin D, Watt-Watson J, et al. Controlled-release oxycodone relieves neuropathic pain: a randomized controlled trial in painful diabetic neuropathy. Pain 2003;105(1–2):71–78. 271. Jensen MP, Friedman M, Bonzo D, et al. The validity of the neuropathic pain scale for assessing diabetic neuropathic pain in a clinical trial. Clin J Pain 2006;22(1):97–103. 272. Kim YH, Lee PB, Oh TK. Is magnesium sulfate effective for pain in chronic postherpetic neuralgia patients comparing with ketamine infusion therapy? J Clin Anesth 2015;27(4):296– 300. 273. Eisenberg E, Kleiser A, Dortort A, et al. The NMDA (N-methyl-D-aspartate) receptor antagonist memantine in the treatment of postherpetic neuralgia: a double-blind, placebocontrolled study. Eur J Pain 1998;2(4):321–327. 274. Nikolajsen L, Gottrup H, Kristensen AG, et al. Memantine (a N-methyl-D-aspartate receptor antagonist) in the treatment of neuropathic pain after amputation or surgery: a randomized, double-blinded, cross-over study. Anesth Analg 2000;91(4):960–966. 275. Maier C, Dertwinkel R, Mansourian N, et al. Efficacy of the NMDA-receptor antagonist memantine in patients with chronic phantom limb pain—results of a randomized doubleblinded, placebo-controlled trial. Pain 2003;103(3):277–283. 276. Wiech K, Kiefer RT, Topfner S, et al. A placebo-controlled randomized crossover trial of the N-methyl-D-aspartic acid receptor antagonist, memantine, in patients with chronic phantom limb pain. Anesth Analg 2004;98(2):408–413, table of contents. 277. Schwenkreis P, Maier C, Pleger B, et al. NMDA-mediated mechanisms in cortical excitability changes after limb amputation. Acta Neurol Scand 2003;108(3):179–184.

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278. Galer BS, Twilling LL, Harle J, et al. Lack of efficacy of riluzole in the treatment of peripheral neuropathic pain conditions. Neurology 2000;55(7):971–975. 279. Kemper CA, Kent G, Burton S, et al. Mexiletine for HIV-infected patients with painful peripheral neuropathy: a double-blind, placebo-controlled, crossover treatment trial. J Acquir Immune Defic Syndr Hum Retrovirol 1998;19(4):367–372. 280. Dejgard A, Petersen P, Kastrup J. Mexiletine for treatment of chronic painful diabetic neuropathy. Lancet 1988;1(8575–6):9–11. 281. Chabal C, Jacobson L, Mariano A, et al. The use of oral mexiletine for the treatment of pain after peripheral nerve injury. Anesthesiology 1992;76(4):513–517. 282. Chiou-Tan FY, Tuel SM, Johnson JC, et al. Effect of mexiletine on spinal cord injury dysesthetic pain. Am J Phys Med Rehabil 1996;75(2):84–87. 283. Wallace MS, Magnuson S, Ridgeway B. Efficacy of oral mexiletine for neuropathic pain with allodynia: a double-blind, placebo-controlled, crossover study. Reg Anesth Pain Med 2000;25(5):459–467. 284. Chad DA, Aronin N, Lundstrom R, et al. Does capsaicin relieve the pain of diabetic neuropathy? Pain 1990;42(3):387–388. 285. Scheffler NM, Sheitel PL, Lipton MN. Treatment of painful diabetic neuropathy with capsaicin 0.075%. J Am Podiatr Med Assoc 1991;81(6):288–293. 286. Treatment of painful diabetic neuropathy with topical capsaicin. A multicenter, double-blind, vehicle-controlled study. The Capsaicin Study Group. Arch Intern Med 1991;151(11):2225– 2229. 287. Tandan R, Lewis GA, Krusinski PB, et al. Topical capsaicin in painful diabetic neuropathy. Controlled study with long-term follow-up. Diabetes Care 1992;15(1):8–14. 288. Low PA, Opfer-Gehrking TL, Dyck PJ, et al. Double-blind, placebo-controlled study of the application of capsaicin cream in chronic distal painful polyneuropathy. Pain 1995;62(2):163– 168. 289. Bernstein JE, Korman NJ, Bickers DR, et al. Topical capsaicin treatment of chronic postherpetic neuralgia. J Am Acad Dermatol 1989;21(2 pt 1):265–270. 290. Watson CP, Tyler KL, Bickers DR, et al. A randomized vehicle-controlled trial of topical capsaicin in the treatment of postherpetic neuralgia. Clin Ther 1993;15(3):510–526. 291. Watson CP, Evans RJ. The postmastectomy pain syndrome and topical capsaicin: a randomized trial. Pain 1992;51(3):375–379. 292. Ellison N, Loprinzi CL, Kugler J, et al. Phase III placebo-controlled trial of capsaicin cream in the management of surgical neuropathic pain in cancer patients. J Clin Oncol 1997;15(8):2974–2980. 293. Paice JA, Ferrans CE, Lashley FR, et al. Topical capsaicin in the management of HIVassociated peripheral neuropathy. J Pain Symptom Manage 2000;19(1):45–52. 294. Simpson DM, Brown S, Tobias J. Controlled trial of high-concentration capsaicin patch for treatment of painful HIV neuropathy. Neurology 2008;70(24):2305–2313. 295. Backonja M, Wallace MS, Blonsky ER, et al. NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia: a randomised, double-blind study. Lancet Neurol 2008;7(12):1106–1112. 296. Backonja MM, Malan TP, Vanhove GF, et al. NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia: a randomized, double-blind, controlled study with an open-label extension. Pain Med 2010;11(4):600–608. 297. Webster LR, Malan TP, Tuchman MM, et al. A multicenter, randomized, double-blind, controlled dose finding study of NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia. J Pain 2010;11(10):972–982. 298. Webster LR, Tark M, Rauck R, et al. Effect of duration of postherpetic neuralgia on efficacy

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analyses in a multicenter, randomized, controlled study of NGX-4010, an 8% capsaicin patch evaluated for the treatment of postherpetic neuralgia. BMC Neurol 2010;10:92. Irving GA, Backonja MM, Dunteman E, et al. A multicenter, randomized, double-blind, controlled study of NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia. Pain Med 2011;12(1):99–109. Clifford DB, Simpson DM, Brown S, et al. A randomized, double-blind, controlled study of NGX-4010, a capsaicin 8% dermal patch, for the treatment of painful HIV-associated distal sensory polyneuropathy. J Acquir Immune Defic Syndr 2012;59(2):126–133. Rowbotham MC, Davies PS, Verkempinck C, et al. Lidocaine patch: double-blind controlled study of a new treatment method for post-herpetic neuralgia. Pain 1996;65(1):39–44. Galer BS, Jensen MP, Ma T, et al. The lidocaine patch 5% effectively treats all neuropathic pain qualities: results of a randomized, double-blind, vehicle-controlled, 3-week efficacy study with use of the neuropathic pain scale. Clin J Pain 2002;18(5):297–301. Estanislao L, Carter K, McArthur J, et al. A randomized controlled trial of 5% lidocaine gel for HIV-associated distal symmetric polyneuropathy. J Acquir Immune Defic Syndr 2004;37(5):1584–1586. Karst M, Salim K, Burstein S, et al. Analgesic effect of the synthetic cannabinoid CT-3 on chronic neuropathic pain: a randomized controlled trial. JAMA 2003;290(13):1757–1762. Wade DT, Robson P, House H, et al. A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms. Clin Rehabil 2003;17(1):21–29. Zajicek J, Fox P, Sanders H, et al. Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebocontrolled trial. Lancet 2003;362(9395):1517–1526. Wade DT, Makela P, Robson P, et al. Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebocontrolled study on 160 patients. Mult Scler 2004;10(4):434–441. Abrams DI, Jay CA, Shade SB, et al. Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial. Neurology 2007;68(7):515–521. Berman JS, Symonds C, Birch R. Efficacy of two cannabis based medicinal extracts for relief of central neuropathic pain from brachial plexus avulsion: results of a randomised controlled trial. Pain 2004;112(3):299–306. Rog DJ, Nurmikko TJ, Friede T, et al. Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis. Neurology 2005;65(6):812–819. Wissel J, Haydn T, Muller J, et al. Low dose treatment with the synthetic cannabinoid Nabilone significantly reduces spasticity-related pain: a double-blind placebo-controlled cross-over trial. J Neurol 2006;253(10):1337–1341. Nurmikko TJ, Serpell MG, Hoggart B, et al. Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, double-blind, placebo-controlled clinical trial. Pain 2007;133(1–3):210–220. Wilsey B, Marcotte T, Tsodikov A, et al. A randomized, placebo-controlled, crossover trial of cannabis cigarettes in neuropathic pain. J Pain 2008;9(6):506–521. Narang S, Gibson D, Wasan AD, et al. Efficacy of dronabinol as an adjuvant treatment for chronic pain patients on opioid therapy. J Pain 2008;9(3):254–264. Skrabek RQ, Galimova L, Ethans K, et al. Nabilone for the treatment of pain in fibromyalgia. J Pain 2008;9(2):164–173. Ellis RJ, Toperoff W, Vaida F, et al. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacology 2009;34(3):672–680. Ware MA, Wang T, Shapiro S, et al. Smoked cannabis for chronic neuropathic pain: a

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CHAPTER 82 Local Anesthetics MICHAEL M. BOTTROS, LARA WILEY CROCK, and SIMON HAROUTOUNIAN

Physicochemical Properties of Local Anesthetics “Cocaine and its salts have a marked anesthetizing effect when brought in contact with the skin and mucous membrane in concentrated solution; this property suggests its occasional use as a local anesthetic, especially in connection with afflictions of the mucous membrane.” Cocaine and its potential clinical use as a local anesthetic were described by Sigmund Freud in his 1884 paper “Uber Coca.” Almost as an afterthought, he describes cocaine’s potential use as a local anesthetic in the very last paragraph1: “Indeed, the anesthetizing properties of cocaine should make it suitable for a good many further applications.” A friend of Freud, Carl Koller, utilized this property of cocaine for ophthalmologic procedures. Thus, Koller is credited with demonstrating the first local anesthetic in modern clinical practice.1 Although still somewhat controversial as to when cocaine was first used as a spinal anesthetic, Corning2 described what he believed was an extradural block using cocaine in 1885, and Bier3 described a spinal anesthetic effect with cocaine in 1898. Clinically useful due to its properties as both a local anesthetic and vasoconstrictor, cocaine has undesirable side effects that limit its routine use.4 Other local anesthetics were developed based on the chemical structure of cocaine, and the clinical application of local anesthetics became widespread in modern medicine. The use of local anesthetics has continued to increase in clinical practice, as there is increased interest in the use of regional techniques for surgery as well as in the treatment of chronic pain.

MOLECULAR STRUCTURE The chemical structure of cocaine was determined by Richard Willståtter 4260

in 1898, allowing for the development of the synthetic analogs of cocaine.5 All currently available local anesthetics have an amine group (usually a tertiary amine) and an aromatic ring. With the exception of benzocaine, these two groups are separated by an intermediate ester or amide linkage (Fig. 82.1). They are classified by their chemical bond as either amino esters (e.g., include cocaine, procaine, chloroprocaine, tetracaine) or amino amides (e.g., lidocaine, prilocaine, bupivacaine, mepivacaine). Esters and amides have distinct properties as a result of their molecular structure. The amino amide bond is more resistant to enzymatic cleavage; therefore, amide local anesthetics are more stable when compared to ester local anesthetics. Amides and esters are metabolized in distinct ways—amides by the liver microsomes and esters by plasma esterases. Chirality, acid– base balance, lipid solubility, and protein binding can all affect the activity of local anesthetics.

FIGURE 82.1 Local anesthetic structure. Similarities and differences between ester and amide local anesthetics.

CHIRALITY Stereoisomers have identical sets of atoms that are configured in the same positions with different spatial arrangements. Furthermore, enantiomers are pairs of stereoisomers that appear as nonsuperimposable mirror images, commonly referred to as chiral. More than one-third of synthetic drugs are structurally defined as chiral.6 Commonly used local anesthetics 4261

with the exception of lidocaine are chiral. The body responds to chiral molecules differently because stereoisomers may have different receptor binding properties. An example of a chiral local anesthetic is bupivacaine, a potent and long-acting local anesthetic with the unfortunate potential for cardiovascular and central nervous system (CNS) toxicity. Bupivacaine is manufactured as a racemic mixture of 50% R-bupivacaine and 50% Sbupivacaine. S- and R-enantiomers have been shown to have unique pharmacodynamic properties (e.g., potency and potential for systemic toxicity). R-enantiomers, like R-bupivacaine, have greater potency for blockade of both neuronal and cardiac sodium (Na+) channels. Rbupivacaine is 1.5 times more potent when compared to S-bupivacaine (also known as levobupivacaine) when the Na+ channel is in an inactive state.6 Because of the potential systemic toxicity and higher potency, Renantiomers are more powerful local anesthetics with a narrower therapeutic index. S-enantiomers on the other hand, have a lower binding potential for cardiac Na+ channels and may be safer.7 Ropivacaine (a pure S-enantiomer propyl homolog of S-bupivacaine) was developed in response to the need for a long-acting amino amide local anesthetic such as bupivacaine, with a greater margin of safety.8 It has been shown in both animal and human studies to have similar clinical efficacy compared to bupivacaine but with 30% to 40% less cardiotoxicity.9–12

ACID–BASE BALANCE The pH and acid dissociation constant (pKa) of local anesthetics have a large effect on their onset of action. The pKa of a specific drug is the pH at which the lipid-soluble neutral form and the charged hydrophilic form are in equilibrium. Most local anesthetics have a pKa value close to but higher than physiologic pH, making them weak bases. At physiologic pH, local anesthetics exist in a positively charged conjugated acid and an unprotonated neutral form. When unprotonated, the local anesthetic can more easily cross into the cell through the lipid bilayer to reach its receptor binding site. At physiologic pH of 7.4, a drug with a lower pKa will more readily cross the cell lipid membrane (higher percentage will be in the uncharged, lipophilic form). Thus, the pKa of a local anesthetic generally 4262

correlates with its onset. The pH inside the cell is lower, which shifts the equilibrium toward a higher ratio of positively charged local anesthetic molecules. It is the charged form that binds to the pore of the voltage-gated Na+ channel, causing the anesthetic effects. Tissue that has been damaged or is infected often produces an acidic extracellular microenvironment, thus increasing the percentage of charged local anesthetic outside the cells. The positively charged local anesthetic cannot easily cross the lipid bilayer and reach the intracellular binding site. For this reason, local anesthetics are not as effective in providing adequate analgesia to infected or damaged tissue. Just as an acidic extracellular environment can prevent adequate analgesia from reaching the intended target, an acidic intracellular environment can prolong the effect of a local anesthetic. For example, the administration of an accidental overdose of local anesthetic can result in CNS toxicity. At lower toxic doses, central inhibitory neuronal pathways are blocked. This neuronal disinhibition can result in a tonic-clonic seizure, leading to a lactic acidosis in the CNS. As the CNS becomes more acidic, the local anesthetic is essentially trapped inside the cell due to its ionization, exacerbating its CNS toxicity.

LIPOPHILIC–HYDROPHILIC BALANCE The lipid solubility, or lipophilic nature of a local anesthetic, influences its ability to pass through a lipid bilayer and thus its potency and duration of action. More lipophilic local anesthetics can not only permeate neurons more readily but also result in sequestration of the local anesthetic in lipidsoluble perineural compartments such as the myelin sheath where they are sequestered. The accumulation of local anesthetics in lipid-soluble neuronal components creates a depot of local anesthetics, resulting in a slow release from these lipophilic compartments. Consequently, although the lipophilic local anesthetics may cross membranes more readily, these drugs often have a lower onset of action and prolonged duration of action.13,14 Increased lipophilicity often translates to greater potency due to drug ability to cross lipid membranes and a greater affinity to bind Na+ channels.14,15

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Local Anesthetic Pharmacology PHARMACODYNAMICS Hodgkin and Huxley used a giant squid axon to determine that electrical signals in the nerves are initiated by voltage-dependent activation of inward sodium currents.16,17 In 1970, Fraizer used squid giant axons and quaternary compounds to demonstrate that local anesthetics need to penetrate into the cell to inhibit depolarization and action potentials.18 It was later discovered that local anesthetics work by binding to and blocking voltage-gated sodium channels (Fig. 82.2). Voltage-gated sodium channels exist in three conformational states: open, closed, and inactivated. Without a stimulus, the channel is in its closed state. In response to a change in membrane potential, the voltage-gated sodium channel will open. After a few milliseconds, an intracellular loop (P) (see Fig. 82.2) will fold inward and occlude the channel pore. This renders the sodium channel inactive, and the channel will temporarily not respond to further changes in membrane potential. Local anesthetics can gain access and bind to the intracellular binding site preferably when the channel is in an open state.19

FIGURE 82.2 Diagram of a voltage-gated sodium channel structure and the site of action of local anesthetics. Local anesthetics exist in an equilibrium as a neutral base (LA) and as a charged form (LAH+). The uncharged form (LA) more easily passes through the lipid bilayer to the interior of the cell. Inside the cell, it can be protonated again (LAH+), thus allowing it to bind to, and inhibit (close), the voltage-gated sodium channel. (Adapted from Drasner K. Local anesthetics. In: Katzung B, Masters SB, Trevor AJ, eds. Basic & Clinical Pharmacology. 12th ed. New York: McGraw-Hill;

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Local anesthetics work by preventing action potential propagation in axons through their inhibitory action on sodium channels.20 These voltagegated sodium channels contain a main α-subunit, where the local anesthetics bind and one or more β-subunits.16,19 Local anesthetics reversibly bind to the α-subunit from inside the cell and inactivate voltagegated sodium channels, thus preventing channel activation and inhibiting sodium influx, preventing depolarization of the nerve cell membrane (Fig. 82.2). When a local anesthetic binds to the open state of a sodium channel, it stabilizes the inactive state of the channel and prevents further activation. Local anesthetics increase the threshold for electrical excitation in nerves, slow propagation of the impulse, reduce the rate of rise of the action potential, and eventually block conduction.21

PHARMACOKINETICS The pharmacokinetic properties of local anesthetics (i.e., absorption, distribution, metabolism/biotransformation, and excretion), patient factors (i.e., age, overall health, and the functional state of eliminating organs), and clinical circumstances must be combined in order to predict the pharmacokinetic profile of a local anesthetic in a particular patient.

Absorption The plasma concentration following systemic absorption of a local anesthetic is highly dependent on the site of administration, the dose, and the physicochemical properties of the drug. The more vascular an injection site, the higher the systemic absorption of the local anesthetic. The highest systemic absorption occurs with intravenous administration. The systemic absorption of local anesthetics after regional anesthesia occurs at decreasing rate after tracheal, intercostal, caudal, paracervical, thoracic/lumbar epidural, brachial plexus, and sciatic nerve blocks and is the lowest with subcutaneous infiltration (Fig. 82.3).22,23 For example, similar plasma concentrations of lidocaine are achieved after 300 mg delivered as an intercostal nerve block, 500 mg via an epidural block, and 1,000 mg subcutaneously.24 All local anesthetics produce some level of vasoactivity, with most producing vasodilatation. However, the 4265

vasoactivity of local anesthetics is dependent on the drug, the dose, as well as the organ targeted.24 Vasodilatation increases absorption of the local anesthetic into the systemic circulation. Enhanced absorption reduces the local anesthetic duration and increases the concentration of the drug in the blood. Cocaine is the only local anesthetic that consistently produces vasoconstriction (following initial vasodilatation). The addition of epinephrine to some local anesthetic nerve blocks can reduce absorption by causing vasoconstriction, thus prolonging the nerve block. The extent of this prolongation appears to vary with the site of the nerve block and the vasoconstrictor agent used. For example, 5 µg/mL of epinephrine, added to lidocaine, reduced the peak plasma concentration of subcutaneously infiltrated lidocaine by 50% but only by 20% to 30% when added to intercostal, epidural, and brachial plexus lidocaine blocks.24 See “Vasoconstrictor Effect” section for further information.

FIGURE 82.3 Degree of systemic absorption based on local anesthetic injection site. The highest systemic absorption occurs with intravenous administration, decreasing after tracheal, intercostal, caudal, paracervical, thoracic/lumbar epidural, brachial plexus, and sciatic nerve blocks and is the lowest with subcutaneous infiltration. (Based on Drasner K. Local anesthetics. In: Katzung B, Masters SB, Trevor AJ, eds. Basic & Clinical Pharmacology. 12th ed. New York: McGraw-Hill;

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2012:452–453.)

Distribution Once local anesthetics are absorbed in the blood, they readily cross into all tissues. Organs and tissues and organs with high levels of perfusion (such as the heart and brain) will have higher levels of local anesthetics. Local anesthetics (in their unionized form) are lipophilic and therefore readily cross the blood brain barrier. Depression of the CNS by local anesthetics causes initial sedation. Local anesthetics raise the seizure threshold by decreasing the excitability of cortical neurons in epileptic patients. However, at toxic plasma (and brain) levels, local anesthetics cause seizures.25

Biotransformation and Excretion The primary site of amino amide local anesthetic metabolism is in the liver through hepatic carboxylesterases and cytochrome P450 enzyme. An exception is prilocaine, which is metabolized in both the liver and lungs. Ester local anesthetics, with the exception of cocaine, are hydrolyzed by plasma cholinesterases and tissue esterases.25,26 The metabolites of both amino ester and amino amide local anesthetics are primarily excreted by the kidneys. Urine concentrations of ester local anesthetics are small due to their metabolism in plasma. Only 2% of procaine is found in urine, whereas 90% is found as its para-aminobenzoate metabolite, paraaminobenzoic acid (PABA).27 The rates of hydrolysis of local anesthetics inversely determine their degree of toxicity. A slowly hydrolyzed ester local anesthetic such as tetracaine is more toxic than chloroprocaine, which is hydrolyzed much faster.

Effects of Disease States on Local Anesthetic Pharmacokinetics Because amide local anesthetics are metabolized primarily in the liver, hepatic perfusion and liver function can affect the rate of amide local anesthetic metabolism. Reduced hepatic function results in a reduced plasma clearance of and prolongation of the elimination half-life of 4267

intravenous lidocaine. This does not significantly affect the duration of action but predisposes a patient to the toxic effects.28 Renal disease has little effect on the pharmacokinetic parameters such as volume of distribution at steady state and total body clearance of intravenous lidocaine.28 In contrast, patients with cardiac failure had reduced volume of distribution and plasma clearance of intravenous lidocaine.28 Metabolism byproducts of amide local anesthetics can have clinical effects if allowed to accumulate in the blood. Sedation due to high doses of lidocaine is due to the formation of the metabolites glycine xylidide and monoethylglycinexylidide. Despite ester local anesthetics, biotransformation by plasma cholinesterases, and tissue esterase, at normal doses, there appears to be little effect in patients with pseudocholinesterase deficiency.

Regional Administration of Local Anesthetics for Pain Relief DIFFERENTIAL BLOCKADE As sodium channels are expresses in both sensory and motor nerve fibers, the regional administration of local anesthetics can result in blocking conduction along both types of fibers. Therefore, along the desired analgesic effect on sensory fibers, other, less desired effects are often observed. Differential blockade is the gradual and sequential inactivation of differing nerve fiber types when exposed to local anesthetics. A number of factors contribute to this phenomenon: 1. Local anesthetic concentration: Higher concentrations can produce both motor and sensory block, whereas low concentrations produce only sensory block. 2. Nerve fiber size: Small diameter axons are more susceptible to block than large diameter fibers. Sensory nerve fibers are classified as A, B, and C. Type A fibers include afferent fibers responsible for proprioception (Aα), thermal sensation (Aδ), and mechanosensation (Aβ). Type B fibers are mainly visceral sensory fibers and preganglionic autonomic fibers. Type C fibers are postganglionic autonomic efferents as well as sensory afferents responsible for the 4268

transmission of pain and heat signals. Type A fibers are thickest, and type C fibers are thinnest. 3. Degree of nerve fiber myelination: Because local anesthetics exert their effect at the node of Ranvier, myelinated fibers are more sensitive to local anesthetic effects than nonmyelinated ones. 4. Circumferential location of fibers: In nerve bundles, fibers that are located circumferentially are affected first by local anesthetics. In large nerve trunks, motor nerves are usually located circumferentially and may be affected before the sensory fibers. In the extremities, proximal sensory fibers are located more circumferentially than distal sensory fibers. Thus, loss of sensation may spread from the proximal to distal part of the limb. Gokin et al.29 studied the preferential block of sensory and motor fibers using lidocaine in a rat sciatic nerve model. They found that the order of fiber susceptibility, ranked by concentrations that gave peak tonic fiber blockade of 50% (IC50s), was Aγ > Aδ = Aα > Aαβ > C. Faster conducting C fibers (conduction velocity >1 m/s) were more susceptible than slower ones. Therefore, this does not strictly follow the “size principle” that smaller axons are always blocked first.

SITE OF INJECTION Local anesthetics are used in a wide variety of anatomical sites. These can generally be grouped into five categories: neuraxial anesthesia, peripheral nerve blockade, intravenous regional anesthesia, infiltration anesthesia, and topical anesthesia.

Neuraxial Anesthesia Neuraxial anesthesia was first reported for clinical use in the late 19th century by Augustus Karl Gustav Bier, who used intrathecal cocaine on six patients undergoing lower extremity surgery.30 Since then, neuraxial anesthesia has progressed considerably and has become widely used for surgical anesthesia and pain management in a number of different clinical situations. The term neuraxial anesthesia may be further categorized into spinal, epidural, caudal, or combined spinal-epidural (CSE) anesthesia. Spinal anesthesia involves the administration of local anesthetics into 4269

the intrathecal (or subarachnoid) space. As the conus medullaris typically terminates near lumbar nerves L1 or L2, this technique is performed below the L2 level to avoid damage to the spinal cord. As such, this technique may be indicated when the surgical site involves the lower extremities, perineum, or lower trunk. Examples include total hip/knee arthroplasty or cesarean section surgeries. Epidural anesthesia is categorized by the deposition of local anesthetics via catheter or needle placed into the epidural space, located between the ligamentum flavum and the dura mater (Fig. 82.4). Key differences between epidural and spinal anesthesia include location of drug deposition (epidural vs. intrathecal), onset of action (spinal is generally quicker than epidural), and local anesthetic dose (because of uptake into extraneural fat, blood, and lymphatics, epidural doses are higher than spinal). Epidural catheter analgesia (using low-dose local anesthetics, sometimes with the addition of an opioid) is typically used for truncal or lower extremity postoperative pain relief, such as postthoracotomy or abdominal resection cases.

FIGURE 82.4 Epidural anesthesia. A catheter exits the epidural needle in the epidural space where local anesthetics may be deposited. (From BruceBlaus/Wikimedia Commons/CC-BY-SA4.0.)

Caudal epidural anesthesia involves the insertion of a needle through the sacral hiatus in order to gain entrance into the sacral epidural space. 4270

Caudal anesthesia is commonly used as a regional technique in neonates and infants for abdominal and pelvic surgeries as it decreases the amount of general anesthetic and intravenous opioids required intraoperatively.31,32 A CSE technique may be used in clinical scenarios during surgery at or below the umbilicus requiring prolonged and effective analgesia. This typically entails performing an intrathecal block for the surgical procedure itself while an epidural catheter is placed (subsequent to the intrathecal block) and used during surgery when the intrathecal block is deficient or an extended duration of relief is needed for unanticipated longer surgical procedures. Postoperatively, the epidural catheter may be used for pain control.33

Peripheral Nerve Blockade Peripheral nerve blockade is the deposition of local anesthetic near a nerve or group of nerves associated with the control of sensation and/or movement of a specific part of the body. This may be performed in lieu of or in addition to general anesthesia for surgery. This may be performed as a single-shot technique to facilitate intraoperative and immediate postoperative anesthesia and analgesia. Alternatively, for a longer duration of postoperative analgesia, one can insert a catheter near the nerve/nerves and provide continuous analgesia by supplying an infusion of local anesthetic. Peripheral nerve blockade may be achieved via blind technique, but most are currently performed with concomitant use of either nerve stimulation or ultrasound to guide needle placement.

Intravenous Regional Anesthesia Intravenous regional anesthesia (IVRA) was first described in 1908 by Augustus Bier, known for his prior work on spinal anesthetics, and is commonly referred to a Bier block.34 The technique involves exsanguinating the extremity to be anesthetized using passive venous drainage by raising the extremity, followed with active drainage by wrapping an Esmarch bandage around the extremity and subsequently inflating a pneumatic cuff/tourniquet. After this, local anesthetic can be injected through an intravenous catheter placed prior to the initiation of 4271

exsanguination on the ipsilateral extremity. The volume of administration can vary based on the potency of the local anesthetic, although 30 to 50 mL of 0.5% lidocaine without epinephrine is typically used.35 This technique is a useful anesthetic option for short-duration (typically less than 1 hour) upper or lower extremity surgeries, such as carpal tunnel release, Dupuytren contracture release, or neuroma excision.

Infiltration Anesthesia Infiltration anesthesia is the injection of local anesthetics directly into the area of terminal nerve endings. Its uses include subcutaneous infiltration prior to intravenous catheter placement or suturing, submucosal infiltration prior to laceration repairs or dental procedures, or wound infiltration to facilitate analgesia during a procedure. A “field” block refers to the common technique of infiltrative anesthesia in a circular or diamond pattern around the desired site. Pain reduction on injection can be achieved by warming the local anesthetic solution or “buffering” the solution.36 Buffering is performed by adding sodium bicarbonate in a local anestheticto-bicarbonate ratio of 9:1. This is typically performed with lidocaine as other local anesthetics such as bupivacaine have a tendency to precipitate when increasing the solution pH37 and is discussed in further detail in “pH Adjustment of Local Anesthetics” section. There appears to be a synergistic effect in pain reduction when warming is coupled with buffering the solution.38

Topical Anesthesia Topical anesthesia is direct application of local anesthetic solutions, ointments, gels, or sprays causing the superficial loss of sensation on skin, mucous membranes, or conjunctiva.39 These drugs reversibly block nerve conduction at the free nerve endings in the dermis or mucosa, producing anesthesia in a limited area. The main barrier for drug delivery is the stratum corneum. Topical anesthetics cross this layer via the intracellular spaces of cornified keratinocytes, openings of hair follicles and sweat glands, and/or a para- or transcellular route. Clinical applications include local analgesia on intact skin; minimizing discomfort prior to an injection; symptomatic relief of chronic pain; or numbing the outermost layers of the 4272

cornea, conjunctiva, or oral tissues. As local anesthetics are poorly absorbed across intact skin, mixtures of local anesthetic agents (called eutectic mixture of local anesthetics, or EMLA) have been used to increase potency, as well as have lower melting points (so that local anesthetic molecules exist in their oil, rather than crystal structure at room temperature), which can promote easier absorption into tissues.40

POTENCY, ONSET, AND DURATION Local anesthetics must cross the lipid membrane to bind to the intracellular portion of the sodium channel, and their anesthetic potency is related to their lipid solubility. In general, more potent local anesthetics are more lipid-soluble. The onset of action is related to pKa, dose, and concentration of the drug. As the drug pKa nears physiologic pH, there is a higher concentration of the drug as a non-ionized base, shortening the onset of action. The administration of a more concentrated local anesthetic typically shortens the onset of the effect and provides a larger degree of nerve blockade. Degree of protein binding greatly influences duration of action. As local anesthetics target protein receptors, the greater the affinity of the drug to the protein, the longer it will remain bound to its receptor, thereby extending its duration of action (Table 82.1). TABLE 82.1 Local Anesthetic Structure and Duration of Action

Agent

pKa

Techniques

Esters Benzocaine Chloroprocaine

2.5 8.7

Topical Epidural, infiltration, peripheral nerve block, spinal Topical Spinal, local

Cocaine Procaine

8.9

Concentrations Available

Maximum Dose (mg/kg)

Typical Duration of Nerve Blocks

20% 1%, 2%, 3%

NA 12

NA Short

4%, 10% 1%, 2%, 10%

3 12

NA Short

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Tetracaine

8.5

Amides Bupivacaine

8.1

Lidocaine

7.9

Mepivacaine

7.6

Prilocaine

7.9

Ropivacaine

8.1

infiltration Spinal, topical (eye) Epidural, spinal, infiltration, peripheral nerve block Epidural, spinal, infiltration, peripheral nerve block, intravenous regional, topical Epidural, infiltration, peripheral nerve block, spinal EMLA (topical), epidural, intravenous regional (outside North America) Epidural, spinal, infiltration, peripheral nerve block

0.2%, 0.3%, 0.5%, 1%, 2%

3

Long

0.25%, 0.5%, 0.75%

3

Long

0.5%, 1%, 1.5%, 2%, 4%, 5%

4.5 7 (with epinephrine)

Medium

1%, 1.5%, 2%, 3%

4.5 7 (with epinephrine)

Medium

0.5%, 2%, 3%, 4%

8

Medium

0.2%, 0.5%, 0.75%, 1%

3

Long

EMLA, eutectic mixture of local anesthetics; NA, not applicable. Data from Liu SS. Local anesthetics and analgesia. In: Ashburn MA, Rice LJ, eds. The Management of Pain. New York: Churchill Livingstone; 1997:141.

pH ADJUSTMENT OF LOCAL ANESTHETICS The addition of carbon dioxide to a local anesthetic solution accelerates onset of action. There are several reported mechanisms for this: direct effect of CO2 on the nerve, decrease in the pH of the surrounding 4274

environment, and an increase in the base form of the local anesthetic. Commercial local anesthetic solutions are manufactured in acidic pH to maximize their chemical stability and water solubility, thereby increasing their shelf life. Several studies have indicated that adding sodium bicarbonate to local anesthetic solutions enhances onset, increases intensity, and prolongs local anesthetic block duration.41,42 This is termed buffering or alkalinization. This increases the proportion of non-ionized drug allowing a theoretical faster rate of diffusion across the cell membrane. Although these buffered solutions are typically less painful when injected,43 there is controversy regarding the clinical utility of this practice as clinical studies have produced inconsistent results.44 Care must be taken in increasing the pH of bupivacaine and etidocaine, as this may cause precipitation, leading to the injection of particulate along with the solution.45

VASOCONSTRICTOR EFFECT As discussed earlier, the addition of vasoconstrictors to local anesthetic solutions reduces vascular uptake, thereby indirectly increasing the concentration of the drug and increasing the duration of contact with the target nerve. This in turn increases the duration and quality (depth) of anesthetic block. It may also reduce the minimum concentration of anesthetic needed as well as reduce the peak plasma concentration of the drug.46 Epinephrine is the most commonly used vasoconstrictor, and its addition to neuraxial block also activates endogenous analgesic mechanisms via α-adrenergic receptors.47 Caution should be used with respect to injection site and local anesthetics containing epinephrine, as end organs (e.g., fingers, toes, penis, nose) may have such blood flow compromise that eventual tissue necrosis could occur. The addition of epinephrine has been shown to increase axonal degeneration following intrafascicular bupivacaine injection.48 However, there is debate about the role of epinephrine and direct peripheral nerve tissue injury, as this has not been proven and clinical observations suggest that this aspect of toxicity generally plays a minor role.49

MIXTURES OF LOCAL ANESTHETICS 4275

Local anesthetics are sometimes combined with the goal to achieve longer duration and/or quicker onset than with just one local anesthetic alone. However, there appears to be no clear advantage to mixing different anesthetic compounds as clinical trials have shown inconsistent results. Smith50 evaluated the combination of chloroprocaine with bupivacaine for brachial plexus block which yielded the desired faster onset and longer duration of action. However, a 1:1 mixture of 1% lidocaine with 0.25% bupivacaine for foot block showed no significant difference in mean onset times compared with either pure anesthetic alone.51 In the same study, the duration of action was longer with pure bupivacaine, but there was no difference between the pure lidocaine solution and the mixture. Interestingly, nerve blockade characteristics by local anesthetic mixtures appear to be affected by the pH value of the mixture.52 Using rat sciatic nerve preparation, Galindo and Witcher52 found that a 1:1 mixture of chloroprocaine 2% and bupivacaine 0.5% resulted in a nerve block with characteristics of a chloroprocaine block. However, changing the pH value of this mixture from 3.60 to 5.56 changed the characteristics to a block resembling bupivacaine.

SPECIAL STATES: PREGNANCY Local anesthetics have enhanced potency in spinal and epidural anesthesia during pregnancy.53,54 In addition, the onset of blockade tends to be faster for spinal, epidural, and peripheral nerve blocks. The true mechanism is unknown but is likely due to anatomical changes from pregnancy as well as the effect of progesterone on the sensitivity of the nerve fibers themselves.55,56 As progesterone levels increase, there is an inverse correlation between the amount of local anesthetic needed and the clinical effect. For example, the dose of local anesthetic should be reduced by 30% regardless of the trimester of pregnancy. A biochemical explanation has been proposed involving pregnancy-induced hyperventilation with a resulting metabolic alkalosis causing local anesthetics to remain in ionized form for a longer time, therefore remaining longer in the area of injection and increasing the time to complete analgesia.55 In addition, anatomical changes may facilitate spread due to epidural venous distension secondary to increased blood volume during pregnancy, resulting in a decrease of 4276

epidural and/or intrathecal volume.57 At term, increased intra-abdominal pressure, compression of the inferior vena cava and pelvic veins by a space-occupying effect, and increased epidural pressures have all been implicated in facilitated spread of local anesthetics in the epidural space.

Systemic Administration of Local Anesthetics for Pain Relief So far, this chapter has discussed the primary mechanism of action of local anesthetics, that is, their action at neuronal voltage-gated sodium channels by local or topical application, infiltration, or regional anesthesia. Considerably less is known about the exact analgesic mechanism of action of local anesthetics such as lidocaine, when administered systemically. Lidocaine is an U.S. Food and Drug Administration (FDA)-approved Class Ib antiarrhythmic, the intravenous administration of which has been used since the 1950s for the acute management of ventricular arrhythmias.58 Lidocaine exerts an antiarrhythmic effect by increasing the electrical stimulation threshold of the ventricle during diastole. However, irrespective of its antiarrhythmic effects, intravenously administered lidocaine can exert analgesic activity. This section summarizes the potential use of intravenous lidocaine in the acute and chronic pain settings and discusses the proposed analgesic mechanisms of action.

INTRAVENOUS LIDOCAINE FOR ACUTE POSTOPERATIVE PAIN Intravenous infusion of lidocaine has been tested as a part of multimodal postoperative analgesic approach in several studies. A recent Cochrane systematic review and meta-analysis has identified 45 randomized controlled trials that have used lidocaine in the perioperative setting,59 mostly in abdominal surgeries. At early (1 to 4 hours after surgery), and intermediate (24 hours after surgery) time points, lidocaine treatment provided better pain relief and resulted in reduced time to first bowel movement, perhaps related to the reduction in postoperative opioid requirements. In general, the effects on early outcomes 4 hours after surgery (~50% of studies positive) were more substantial than at the 244277

hour postoperative time point (~20% of studies positive). About 48 hours after surgery, the outcomes of intravenous lidocaine and placebo were generally not different. For example, patients undergoing laparoscopic bariatric surgeries were randomized to intraoperative lidocaine (1.5 mg/kg bolus followed by a 2 mg/kg/hour infusion until the end of the surgical procedure) or corresponding placebo. The intervention resulted in less postoperative pain and nausea and reduced opioid consumption.60 In patients undergoing complex spine surgery, intravenous lidocaine (2 mg/kg/hour, maximum 200 mg per hour, starting at induction of anesthesia and continuing until discharge from the postanesthesia care unit) not only resulted in lower pain scores but also improved quality of life parameters.61 Other studies, for example, administering intravenous lidocaine in laparoscopic renal surgery,62 did not demonstrate any difference in lidocaine versus placebo on outcomes such as length of stay, readiness for discharge, opioid consumption, nausea, or return of bowel function. The study used a 1.5 mg/kg bolus dose at anesthesia induction, followed by 2 mg/kg/hour intraoperative infusion, and a 1.3 mg/kg/hour 24-hour infusion.

INTRAVENOUS LIDOCAINE FOR CHRONIC NEUROPATHIC PAIN Several studies have been published supporting the effectiveness of intravenous lidocaine for the treatment of neuropathic pain. A systematic review and meta-analysis concluded that overall lidocaine was not only more effective than placebo in alleviating neuropathic pain but also resulted in more adverse effects.63 The adverse effects seen with intravenous lidocaine usually include dizziness, perioral numbness, drowsiness, blurred vision, and more rarely cardiac rhythm abnormalities and are generally dependent on lidocaine plasma concentration. Various dosing regimens have been implemented, most of them in the range of 2 to 5 mg/kg, infused over 30 to 60 minutes. The duration of the analgesic effects is uncertain, with some studies assessing pain relief anywhere between 35 minutes and 6 hours,64–66 whereas other studies reporting pain reduction in individual patients for up to 1 to 2 weeks.67,68 However, it is unclear which patients are more likely 4278

to have long-term effects with this approach, as daily or weekly treatments with intravenous infusions are not a particularly feasible approach for treating chronic pain. Mexiletine, which is an orally bioavailable analog of lidocaine, has also been used for the management of chronic neuropathic pain. In a 2005 meta-analysis, the average reduction in pain intensity was demonstrated to be comparable to that of intravenous lidocaine.63 On the other hand, a recent meta-analysis of high-quality studies found that most (7 of 8) clinical trials with mexiletine in neuropathic pain have been negative, and considering the relatively high incidence of adverse effects, the guidelines currently recommend against the use of mexiletine for managing neuropathic pain.69 The exact analgesic mechanism of action of systemic lidocaine is not completely understood. The primary discussed mechanism is the sodium channel–mediated activity affecting signal transduction and transmission in nociceptors, as discussed previously. However, it is unclear whether the main effect in neuropathic pain is peripheral (at the primary afferent fibers), or more centrally (spinal cord or brain). Data from Devor and colleagues suggest that the activity of lidocaine on silencing signal generation in the dorsal root ganglion (DRG) is the primary mechanism by which the drug alleviates pain in peripheral neuropathies.70,71 This has been demonstrated in a clinical study, where local intraforaminal application of low-concentration lidocaine (0.3%) at the DRG72 resulted in substantial alleviation of pain and phantom sensations in lower limb amputees. In addition to sodium channel–mediated mechanisms, several additional mechanisms of lidocaine have been recently been proposed. Microglial hyperactivation at the spinal cord dorsal horn has been shown to contribute to sensitization of somatosensory neurons and accompany the development of thermal and mechanical hypersensitivity after peripheral nerve injury.73 It was shown both in vitro74 and in vivo75 that lidocaine may prevent microglial activation and injury, a mechanism that can possibly contribute to its systemic analgesic effect. Glycine has been demonstrated as an important neurotransmitter involved in inhibition of sensitization in the spinal cord dorsal horn.76 4279

GluT1 glycine transporter, expressed on glial cells and a subset of sensory neurons, removes glycine from the synaptic cleft, resulting in disinhibition of sensory neurons.77 Lidocaine metabolites have been also shown to inhibit the GlyT1 transporter,78 thus potentially contributing to analgesia by a different mechanism.

Adverse Effects SYSTEMIC TOXICITY Local anesthetic systemic toxicity (LAST) is usually a result of an inadvertent intravascular injection of a local anesthetic solution during a regional anesthesia procedure.79 As stated earlier, the site of injection affects the risk of toxicity as different anatomic locations vary in systemic uptake of each drug. As discussed previously in this chapter, the route of administration of local anesthetics has a direct impact on systemic absorption. Intravenous injection is the highest, whereas subcutaneous is the lowest. However, one must be careful when injecting local anesthetic in multiple places as local anesthetic toxicity is essentially additive.80 Local anesthetic toxicity can manifest as CNS excitation (agitation, confusion, seizure), CNS depression (drowsiness, apnea, coma), or nonspecific CNS signs (metallic taste, circumoral numbness, diplopia, tinnitus, and dizziness).81 In addition to CNS signs, cardiovascular manifestations can include hypertension (that may progress to hypotension), conduction block, bradycardia, ventricular arrhythmias, or asystole. The key approach to managing LAST is to provide airway management, circulatory support, and diminution of systemic effects of the local anesthetic. If seizures occur, they should be rapidly controlled (preferably with benzodiazepines) to prevent injury to the patient and acidosis. It is usually recommended to initiate lipid emulsion (20%) therapy as soon as possible, which reduces the concentration of free local anesthetic in the systemic circulation. Studies have shown that this approach is effective in acting as a “lipid sink” to remove lipophilic local anesthetic molecules from the cardiac tissue into the lipid particles.82,83 Specific dosing guidelines are available via the American Society of Regional 4280

Anesthesia and Pain Management (ASRA).81 A recent study comparing the effectiveness of removing bupivacaine from the systemic circulation by long-chain triglyceride (LCT, e.g., Intralipid) emulsion (Fig. 82.5) versus an emulsion of combined long- and medium-chain triglycerides (LCT/MCT) confirmed that LCT was more effective in clearing bupivacaine from the systemic circulation.84

FIGURE 82.5 Intralipid. A long-chain triglyceride emulsion used to clear local anesthetic from systemic circulation during local anesthetic systemic toxicity (LAST) syndrome.

ALLERGIES Rare individuals are hypersensitive to local anesthetics. The hypersensitivity reactions may appear as allergic dermatitis or as an asthmatic attack.85 Hypersensitivity seems to occur more frequently with ester-type, rather than amide-type, local anesthetics because they are derivatives of PABA, a known allergen. There can also be cross-reactivity, primarily within the same chemical group. For example, a patient hypersensitive to procaine is more likely to develop hypersensitivity to 4281

tetracaine than to ropivacaine. Local anesthetic preparations may contain a preservative such as methylparaben (which has a chemical structure similar to PABA), or local anesthetic–vasoconstrictor combinations may contain sulfites added for preventing vasoconstrictor oxidation. Sometimes, these additional compounds may be the cause of hypersensitivity rather the local anesthetic itself.

METHEMOGLOBINEMIA Local anesthetics such as prilocaine may cause methemoglobinemia. A popular topical local anesthetic—EMLA—contains prilocaine. The metabolism of prilocaine includes derivatives of o-toluidine, which can result in the conversion of hemoglobin (Hb) to methemoglobinemia when seen in doses greater than 10 mg/kg. Typically, methemoglobin (metHb) concentration is lower than 1% of total Hb concentration. When 3% to 15% of Hb consist of metHb, a slight gray or pale discoloration of the skin may occur. As it increases to 15% to 20%, cyanosis occurs; concentrations >20% substantially increase the risk of headache, dyspnea, respiratory depression, unconsciousness, shock, and seizures. The treatment for methemoglobinemia includes hemodynamic support as well as methylene blue administration (1 to 2 mg/kg over 5 minutes) which reduces metHb to Hb.

Prolonged-Duration Local Anesthetics Local anesthetics have been extremely effective in providing regional anesthesia and analgesia. One of the main limitations is their temporary effect, which is typically lost within a few hours. Techniques utilizing continuous infiltration of local anesthetics have been developed and are effectively used primarily for managing acute postoperative pain.86–88 One of the disadvantages of these techniques is the costs associated with catheter placement, maintenance, and the increased risks of infection associated with regional catheter use. To address these limitations, various pharmaceutical formulations of long-acting local anesthetics have been developed. The formulations are primarily based on liposomes, which release the local anesthetic, for

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example, bupivacaine, over a prolonged period of time after injection.89–91 One such formulation of bupivacaine (Exparel) is currently approved by the FDA for local infiltration in the perioperative setting. The advantages of long-acting local anesthetics include primarily prolonged duration of action, reported to be up to 4 days following a single injection.92 Some of the disadvantages include stability issues with liposomal formulations93 and high costs associated with liposome manufacturing.94 The outcome results have been mixed, and a recent Cochrane review cites lack of evidence to support or refute the use of liposomal bupivacaine in peripheral nerve blocks for the management of postoperative pain.95 Furthermore, a Cochrane review evaluating surgical site infiltration of liposomal bupivacaine demonstrated superiority over placebo but not to bupivacaine hydrochloride in a comparison of postoperative pain scores.96 However, more work is currently being done to compare single-shot liposomal bupivacaine to continuous catheters.97 Recently, novel approaches of simplifying the production process by developing proliposomal formulations have been introduced,98,99 and they appear to provide a similar long-acting anesthetic and analgesic effect. Future developments will hopefully enable the goal of prolonged analgesic effect with single-dose, low-cost local anesthetic solutions. References 1. Markel H. Uber coca: Sigmund Freud, Carl Koller, and cocaine. JAMA 2011;305(13):1360– 1361. 2. Corning JL. Spinal anaesthesia and local medication of the cord. N Y Med J 1885;42:483– 485. 3. Bier A. Experiments in cocainization of the spinal cord. Dtsch Z Chir 1899;51:363–369. 4. Catterall WA, Mackie K. Local anesthetics. In: Brunton LL, Chabner BA, Knollmann BD, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. New York: McGraw-Hill; 2011:565–582. 5. Calatayud J, González A. History of the development and evolution of local anesthesia since the coca leaf. Anesthesiology 2003;98(6):1503–1508. 6. Nau C, Strichartz GR. Drug chirality in anesthesia. Anesthesiology 2002;97(2):497–502. 7. Casati A, Putzu M. Bupivacaine, levobupivacaine and ropivacaine: are they clinically different? Best Pract Res Clin Anaesthesiol 2005;19(2):247–268. 8. Simpson D, Curran MP, Oldfield V, et al. Ropivacaine: a review of its use in regional anaesthesia and acute pain management. Drugs 2005;65(18):2675–2717. 9. Dony P, Dewinde V, Vanderick B, et al. The comparative toxicity of ropivacaine and bupivacaine at equipotent doses in rats. Anesth Analg 2000;91(6):1489–1492. 10. Knudsen K, Beckman Suurküla M, Blomberg S, et al. Central nervous and cardiovascular

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11.

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26.

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PSYCHOLOGICAL TECHNIQUES CHAPTER 83 Anger and Pain R. JOSHUA WOOTTON

Cultural Background Aristotle,1 referencing Homer’s Iliad, suggested that “anger may be defined as an impulse, accompanied by pain, to a conspicuous revenge for a conspicuous slight,” emphasizing that “the angry man feels pain.” There was no suggestion of the separation of emotional distress from its physical consequences. Unlike many of his contemporaries, Aristotle undertook a reasoned approach to the understanding of anger but nevertheless placed it clearly in the context of emotional and physical pain. In his essay On Anger, Seneca2 urged his elder brother Novatus to eschew anger and agreed that he was “right to have a particular dread of this most hideous and frenzied of all emotions,” even likening the emotional experience to “a brief insanity.” It was a common thematic thread to philosophers and physicians in ancient Greece and Rome that anger tended to reveal itself as a form of madness and that attempts to control it reflected strength of character and spirit.3 Attempts to control anger in antiquity, however, were usually concerned with altering its often dramatic appearance, not with regulating its impact on the body. The possible harmful effects of managing the expression of anger were paid little consideration. Scripture, too, characterizes anger as being at the heart of sin or separation from God and admonishes against the dangers of its excesses. In Hebrew, Christian, and Islamic religious writings, God is often portrayed as angry toward those who oppose his will,2 but the faithful are taught to suppress their angry impulses “for the anger of man does not work the righteousness of God” (James 1:20). The Qur’an teaches that “Allah loves those who restrain anger” (‘Al-‘Imran 3:134), whereas the 4289

Psalms caution us to “be angry, but sin not” (Psalms 4:4). In other passages, we are encouraged not only to avoid expressions of anger but also to resist even the emotion itself. In the Gospel of Matthew, we find that “everyone who is angry with his brother shall be liable to judgment” (Matthew 5:22), whereas elsewhere in the Psalms, we are exhorted to “refrain from anger; and forsake wrath!” (Psalms 37:8), and in the Sunnah of Islam, the Prophet advises, again and again, “Do not become angry and furious” (Hadith-Sahih Al-Bukhari 8.137). This deeply ingrained cultural awareness—that not only are angry actions dangerous, but the emotion of anger itself can be harmful—led to the inclusion of anger as one of the “seven deadly sins” in the religious West,4 a theme popularized and later woven into the fabric of Western cultures through literature, drama, and art, including in European cultures the enduring and influential classics of Dante’s Divine Comedy and Chaucer’s Canterbury Tales.

Psychoanalytic Background One important difference between historical and more contemporary discussions of anger is that the former, although often concerned with the negative consequences of expressing anger, were seldom concerned with the possible harmful effects of its inhibition.3 Anger in psychoanalytic theory does not carry the metaphysical weight of sin, but its expression through hostility and aggressive impulses often lies at the core of conflict, competing drives, and the formation of pathologic symptoms, including pain. Although Freud was an atheist, his frequent excursions into the fields of religion, religious experience, and anthropology are testimony to his respect for the conscious and unconscious impact of culture on the individual; he was the first to emphasize the idea that the individual and culture are linked dynamically and that disturbances may occur in the developmental interaction between the two, leaving behind a disposition to future neuroses.5 He was also an astute observer of the phenomenon of pain from organic origins being maintained for intrapsychic reasons, long past the point of expectable physical healing and recovery.6,7 Early in his work, Freud arrived at the idea that pain is a common 4290

symptom of conversion and that, although there is usually an organic basis for the onset of pain, it can later be influenced and extended in duration and scope by a process through which mental conflict is displaced onto the body, resulting in the somatic expression of symptoms. Conversion, in this context, is closer to the contemporary term somatization, referring both to conversion and psychophysiologic disorders. The repression of negative affects, such as anger, resentment, and guilt, is transmuted into the expression of physical symptoms. The defensive process of somatization continues until relief from the intrapsychic burden of intolerable affect is no longer necessary or desomatization takes place through support—often psychotherapeutic—of the individual’s more mature defenses and coping strategies. Freud’s later work was focused more on patients whose pain was less directly associated with an original organic insult and more configured with mood disturbance. In “Mourning and Melancholia,” he delineated the intrapsychic origins of depression as a process through which aggression, originally directed toward the lost object, is turned against the self8— somewhat oversimplified in the popular formula “anger turned inward.” According to this template, pain and mourning may be seen as affective responses to separation and as unconscious defenses against aggression.8–10 Freud’s successors related pain to aggression and hostility more directly, and the idea that the symptom of physical pain can be an unconscious defense against anger and aggression became a widely shared interpretation in psychoanalytic theory; however, as Merskey7 points out, the evidence has been largely anecdotal, with the relationship between anger and pain often being made more plausible by retrospective analysis. Like Freud, Engel11 acknowledged that pain may originate with actual physical injury, but his study of the “pain-prone patient” gave the most enduring and widely influential psychoanalytic expression of chronic pain as a symbolic displacement of anger and aggression. He also suggested that patients are frequently unwilling or unable to acknowledge the hostility and aggressive impulses behind their pain, leaving them with the difficult task of attempting to adjust to symptoms that are borne of conflicts that they can neither recognize nor accept. The presence of chronic pain, then, may reflect underlying conflicts—in turn, giving rise to 4291

intolerable affects, which, when repressed, are given dynamic expression through the body. Szasz,12 as well, held that repression of emotional distress is often the principal mechanism underlying chronic pain and suggested that, by focusing their attention on their pain, many patients are coping with their distress symbolically and through a more socially acceptable expression of their conflicts. Burns13,14 summarizes the evidence supporting this view that repression of affect is the mechanism at the heart of chronic pain. First, he cites the phenomenon of the “conversion-V” profile on the Minnesota Multiphasic Personality Inventory (MMPI and MMPI-2), depicted by clinical elevations on scales 1 and 3, Hypochondriasis and Hysteria, with a comparatively lower score on scale 2, Depression. The resulting V configuration suggests the presence of somatic preoccupation and a hysterical constellation of defenses, deployed in the service of relieving depressed affect. Second, he further reports evidence of the link between the tendency to suppress anger and aggression and the symptomatic expression of chronic pain and disability. Finally, he points to the persistent observation that inhibition of emotion, particularly emotions arising in the context of traumatic events, has physiologic consequences. Where the first of these three lines of evidence is concerned, the conversion-V configuration of scores on the MMPI and MMPI-2 has been studied extensively, and applied to chronic pain, for more than 40 years.15,16 The first scale of this “neurotic triad” of scores is Hypochondriasis. High scores on Hypochondriasis tend to reflect patterns of neurotic concern over physical health.17,18 The third scale, Hysteria, was developed specifically as an aid to measuring the predisposition to develop symptoms of conversion or somatization and reflects a high degree of reliance on hysterical defenses.17,18 When these two scales are clinically elevated and the second scale, Depression, which reflects both mood and neurovegetative aspects of depression, is comparatively lower, the indication of the resulting V configuration is that intolerable affect is being displaced onto somatic concerns, principally through the mechanism of repression.14–20 Much of this research occurred prior to 2008 and the publication of the revised and restructured form of the MMPI-2. In the MMPI-2-Restructured Form (MMPI-2-RF), the traditional clinical scales 4292

are no longer available and have been replaced with restructured scales in an effort to address the shortcomings of the original instrument.21–25 However, the restructured scales function quite similarly to the original scales in their ability to identify somatization and malingering, albeit without the traditional conversion-V format.26 Where the second line of evidence is concerned, Burns’s14 observations of trends in the scientific literature suggesting the link between chronic pain and the inhibition of anger have been replicated and amplified by numerous subsequent studies, although not always with psychoanalytic theory in the foreground.27–37 The suggestion is that patients with chronic pain are more likely to experience anger than those without pain and more likely also to inhibit their anger.31–34,36 Burns’s13 third source of evidence concerns the physiologic response, both conscious and unconscious, to efforts at inhibition. Suppression reflects the more obvious example of physiologic cost; however, repression also has a dynamic element that must be balanced in the psychosomatic economy of mind and body interrelationship.27–29,31–34,36 Within the framework of psychoanalytic theory, the physiologic exertion demanded by inhibition was often seen as related to the persistence of conversion as well as the intensity and duration of somatization.8,10,38–41 The following case of a young woman referred for evaluation of her chronic abdominal pain will serve to illustrate the psychoanalytic perspective on inhibition and its relation to anger and pain. Case 1: Ms. Ostrakova was a 20-year-old single library aide and parttime student at a nearby community college, who presented with a 2year history of chronic abdominal pain. She had undergone two separate, complete gastroenterologic workups at two different medical centers, without any positive findings. She associated the beginning of her difficulties with a chicken sandwich, prepared by her elder sister, in which the meat was apparently undercooked. She explained that she had become quite ill within a short time, with fever, nausea, and vomiting. These symptoms resolved after a few days, but her abdominal pain persisted and became progressively more debilitating until, by the time she arrived in clinic, she had taken a leave of absence from both college and her job and was attempting 4293

to manage her pain with a medication regimen that included shortacting opioids. Ms. Ostrakova was fit and slender and her demeanor, although somewhat subdued, was affable and cooperative. She had no psychiatric history or history of substance abuse, and her medical history was notable only for robust health prior to the onset of her abdominal pain. Her psychosocial history, however, was remarkable for early childhood trauma and abuse and a childhood household of domestic turmoil and violence. She described a history of fighting in school and finally being remanded at age 17 years by the juvenile court system to a residential treatment facility for “anger management” in another state. When asked about the therapeutic aspect of her 1-year treatment program, she replied, “They just taught us how to keep our anger inside, not to let it out, so we wouldn’t always get into fights. We had to avoid fighting to prove we had learned how to manage our anger.” As the interview progressed, it became clear that the patient had learned much about recognizing anger when she experienced it, and suppressing it in the moment, but little about the potential cost to herself and her body. A psychometric assessment reflected little endorsement of depressive symptoms on the Beck Depression Inventory or the MMPI-2 but clinically elevated scores on Hypochondriasis and Hysteria, and her history reflected many of the psychosocial factors depicted by Engel as disposing toward “pain proneness.” The latter included parents who were abusive toward each other and toward their children, a father who was alcoholic and emotionally and physically domineering, and a mother who was often debilitated by pain of uncertain etiology.11,40,42 In her treatment program, the patient appeared to have gotten the message, right or wrong, that, if she showed no outward signs of anger, she would be considered successfully rehabilitated. The experience of anger, therefore, became an obstacle between her court-mandated residential treatment and her successful return home. Over time, the experience of anger was transformed by a developing awareness of intolerable affect—displaced onto her body in the more acceptable symptomatic expression of physical pain. When Ms. Ostrakova’s elder sister provided the organic insult of an undercooked chicken sandwich, 4294

resulting in gastroenterologic distress, the patient, who might previously have responded with anger leading to physical confrontation, began instead to experience the pain associated with simple repression of her affect—unconsciously “keeping her anger inside.” This is the classic picture of somatization, depicted in psychoanalytic theory, which continues to be influential in our assessment of patients with chronic pain.

Current Research in Anger and Its Relation to Pain The role of anger in exacerbating pain and in disposing toward the development of chronic pain is, in some respects, similar to that of other negative emotions or distressed affective states, such as anxiety and depression.35,37,43 According to the prevailing gate control and neuromatrix theories of pain, negative emotions can increase the intensity and duration of pain by altering or dysregulating the descending and central pain modulation systems.44–51 Precisely how this takes place remains an open question for further research, but an integrated neurobiologic model is emerging with implications for treatment of both chronic pain and disorders of anger.

PHYSIOLOGIC MECHANISMS IN ANGER AND PAIN RESEARCH Merskey7 noted that pain can make individuals aggressive for purely biologic reasons, associated with the activation of the fight-or-flight mechanisms and high autonomic arousal. He added that we may not need to look much further in our attempts to explain why patients with chronic pain become angry. Whereas angry responses can be adaptive, especially when they prompt the search for constructive solutions to problems within the medical setting, chronically angry reactions of the sort observed in some patients with chronic pain are often seen as maladaptive and disruptive—indicative not of discrete situations of fight or flight but of sustained and simmering autonomic arousal.33,34,36,37,47,52 Parsing the relationship here has proven challenging because of two related questions: Does chronic pain induce sustained sympathetic arousal and therefore lead to continual expressions of anger? Does the situation of chronic pain arise 4295

more easily among individuals who are disposed to express anger and aggression? Robinson and Riley43 outlined four models or mechanisms through which the relationship between pain and negative emotion has been usefully described, both from a clinical perspective and as a template for empirical design: • Negative emotion increases sensitivity. • Pain is caused by negative emotion. • Negative affect occurs as a result of chronic pain. • Pain and negative emotion are concomitant. The first of these is simply the observation that negative emotion increases somatic sensitivity. In other words, negative emotions increase awareness and recognition of pain. Evidence in support of this mechanism comes from studies in which induced changes in mood have been correlated with increased reports of pain and decreased tolerance for experimentally induced pain, as well as in the clinical observation that depressed patients tend to interpret sensations negatively, experiencing them more often as painful.43 The second mechanism—that pain is caused by negative emotion—is most closely allied with the psychoanalytic view of pain as a symptom of underlying or repressed conflict, but inhibition of negative emotion and affect can also result in elevations of autonomic and central nervous system activity, raising serum cortisol levels and leading to neurovegetative dysfunction and increased pain. Cacioppo et al.’s53 metaanalytic study of the physiologic correlates of negative emotions concluded that the experience of anger, whether expressed or suppressed, tends to be accompanied by increased diastolic blood pressure, skin conductance, stroke volume, cardiac output, peripheral resistance, finger pulse, and heart rate, all suggesting a high sympathetic response. Considering the impact of sustained autonomic arousal, negative emotions, not surprisingly, may also be seen as causal in the expression of stressrelated illness and pain in which somatic reactivity can lead to musculoskeletal disorder.34,36,43,54–57 Robinson and Riley’s third mechanism echoes Merskey’s suggestion that negative affect may be seen simply as a reaction to the situation of chronic pain, arising within a stress4296

diathesis framework,7,43,58 whereas their fourth proposed mechanism posits that pain and negative emotion arise concomitantly from shared neurobiologic pathways.34,36,43,56 Taken together, these four mechanisms are broadly consistent with the gate control and neuromatrix theories of pain; however, the last—that anger, anxiety, depression, and pain share neurobiologic pathways— suggests a physiologic context in which negative emotions can alter the descending and central pain modulation processes.48–50,59 Serotonin, norepinephrine, and dopamine all play roles in the modulation of pain as well as in the development of negative emotions. That pain and depression both respond to certain antidepressant medications has long been cited as evidence of common neurobiologic pathways.43,60–63 Relative cortisol levels and dopaminergic transfer and regulation have also been implicated in the relationship between anger and pain,43,64–67 but the key neurotransmitter implicated in the modulation of anger is dopamine, with the focus of activity in the nucleus accumbens.63,67–71 From an evolutionary perspective, the emotion of anger is clearly primitive and derived from ancient limbic regions of the brain, as opposed to the cortex and prefrontal cortex, which assume a more modulatory role in its experience and expression.68 The regions of primary activity for anger—along with its conceptual counterparts, appetitive impulsivity, drive, motivation, pleasure, and psychoticism—appear to be associated with the core regions of temperament: the amygdala and nucleus accumbens or ventral striatum as well as the cingulate cortex.68,69 Lara and Akiskal68 suggest that anger is influenced by dopaminergic transfer and regulation in these regions, with high anger being associated with either enhanced postsynaptic response to dopamine or increased synaptic dopamine concentration or both. Wood67 outlines evidence to suggest that the inhibition of tonic pain is mediated by activation of mesolimbic dopamine neurons, arising from the ventral tegmental area and projecting to the nucleus accumbens. Ironically, anger may be associated both with an increase or a decrease in the experience of pain.27,59,72,73 Acute stress may activate mechanisms of pain suppression through the release of endogenous opioids and substance P within the ventral tegmental area, but prolonged exposure to 4297

stress—as in the case of sustained anger or proneness to anger—tends to result in a reduction of dopaminergic output in the nucleus accumbens, potentiating the subsequent development of hyperalgesia.67 The outcome appears to be that inhibition of pain may occur initially when a painful stimulus is first perceived but that, on further exposure and evaluation, sensitization may occur.59 The experience of anger appears to undergo change over time, leading to associations with both traits and temperament —factors related to the thematic and serial evaluation of stimuli—an observation that has led to the study of anger-related features of both mood and personality disorders.68,74–80 The influence of anger on the changes involved in mood states suggests a dynamic relationship associated with the tonic and phasic balance of dopaminergic activity.67,68 In this case, the inhibition of pain may be principally related to physiologic changes occurring in the initial or situational experience of anger, such as changes in cardiovascular reactivity and autonomic arousal that have been shown to modulate the experience of pain.27 Pain sensitization, on the other hand, appears more associated with the ability to regulate anger and the emotional evaluation of the experience—individual differences that influence dopaminergic output.59,68 This, in turn, suggests that the experience of anger, relative to personality and temperament, as well as how we manage anger, are important variables in the modulation of pain.56,59,63,68,70,76 Other physiologic mechanisms under study include the effects of anger on muscle reactivity, the immune system, and endogenous opioid dysfunction.47–52 Consideration of the last of these will be deferred to discussion of the related work on anger management, later in this chapter. Where the first is concerned, studies on muscle reactivity have suggested that anger may increase musculoskeletal tension in specific sites that contribute to pain.33,34,36,37,81,82 The experience of anger, whether inhibited or expressed, and the trait of hostility have been associated with increased likelihood of reporting high levels of tension near the site of pain and injury.83 A further mechanism through which anger may influence pain is distress-related immune dysregulation.84 Although brief, situational stressors involving activation of the fight-or-flight mechanisms have been shown to result in potentially beneficial changes to the immune system, 4298

exposure to prolonged stress and negative emotion, such as sustained anger and hostility, have been associated with deleterious effects in a broad range of health concerns, immunologic suppression, and generalized inflammatory processes associated with chronic pain.85–91 Because immunologic changes must be observed longitudinally, this work has tended to emphasize the impact of sustained anger and hostility associated with enduring personality traits and temperament.87,88

PSYCHOLOGICAL CONSTRUCTS IN ANGER AND PAIN RESEARCH The etymology of “anger” is not the same for every modern language, but it appears to have come into modern English usage via Old Norse, angra, “to grieve, vex,” later angr, “distress, grief,” Old English, enge, “narrow, painful,” influenced by the Proto-Indo-European root, angh-, “painfully constricted,” and finally into Middle English, where its associations with pain endured.92 The relative importance of the term in ordinary discourse can be illustrated through the frequency of its use: Of the roughly 700,000 words in common English usage, “anger” is ranked 2,382nd in frequency of appearance in spoken and written communication.93 Focusing on the logic underpinning the ordinary language use of the word anger, Smedslund offered a contemporary definition of anger that depicts the psycholinguistic core of the construct rather than emphasizing the characteristic features of its expression: “a feeling involving a belief that a person one cares for has, intentionally or through neglect, been treated without respect, and a want to have that respect reestablished.”54,55,94 In Smedslund’s conceptual framework, the “person one cares for,” particularly in the context of pain, is ordinarily the self. Fernandez emphasizes the dimensions of action tendency and cognitive appraisal in the study of the relationship between anger and pain.54,55,95 The former concerns the behavioral tendencies associated with anger, including aggression and impulses directed toward the restoration of control, the removal of obstacles, and the seeking of redress. This becomes an important consideration in the context of whether action is expressed or suppressed and, if expressed, how adaptively. The latter suggests a framework within which the individual seeks to explain otherwise 4299

ambiguous interior experiences or changes in arousal. Both of these dimensions are anticipated by and subsumed under Smedslund’s ordinary language definition of anger, and both have proven critical to the study of the relationship between anger and pain. The cognitive appraisal theory of emotion—perhaps most elegantly and economically portrayed in Lazarus’s96 cognitive-motivational-relational theory—suggests that the experience of an emotion, like anger, is the joint effect of (1) the event of physiologic arousal in response to incoming stimuli and (2) the cognitive appraisal of its meaning with respect to the particular setting in which the event occurs (Table 83.1). Cognitive appraisal, then, is the process through which physiologic states, such as arousal, are interpreted in light of the perceived situation. This becomes critical in the management of anger and, by extension, to the psychotherapeutic treatment of patients with chronic pain, because how events are appraised tends to influence selection and deployment of coping strategies.97–100 Lazarus96 further distinguished between primary and secondary appraisals, with the former referring to the interpretation of how a particular situation affects considerations of well-being and the latter, referring to considerations of how to cope with the situation.96 Secondary appraisals, he suggests, can actually shape the experience of an emotion through the selection of a particular coping strategy.96,101,102 TABLE 83.1 Lazarus’s Cognitive-Motivational-Relational Theory of Emotion Event (Stimulus)

Physiologic Response

Setting/Circumstances

Cognitive Appraisal

Feeling oneself being pushed or shoved

Autonomic arousal, pain

A cashier’s line in a busy store where customers are jostling for position

“A stranger has pushed me aside! This is unfair!”

Anger (increased pain associated with the unfair slight to one’s identity or ego)

Feeling

Autonomic

A pedestrian crosswalk

“A stranger has

Relief,

4300

Emotion

Secondary Appraisal The setting may suggest that an angry outburst will prove less effective than a sympathetic, reasoned appeal to civility. The setting

oneself being pushed or shoved

arousal, pain

at a busy urban traffic intersection

pushed me out of harm’s way! I was nearly struck by that automobile!”

gratitude (reduced pain); if anger is experienced, it is likely directed toward the impatient motorist or toward oneself for being careless.

may suggest that a personal expression of gratitude toward one’s protector is more appropriate than an angry outburst directed toward the fleeing motorist.

NOTE: The same or similar events and physiologic responses may be interpreted or appraised differently, depending on the setting or circumstances, resulting in different emotional responses.

ANGER MANAGEMENT STYLE Much of the research on anger and its relationship to pain has highlighted the related constructs of hostility, aggression, and anger management style.47,52,103,104 Anger is the term denoting the emotion, characterized by physiologic arousal and accompanying conscious and unconscious impulses toward aggression. Aggression typically refers to the behavioral expression of the emotion, ordinarily through acts of vindication, punishment, and destruction, directed toward others or objects.105–107 Freud’s focus was ultimately less on anger than on aggression, as one of the two primary instinctual drives.6,108 In psychoanalytic theory, aggression in its stimulation of defensive functions and coping strategies plays an important role in the development of personality. This distinction between anger and aggression suggests that whereas anger is usually conceived as a transient state, aggression is a more durable and endogenously derived motivational force. The word anger can be used in this manner—to denote a more dispositional quality—but, frequently, the term hostility is used in reference to the tendency to make consistently negative cognitive appraisals regarding the motivations of others.55 Conceptual links with aggression and hostility further raise the 4301

distinction between state anger and trait anger, a critical consideration in researching the influence of anger on chronic pain. A good starting point for the distinction is offered by Spielberger,105 who characterizes state anger as a transitory emotional episode, whereas trait anger is described as a more stable pattern of personality attributes, similar to hostility. One way of representing this is that trait anger reflects a relatively stable dimension of proneness to anger in which individual differences are reflected in the frequency, intensity, and duration with which state anger is experienced over time.33,52,109 This, in turn, suggests that characteristic defensive patterns and reliance on particular coping strategies tend to result in what may be described as more enduring styles of anger management. Anger management style is a term denoting the relative tendencies of individuals either (1) to suppress or internalize their anger or (2) to express or externalize their anger. The construct of anger management style is often represented in research as anger-in, anger-out, and angercontrol.33,47,103,104 Anger-in characterizes the tendency to inhibit the expression of angry thoughts and feelings, whereas anger-out describes the tendency to express angry thoughts and feelings directly, whether verbally, physically, or both. High trait anger, according to Deffenbacher,109 is more associated with the tendency to express anger negatively, less constructively, and with less control than with the tendency to suppress anger; he further notes that there is a stronger connection between the suppressed anger and anxiety than between suppressed anger and forms of expressed anger. Anger-control refers to an individual’s perceived control over the experience and expression of anger and is usually interpreted as positive, unless too much control approaches no expression at all.47 Although the International Association for the Study of Pain (IASP) appears to separate the sensory and emotional dimensions of the experience of pain, when it defines pain as an “unpleasant sensory and emotional experience associated with actual or potential tissue damage,”110 several studies point to the simultaneous processing of pain in the somatosensory cortex and emotion-related cerebral systems.59,111–113 Mollet and Harrison59 summarize the case for the application of emotional theories to the study of pain and propose that emotion may influence the processing of pain in several ways: 4302

• Negative emotion increases pain intensity and decreases threshold and tolerance. • Positive emotion decreases pain intensity and increases threshold and tolerance. • Pain may produce negative emotion or increase the memory for negative emotion. This template emphasizes the relationship between anger and pain and strongly implicates anger in the development and maintenance of chronic pain. It further highlights the role of anger management style as a critical influence in how pain is experienced.

Anger-In In his study of emotion regulation, Gross114 utilized a process model to illustrate two features of trait anger-in: First that, while the mechanism of suppression tends to decrease negative emotional expression, it also decreases positive emotional expression and second that although suppression has little impact on the experience of negative emotion, it tends to decrease the experience of positive emotion. In his analysis of emotion regulation, he concluded that, as a means of regulating negative emotion, cognitive appraisal is more adaptive than suppression and tends to decrease both the experience and expression of negative emotion while increasing the experience and expression of positive emotion. He added that there may be times when cognitive appraisal cannot adequately be mobilized, and suppression may be, in the moment, the best available means of regulating negative emotion, but such instances are more likely to involve evaluation in the moment of state anger. The overarching conclusion is that suppression as a trait mechanism for modulating intolerable affect is problematic. Engel noted that inhibition of anger, whether through repression or suppression, is a common attribute among pain-prone patients, but psychoanalytic theory offered little insight into the causal relationship or cognitive, emotional, and physiologic mechanisms through which inhibited anger can affect pain.11,31,32 More recent studies of anger-in as a form of emotional regulation confirm that suppression is a prevalent style of management among patients with chronic pain but also point to 4303

applications of Wegner’s ironic process theory as a means of delineating the mechanisms involved.31,32,115–117 According to this template, suppression of negative emotion requires the coordination of two distinct cognitive processes: The first represents a resource-dependent operating process that serves to eliminate awareness of unwanted thoughts and feelings, whereas the second represents a monitoring process that remains vigilant to the awareness of unwanted thoughts and feelings to be suppressed (Table 83.2). Under ordinary conditions, the monitor works to identify material to be suppressed, whereas the operating process performs the suppression; however, when under stress or high demand, the operating process may not have sufficient resources to perform its task. Stress, in this context, may be reflected in both cognitive and somatic symptomatology, with cognitive dissonance thwarting both suppression and cognitive appraisal and the corresponding demands on the body being expressed through cardiovascular and musculoskeletal symptoms. Burns et al.83 reported that patients with chronic low back pain who reflect an anger-in style of management are more likely than other groups to experience high levels of muscle tension at the site of pain and injury when experiencing anger and to show relatively high systolic and diastolic blood pressure. TABLE 83.2 Wegner’s Ironic Processes Theory of Mental Control Monitoring Cognitive Processes Vigilance toward unwanted thoughts or reminders of previous events leading to overwhelming anger

Setting/Circumstances Stress-free or low-stress circumstances evoking occasional or random thoughts or reminders of previous events leading to anger

Stress-laden or high-stress circumstances evoking frequent thoughts or reminders of previous events associated with harm or an unfair slight to one’s ego or identity leading to anger

4304

Operating Cognitive Processes Effortful, conscious attempts at suppression of or distraction from unwanted thoughts and reminders

Mental Control Outcome Successful suppression of or distraction from monitored thoughts and reminders

Failed suppression of or distraction from monitored thoughts and reminders leading to preoccupation and rumination

NOTE: When the operating processes are under high stress, the monitoring processes, which ordinarily serve to identify thoughts to be suppressed, can become the source of continual unwanted reminders of events leading to overwhelming anger.

The irony implicit in Wegner’s theory of mental processing is that, under such conditions, the monitor may be serving to bring unwanted thoughts and feelings into conscious awareness without sufficient resources for suppression to take place. The result is that unsuccessful efforts to suppress anger can paradoxically lead to heightened awareness of the cognitive and emotional experience of anger, thereby increasing sensitivity to pain and influencing subsequent perceptions and interpretations of pain according to the unsuccessfully suppressed, unwanted cognitions and intolerable affect.31,32,116,117 Carson et al. conducted studies on constructs related to anger-in, including the construct of ambivalence of emotional expression (AEE) and the construct of forgiveness.52,118–120 Theirs and related findings suggest that those who are ambivalent about expressing their emotions and those who cannot forgive others for perceived wrongs and insults may experience higher levels of low back pain and psychological distress, mediated by higher levels of anger. Where treatment is concerned, it is possible that psychotherapeutic interventions designed to resolve patients’ ambivalence toward expressing their emotions and to encourage the development of cognitive reappraisals supportive of conciliation and forgiveness may facilitate the management of pain.

Anger-Out Like anger-in, the emotional regulatory strategy of anger-out—managing anger directly with physical or verbal expression—has been shown repeatedly to be associated with increased responsiveness to pain and higher levels of chronic pain intensity and disability.47,121,122 It must be noted, here, that anger-out, in this context, usually refers to the trait of immediately responding to the emotional experience of anger with expression of anger—not the same as the considered, constructive expression of anger signifying the mobilization of more mature defensive processes. Hostility and tendencies toward aggression are hallmarks of trait anger-out. Bruehl et al. have done the most complete review of anger4305

out studies to date and conclude that elevated trait anger-out is associated with heightened chronic pain intensity and low levels of improvement in individuals suffering from a broad range of medical conditions associated with chronic pain.33,34,36,121 They examine a number of proposed mechanisms underlying the effects of trait anger-out on acute experimental, acute clinical, and chronic pain, but the emphasis here will be on chronic pain. The authors submit that there is little evidence for the influence of either neuroticism or the psychoanalytic construct of repression.121 The former— a willingness to overendorse a broad spectrum of symptoms—has sometimes led to spurious correlations between elevated pain and indicators of an anger-out style of management, but the available evidence tends to suggest that the relationship of anger-out to pain is independent of the broader palette of negative affect, including depression and anxiety. Where the latter is concerned, one might expect that trait anger-out would be negatively associated with the classic psychoanalytic constructs of conversion and somatization and therefore consistently lead to an amelioration of pain. As previously noted, however, the hostility and aggression embodied in trait anger-out do not promote the mature and adaptive expressions of anger reflecting successful management that might lead to reduced pain intensity and sensitivity. Other behavioral mechanisms have been considered, including the observation that individuals whose scores are elevated on measures of anger-out show decreased cardiovascular reactivity when encouraged to express their anger versus suppress it, and among a high anger-out group of women, verbal expression of anger during provocation was associated with improved blood pressure recovery, following the stressful event. Although there are some indications that these findings are related to improvement in situations involving acute pain, Bruehl et al.121 point out that implications for the effect of behavioral anger expression on chronic pain have yet to be fully delineated. Although not specifically applied to the variable of management style, Greenwood et al.47 suggest several behavioral mechanisms that may influence the relationship between anger and pain. First, anger may foster the development of pain behaviors associated with the negative 4306

consequences of expressing anger. The high correlation between hostility and absenteeism from work, for example, suggests that anger may contribute to the maintenance of pain-related illness. Second, the effects of anger on marital functioning may lead to spousal responses that exacerbate and maintain pain and pain behaviors. Finally, anger can impact pain by contributing to conflicts and mistrust in relationships between patients and their medical providers. Studies by Burns et al. concluded that high scorers on anger-out and hostility were correlated with patients’ reports of weaker alliances with their physicians and with interference in their abilities to improve with pain management.36,123,124 Proposed mechanisms underlying the relationship of anger-out and pain have also included a number of physiologically based models.121 Angerout has been associated with greater visceral adipose tissue in some studies, a potential source of impact on lower spine mechanics. Like anger-in, anger-out has also been found to be correlated with increases in stress-induced muscle tension among patients with low back pain. Neither of these models, however, can account for the effects of anger-out on acute pain responsiveness and sensitivity. Genetic mechanisms have been suggested as well, but Bruehl et al.121 assert that none has been adequately investigated, to date, despite promising connections with genetic factors related to personality traits, emotional reactivity, and endogenous opioid system functioning. A related mechanism, referred to as “trait X,” suggests that high anger-out individuals express their anger because they believe it is beneficial and it feels better to discharge it than the alternative. The idea is that behaviorally expressing anger for high anger-out individuals actually reduces arousal and restores emotional and physiologic homeostasis more efficiently. The authors comment that trait X state interactions may well reflect some degree of functional regulatory benefit, especially in the immediate aftermath of expressing anger, but the more enduring trait anger dimension has yet to be sufficiently investigated.

Opioid Deficit Hypothesis and the Role of Endogenous Opioid Functioning Bruehl, in collaboration with others, has also called attention to the role of endogenous opioid dysfunction in the relationship between anger-out and 4307

pain.28,30,121,122,125–131 The essential premise is that mechanisms associated with anger-out may impose an excessive burden or strain on the body’s ability to produce endogenous opioids, inhibiting the natural management of chronic pain. Bruehl et al. conducted studies in which subjects with low scores in anger-out reported increased acute pain intensity following opioid blockade with naloxone versus following placebo blockade, whereas subjects high in anger-out reported smaller naloxone blockade effects.28,30 The implication is that there is less effective endogenous opioid response among those who score high in anger-out, with opioid dysfunction partially mediating the positive correlation between anger-out and chronic pain intensity.122 Burns and Bruehl126 further established that the use of exogenous opioid analgesics remediates opioid deficits such that anger-out is related to chronic pain severity only among patients not taking opioid medications. The results suggest that regular use of opioid medications among those who are high in anger expression may compensate for overtaxed endogenous opioid mechanisms. In another, related study, Bruehl et al.122 investigated whether impaired central opioid inhibitory functioning, assessed via changes in plasma β-endorphin release, could explain exaggerated pain responsiveness and anger expression in high anger-out subjects. As with the opioid blockade studies and the study of the mediating effects of exogenous opioids, the results of this pain-induced endogenous opioid release study support the opioid deficit hypothesis and demonstrate that greater trait anger-out is associated with higher perceived pain intensity and less endogenous opioid release. Taken together, these studies provide strong evidence for the idea that patients whose anger management style involves physical and verbal expression show comparative deficits in opioid analgesia because of endogenous opioid dysfunction. Bruehl et al. have taken this one step further with the opioid triggering hypothesis, suggesting that, for individuals high in anger-out, the dramatic expression of anger serves to activate endogenous opioid response that would otherwise remain quiescent when anger associated with pain and stress is either not expressed or only moderately expressed.121,128–130 Those who are low in anger-out appear to elicit a sufficient endogenous opioid response without 4308

expressing their anger, but the expression of anger among high anger-out individuals may actually represent an adaptive mechanism designed to trigger the release of endogenous opioids. Patients high in anger-out may therefore have a higher threshold for the activation of endogenous opioid response, with the increased arousal of dramatic anger expression serving as a triggering mechanism.

Measurement of Anger Anger, both state and trait, as well as the related constructs of aggression, hostility, and anger management style have been assessed for research purposes with a broad spectrum of tools, ranging from projective tests, like the Rorschach and thematic apperception test (TAT), to physiologic measures principally associated with autonomic arousal.55,132 Self-report questionnaires and inventories tend to predominate in anger-related research, however, both for their ease of administration and for their more readily documented validity and reliability. Several of the self-report instruments measuring anger that are more widely utilized or particularly suited to pain research are reviewed in the following discussion. Extensive commentary on each, as well as critical reviews of many instruments designed to measure some aspect of anger, are available in Tests in Print VII133 and the The Seventeenth Mental Measurements Yearbook, 17th ed.134 The instruments discussed in the following text are summarized in Table 83.3. TABLE 83.3 Instruments Designed to Assess Anger Instrument

Format

Administration

Availability

State-Trait Anger Expression Inventory (STAXI-2)

57 items distributed across 6 scales, 5 subscales, and an anger expression index; ages 16 years and up 10-point Likert

5–10 min; scored by hand

PAR: Psychological Assessment Resources Inc (www4.parinc.com)

10–20 min for an

Fernandez E, Salinas N, Swift P, et

Targets and

4309

Reasons for Anger in Pain Sufferers (TRAPS)

Multidimensional Anger Inventory (MAI)

Novaco Anger

scale assessing degree or intensity of anger toward a variety of common objects of anger (e.g., self, significant others, employer, physician) and 10 common reasons for anger

30-item instrument, with multiple variations, assessing the duration, frequency, and magnitude of anger, including differentiation between anger-in and anger-out expression and common situations leading to anger 60 items

interactive administration; has been adapted for briefer selfadministration; scored by hand

10–20 min; scored by hand

25 min; scored

4310

al. Psychosocial factors that predict anger in chronic pain sufferers. Ann Behav Med 1995;17:S164.

Fernandez E, Salinas N, Swift P, et al. Psychosocial factors that predict anger in chronic pain sufferers. Paper presented at: Sixteenth Annual Scientific Meeting of the Society of Behavioral Medicine; 1995; San Diego. (Used with permission of primary author.) Siegel JM. The multidimensional anger inventory. J Pers Soc Psychol 1986;51:191–200. (Used with permission of author.)

WPS: Western Psychological

Scale and Provocation Inventory (NASPI)

Anger Disorders Scale (ADS)

Minnesota Multiphasic Personality Inventory-2Restructured Form (MMPI-2RF)

distributed across 3 subscales (cognitive, arousal, behavioral) plus a 25-item inventory eliciting responses to specific situations 70 items distributed over 5 categories (provocations, cognitions, arousal, motives, behaviors) 338 true–false items distributed across multiple validity and clinical scales, with multiple scales assessing some aspect of anger, hostility, or aggression

by hand

Services (www.wpspublish.com/app/)

Short form, 5–10 min; long form, 10–20 min; scored by hand or software

MHS: Multi-Health Systems Inc (http://www.mhs.com)

35–50 min; scored by hand or software

Pearson Inc (http://www.pearsonclinical.com)

STATE-TRAIT ANGER EXPRESSION INVENTORY-2 The State-Trait Anger Expression Inventory-2 (STAXI-2) was developed by Spielberger and is widely regarded as the most psychometrically sound and comprehensive tool in the assessment of anger and hostility.55,105,135 It represents the integration and culmination of several precursors developed by Spielberger, including the State-Trait Anger Scale (STAS), the Anger Expression Scale (AES), and the first version of the STAXI-2. The instrument consists of six scales: Trait Anger, Anger Expression-Out, 4311

Anger Expression-In, Anger Control-Out, Anger Control-In, and State Anger as well as five subscales and an Anger Expression Index. It can be administered in 5 to 10 minutes and is scored by hand, making it practical for clinical applications as well as research. The STAXI-2 purports to measure tendencies toward angry action, as well as more dispositional or trait-based hostility, along with tendencies to suppress or express the experience of anger. This makes the inventory well suited for research in anger management styles and clinically well adapted to assess the needs of patients for psychotherapeutic applications of anger management. Normative data are published for adolescents, adults, and psychiatric patients, and evidence for high reliability and validity are detailed in the testing manual.

THE TARGETS AND REASONS FOR ANGER IN PAIN SUFFERERS Although the STAXI-2 is applied to the study of pain more frequently than other inventories of anger, it was not designed for use with chronic pain patients and does not assess specifically pain-related dimensions of anger. Fernandez55 developed a structured inventory, the Targets and Reasons for Anger in Pain Sufferers (TRAPS), later adapted for self-administration by Okifuji et al.,136 that allows chronic pain patients to rate their levels of anger on a Likert-type scale toward a variety of common objects or targets of their anger: whole world, self, God/destiny, significant other, employer, insurance company, attorney or legal system, health care providers, and person who caused the accident. Patients may also be instructed to identify and rank their reasons for being angry toward these targets. The results, especially when the TRAPS is administered in a structured interview, allow clinicians and patients to explore together the relative importance of specific targets of and reasons for anger, suggesting interventions and strategies for reducing the impact of anger on pain. Normative data and information on reliability and validity are not yet available.

MULTIDIMENSIONAL ANGER INVENTORY Siegel developed the Multidimensional Anger Inventory (MAI) as a brief instrument designed to assess responses to anger-eliciting situations in an 4312

attempt to increase sensitivity to the multidimensional nature of the construct.55 Factor analytic solutions arrived at the following dimensions or factors: anger arousal, hostile outlook, range of anger-eliciting situations, and anger expression, the last being divided into anger-in and anger-out. Although it was developed specifically to assess anger in cardiovascular patients, factor analytic replications in more heterogeneous populations suggest its utility on a broader scope, especially with other health-related groups. Reliability and scale validity information are available through the author’s report.137

NOVACO ANGER SCALE AND PROVOCATION INVENTORY This inventory, developed by Novaco,138 consists of two principal sections: The Novaco Anger Scale (NAS) purports to measure the general inclination toward reacting with anger, whereas the Provocation Inventory (PI) asks patients to respond to descriptions of specific situations that tend to elicit anger. The NAS contains 60 items divided equally over three subscales: (1) a cognitive subscale, measuring anger justification, rumination, hostile attitude, and suspicion; (2) an arousal subscale, measuring anger intensity, duration, somatic tension, and irritability; and (3) a behavior subscale, measuring impulsive reaction, verbal aggression, physical confrontation, and direct expression. The PI contains 25 items, each describing a situation that tends to elicit anger, with subjects being instructed to rate their degree of anger or annoyance on a 5-point Likerttype scale. The situations include scenarios such as “getting your car stuck in the mud or sand” and “being joked about or teased.” The items are grouped into five subscales summarizing the theme of the provocation: disrespectful treatment, unfairness, frustration, annoying traits of others, and irritations. The Novaco Anger Scale and Provocation Inventory (NASPI) attempts to characterize how an individual experiences anger and what sorts of situations provoke it. The instrument has been widely used to evaluate the role of anger in diverse environments, from community based to correctional settings, and may prove useful in evaluating the role of anger in health care settings. Normative data, reliability, and validity are well documented in the testing manual.138 4313

ANGER DISORDERS SCALE The Anger Disorders Scale (ADS) is a self-report instrument consisting of 70 items distributed over five categories characterizing human emotion: provocations, cognitions, arousal, motives, and behaviors.139 A short form consisting of only 18 items may be used as a screening tool to obtain scores on three factors: reactivity/expression, anger-in, and vengeance.140 The ADS is designed to assess and identify dimensions of anger that are associated with dysfunction and impairment in clinical populations. It yields information concerning the duration that an individual stays angry, the breadth of stimuli that may serve as triggers for an individual’s anger, and the frequency of angry episodes. Information on reliability and concurrent and discriminative validity are available in the testing manual.

MINNESOTA MULTIPHASIC PERSONALITY INVENTORY-2-RESTRUCTURED FORM The MMPI-2-RF is a 338-item, true–false, self-report instrument designed to assess a broad range of psychopathology and personality traits and characteristics.24,25 It is arguably the best known and most widely used psychometric assessment tool available, and it and its predecessors, the MMPI and MMPI-2, have been applied to the investigation of pain in hundreds of empirical studies.15 Several MMPI-2-RF scales are relevant to the study of anger and its relationship to pain, with all scales relating to anger being well validated and designed to reflect some aspect of trait anger (e.g., anger proneness [ANP] and aggressiveness, revised [AGGR-r] scales).

Psychotherapeutic Management When anger and problems with the management of anger are aspects of a patient’s presentation with chronic pain, ignoring the indication for psychotherapeutic intervention may well jeopardize any chance of successfully treating or managing his or her pain.141 As we have seen, trait anger and certain styles of anger management are fertile ground for the development of chronic pain, but anger may emerge as a critical factor in response to chronic pain as well. The following case of a middle-aged 4314

patient with chronic headaches will serve to illustrate the mutually influential roles of anger and pain in the context of treatment. Case 2: Mr. Alvarez was a 45-year-old single man, referred to the Pain Center by his new primary care physician and his new neurologist for the treatment of long-standing chronic daily headaches with tension-type and migrainous features. He arrived for his initial evaluation more than an hour late but loudly insisted upon being seen, saying that the traffic was not his fault and that he had a severe headache requiring immediate attention. He was irritable in his exchanges with support staff and paced back and forth in the waiting area, to the discomfiture and consternation of other patients. When he was finally escorted to an examination room, he informed the nurse that he hoped he did not have to wait long to see the physician. Once his pain physician joined him for the evaluation, he seemed deferential and cooperative, as he related his medical history and the history of his headaches. His physician noted, however, that he expressed considerable anger toward previous providers, toward his wife and children, and toward his employer, none of whom, according to the patient, responded with adequate sympathy to his distress or provided any respite from his pain. As his physician rose to conclude the interview, the patient looked at the prescriptions he had been given as a first line of intervention and, tossing them onto the desk, said, “I didn’t come here for more pills. I told you, I came for Botox injections, and I’m not leaving here without them.” When it was explained that authorization from his insurance carrier had to be obtained and that he might well respond favorably to a less invasive procedure, the patient’s anger became increasingly confrontational. When it became clear that he was not going to get what he wished, he vociferously decried “the incompetence of doctors” and stormed from the examining room, upsetting a chair and waste bin in the process. In the succeeding days, as the patient’s stricken pain physician consulted with Mr. Alvarez’s referring providers and assembled his medical records, several points became clear. This was not the patient’s only reported angry exchange in health care settings and, indeed, it appeared that Mr. Alvarez frequently changed primary care physicians and 4315

specialists, whether by his own decision or mutual agreement. It was a surprise when Mr. Alvarez made and kept a follow-up appointment but less surprising when the outcome was much the same, with the patient discharging his anger and frustration toward staff and his pain physician. It was at the conclusion of his second appointment that he was referred to the pain psychologist to do biofeedback and learn relaxation techniques. This puzzled but did not threaten him because the physiologic benefit of treatment was emphasized, and he was affable enough during the initial visit and anamnesis, which revealed much about the relationship between his anger and his pain. He exhibited many of the behavioral mechanisms, previously mentioned, through which anger can exercise influence over pain.47 His anger toward his employer led to frequent arguments and resulting exacerbations of his headaches, in turn resulting in high absenteeism, which led to further conflicts at work. His anger toward his wife frequently led to retaliation in various forms on her part, which, again, resulted in exacerbations of his pain and the development of pain behaviors designed both to justify his disability and to elicit sympathy. Finally, his anger in the medical setting led to inconsistent and poorly planned care that, in turn, thwarted his attempts to gain relief, allowing his headache and associated behavioral patterns to become firmly entrenched. It was nevertheless an unexpected development to Mr. Alvarez when the pain psychologist suggested that his anger may be exerting a dramatic impact on his headaches. The patient characterized himself as “quick to anger but quick to get over it” and cited trends within his family of origin, especially his own parents, to be dramatically expressive of anger. He added with irony, “I thought that’s what you psychologists were always saying—‘to get it off my chest and not hold it in.’” He portrayed himself honestly and clearly as a high anger-out individual, a style of anger management shown repeatedly to be associated with increased responsiveness to pain and higher levels of pain intensity and disability.34,36,47,52,103,121,122 In addition to doing biofeedback training and learning relaxation techniques, the goal of psychotherapy in this second case was to encourage the patient to adopt and practice more adaptive strategies for anger management. Neither Mr. Alvarez’s anger-out style 4316

nor Ms. Ostrakova’s anger-in style, depicted in the first case, was conducive to the successful management of their chronic pain.

CONSIDERATIONS IN THE SELECTION OF PSYCHOTHERAPY Where the special practice of pain psychology is concerned, supportive and psychoanalytically informed psychotherapies have been viewed as useful in the management of pain, primarily when behavioral and cognitive-behavioral treatments have failed to bring relief.142,143 The psychodynamic approach may nevertheless be a logical starting point for patients whose anger, pain, and disability are sustained by intrapsychic conflicts or unconscious motives associated with childhood trauma or primary or secondary gain.141,144 The drawbacks associated with pursuing such a course of treatment can be manifold, but there may be times when patients are unable to move forward until they are satisfied that their conflicts and motives are revealed and understood. A problem for the successful management of pain, however, is that psychotherapies focusing on the primacy of the experience of emotion are typically long term and may require many months, if not years, to result in meaningful insight and progress. Such treatments, at least near their outset, can also lead patients to an uncritical acceptance of their feelings, further validating the experience of negative emotions such as anger; therefore, the selection of appropriate psychotherapy and the skill of the psychotherapist are perhaps most critical in cases where a psychodynamic or supportive approach is indicated. If the principal obstacles to successful adjustment to chronic pain are factors, such as anger management style and negative cognitions underlying anger and hostility, then a more direct approach to treatment would be to challenge the behaviors reflecting and maintaining anger as well as the negative cognitions driving it. Challenging established behaviors with new, more adaptive ones is the goal of behavioral therapy, whereas identifying, examining, and restructuring the negative cognitions behind negative emotions is the work of cognitive therapy. Both are well established as offering greater efficacy in the implementation of change and the modulation of the effects of anger on chronic pain, but both 4317

depend on the patient’s willingness to collaborate with treatment and his or her readiness for and motivation to change.141,145,146 The influence of any psychosocial risk factor, such as trait anger and hostility, may signal reluctance on the part of the patient to give up his or her pain and suffering or relinquish the refuge of disability.141 In the first case study, Ms. Ostrakova complained of pain, but her symptoms were driven by powerful and enduring unconscious conflicts associated with her history of childhood trauma and abuse. The high correlations between histories of abuse and the subsequent development of difficulties with both anger and chronic pain are well documented in the psychoanalytic and scientific literatures.11,42,147–156 For patients who have suffered abuse as children or who have been exposed as adults to situations involving catastrophic loss or harm, chronic pain may come to represent a means of psychologically symbolizing and organizing unbearable memories and intolerable affects.141 In Ms. Ostrakova’s case, coming to an understanding of the relationship between her history and the development of her symptoms may well represent an essential step toward taking an active role in her treatment, and the selection of treatment to facilitate this step is likely to involve a form of supportive and psychodynamic psychotherapy. Ironically, a year of inpatient treatment with behavioral and cognitive-behavioral interventions appears only to have altered the patient’s style of anger management from anger-out to anger-in. Investigators have found that patients vary widely regarding how prepared they are to collaborate in their own treatment and make the changes necessary to manage their anger and their pain more effectively. Assessing a patient’s readiness to change is frequently a critical prelude to effective psychotherapeutic intervention and may shed insight into why some patients never seem to improve. Cognitive therapy often begins with the patient’s response to two questions: What do you want (to change)? What are you willing to do to get it?141,151 The first question is easy for most patients with chronic pain, but the second implies work and sacrifice and is not so easy when patients are prone to anger and preoccupied with their own suffering and deprivation. Assessing a patient’s readiness for change is one way of answering the second question. Kerns et al. applied Prochaska’s transtheoretical model of the stages of 4318

change to the situation of chronic pain and arrived at four successive levels in patients’ willingness to collaborate with treatment and undertake the behavioral changes necessary to manage their pain more effectively157–160: • Precontemplation: patients who have no intention of changing their current patterns of behavior—“You’re the doctor. Fix my pain!” • Contemplation: patients who have begun to recognize the necessity of making changes in their behavior but have not yet committed to doing so—“I know it’s up to me. I just don’t know how to do it.” • Action: patients who have committed to a plan of action and are engaged in making changes—“I’m doing something about my pain.” • Maintenance: patients who are attempting to sustain the changes they have undertaken—“I’m using what I’ve learned in treatment to manage my pain better.” Angry and hostile patients, in particular, may be stuck in the precontemplative stage of readiness for change, and their often unrealistic expectations of their physicians may lead them to feel that effective treatment is being withheld. This was the case with Mr. Alvarez, whose anger was driven by his disappointment in providers who never seemed willing to do enough to help him manage his pain. Unlike Ms. Ostrakova, however, his style of managing anger did not reflect defensive inhibition of affect, and his chronic pain was not associated with unconscious conflicts. His anger, although more volatile, also proved more tractable to the psychoeducational component of cognitive therapy, and he was ultimately able to make the transition more easily from the precontemplative to the contemplative stage of readiness for change.

BEHAVIORAL AND COGNITIVE-BEHAVIORAL THERAPIES Templates for behavioral and cognitive-behavioral intervention in cases of chronic pain are offered in succeeding chapters, but it is instructive to note that their number and applications have burgeoned in recent years, largely through the proliferation of acceptance and commitment therapy (ACT), contextual cognitive-behavioral therapy (CCBT), mindfulness-based stress reduction (MBSR), and mindfulness-based cognitive therapies (MBCT) as well as mindfulness-based behavioral techniques, such as 4319

meditation.161–165 Behavioral approaches to the treatment of anger have tended to revolve around relaxation training and applications of relaxation techniques to reducing autonomic arousal and uncomfortable musculoskeletal tension. Suinn’s template for anxiety/anger management training (AMT) represents one of the more enduring expressions of this form of treatment.166,167 He proposes a brief, structured therapy involving six to eight sessions in which guided imagery directed toward arousing anger is subsequently and serially paired with relaxation techniques designed to deactivate arousal. Patients are first instructed in the elicitation of the body’s natural relaxation response—which can be accomplished using meditation, progressive muscle relaxation, body scans or other forms of autogenic training, or diaphragmatic breathing techniques—and, once they have mastered this, the psychotherapist offers structured practice in the use of the technique to contain or defuse sympathetic nervous system reactivity cued by suggestions and visualizations of stressful images. The use of biofeedback technology in the assessment of progress can frequently hasten mastery of this strategy by presenting the patient with tangible evidence of progress. Fernandez proposes that if the injury or perceived injustice resulting in chronic pain—whether physical or psychological in origin—cannot be altered or undone, then switching the focus to what can be changed becomes the logical object of therapy. What can be changed is the way the patient with chronic pain construes what has transpired.168,169 Recall that in Lazarus’s96 cognitive appraisal theory of emotion, the experience of anger is the joint effect of (1) the event of physiologic arousal and (2) the cognitive appraisal of its meaning. Whereas much of behavioral therapy directed toward the management of anger is concerned with the former, cognitive therapy is directed toward the latter. As we have seen, anger, by Smedslund’s definition, involves the appraisal by the subject that he or she —or a person for whom he or she cares—has been treated without respect.94 This, of course, may actually be the case in a given situation and therein lies the foundation of the biologic basis for anger,67,68,114 but anger, as our Greco-Roman and Judeo-Christian roots attest, does not necessarily conform to logic. The experience of anger can quickly and 4320

easily become associated with irrational, automatic thoughts and beliefs concerning the motives of others and the sources of threat to our wellbeing. The approach of cognitive therapy is to offer a corrective process to the development and maintenance of errors in our thinking and beliefs.55,141,161,164,170–173 Through the process of cognitive restructuring or reappraisal, patients are led to examine whether, in the process of trying to make sense of their anger and pain, they may be making fundamental errors in their thinking and relying on mistaken beliefs. Patients are encouraged to challenge their automatic thoughts and uncritically held beliefs regarding their experiences of anger through the template of cognitive appraisal theory—that is, that situations are ordinarily neutral until we assign meaning to them. We are often unaware of this step of assigning meaning because we do not usually stop to examine the thoughts and beliefs that influence our emotional responses to certain situations, and even when we do, we may not consider the accuracy of these thoughts and beliefs. The essence of the cognitive model of treatment suggests that much of our emotional distress and self-defeating behavior is based simply on inaccurate and irrational thinking and that once our attention is drawn to these upsetting cognitions, we can test their veracity and value to see whether they form an appropriate basis for our emotions and behavior. As they learn to identify negative cognitions, patients begin to monitor their cognitive appraisals more rigorously and critically, cognitively restructuring their primary and secondary appraisals of situations resulting in anger. Common reappraisals of the experience of anger might include reexamining the intention of the one toward whom our anger is directed, reconsidering the harm done by the perceived slight or insult, or reinterpreting the outcome of a situation to determine whether a perceived breach of respect actually resulted in harm or injury.55 Fernandez’s proposed cognitive-behavioral affective therapy (CBAT) serves as a model of integrative treatment for anger in the context of chronic pain because it combines behavioral and affective interventions for self-soothing while the patient undertakes the cognitively challenging work of restructuring his or her appraisals of what has transpired.168,169 These behavioral and affective techniques target the feelings of distress inherent in the experience of 4321

anger, providing both support and respite as the often difficult and taxing work of the cognitive therapy progresses. In the case of Mr. Alvarez, he was taught meditation as a means of assuaging his sometimes high, reactive affect, although several negative cognitions were identified as being based on dysfunctional family-oforigin models and overrehearsed expression. His primary negative cognition—“Everyone is out to take advantage of me”—may have reflected some degree of utility in the gang-controlled streets of his childhood barrio, but it was dysfunctional and even harmful in the medical setting, where his physicians and other providers were genuinely concerned to help him. Their response to his anger was to defend themselves by disengaging and retreating, often to the detriment of his care. A corollary negative cognition—“No one will help you voluntarily; you have to demand what you need from people”—was equally destructive of the medical alliance. Through cognitive reappraisal and the opportunity to test different interpretations, the patient ultimately proved to himself that people, especially people whose job is to take care of him, really are often willing to help and that consistently making demands of others tends to result in less return than welcoming their responses to reasonable requests. Mr. Alvarez’s anger-out style, once a barrier to his receiving the best from his medical care, receded and was replaced by a more genuinely collaborative attitude toward his physicians.

Summary The cultural background of anger lays the groundwork for understanding its role both as an emotion and as a trait, as well as its relationship to pain. Psychoanalytic theory emphasized the harmful effects of inhibiting the experience and expression of anger, placing it at the core of conflicts between competing drives and the formation of pathologic symptoms. More recent research has brought additional clarity to the relationship between anger and pain, suggesting a number of possible mechanisms through which state and trait anger can influence sensitivity to pain and the development and maintenance of chronic pain. This trend, in turn, has led to improved objective psychological measures of anger and the

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CHAPTER 84 Cognitive-Behavioral Therapy for Chronic Pain LAYNE A. GOBLE, CHRISTOPHER D. SLETTEN, TAYLOR CROUCH, and KELLY BARTH

Introduction Cognitive-behavioral therapy (CBT) is an evidence-based treatment approach that has been effectively applied to the management of chronic pain. This approach is influenced by behavioral techniques (i.e., relaxation therapies, time-based pacing, and behavioral activation) combined with cognitive therapies (i.e., cognitive restructuring) with a goal of better integrating pain management within a biopsychosocial model of care. Additional components that address common comorbidities such as sleep and relationship difficulties are often included in treatment protocols. The main outcome of CBT for chronic pain (CBT-CP) is development of healthy coping techniques to improve functioning in the face of ongoing pain complaints. For the past three decades, the vast majority of research on psychological approaches to chronic pain has focused on traditional CBT. However, there has been a growing interest in recent years on interventions that include mindfulness and acceptance-based components, which have been called the “third wave” of behavioral and cognitive psychotherapies. As a brief (and certainly incomplete) background review, “first wave” treatments employed classic behavioral therapy, including methods such as contingency management and operant conditioning, to change behavior (e.g., Zinbarg and Griffith1). “Second wave” treatments integrated cognitive methods (i.e., identifying and modifying maladaptive cognitions) into behavioral treatment in order to change problematic 4331

behaviors and emotions (e.g., Beck2). “Third wave” treatments can also be considered cognitive-behavioral interventions, but they collectively emphasize mindfulness and acceptance-based processes while deemphasizing cognitive change or control. Each of these is reviewed within this chapter.

HISTORY AND DEVELOPMENT OF COGNITIVEBEHAVIORAL THERAPY FOR PAIN CBT-CP developed out of a need for an approach outside of the traditional biomedical model. Clinicians and researchers recognized that psychosocial factors had an influence on pain-related behaviors that significantly impacted treatment outcomes. Henry Beecher3 was a pioneer in pain management who first recognized the impact of psychosocial factors on chronic pain while serving in the Army Medical Corps during World War II. During this time, he first observed that the individuals in his care responded very differently to their traumatic injuries. Namely, he observed that soldiers with serious wounds reported less pain than did his postoperative patients at Massachusetts General Hospital. In interviews with his patients, he found that their pain experiences were mediated by the meaning that they had attributed to their injuries. He concluded, “There is no simple relationship between the wound per se and the pain experienced. The pain is in very large part determined by other factors, and of great importance here is the significance of the wound.” He found that only one in four injured soldiers requested analgesic medications despite experiencing severe wounds. Many of these soldiers were grateful to have survived their injuries and directed their thoughts to the positive aspects of their situation—namely, gratitude for having survived their injuries and thoughts of going home. He also found that similar attributions to injury also impacted individuals with injuries outside of combat settings. Beecher was one of the first researchers to acknowledge the complex interplay of the physical, psychological, and sociocultural factors that impact the chronic pain experience. This interplay of factors affected not only the experience of pain but also the behaviors and disability that accompanied chronic pain. This theory would later become the biopsychosocial model of chronic pain. 4332

By the 1960s and 1970s, the health care community began to adopt a new view of chronic pain; first, by distinguishing acute and chronic pain as separate entities and then by developing behavioral and rehabilitation approaches to chronic pain. During this time, Wilbert Fordyce worked with John Bonica to develop groundbreaking behavioral therapies for chronic pain based on operant conditioning approaches. Essentially, he encouraged (i.e., reinforced) individuals with chronic pain to reengage in exercise and other physical activities while reducing (i.e., extinguishing) their maladaptive pain behaviors.4,5 His approach encouraged individuals to take a more active role in their recovery, thereby helping them to experience a greater sense of control over their chronic pain complaints. This approach was considered revolutionary at the time because these basic changes in behavior led to a reduction in their use of analgesic medications and improved function during their time in treatment. The growth of cognitive therapy6 likewise expanded our understanding of psychosocial factors that impact chronic pain. This model addresses the influence that thoughts can have on our emotions, behaviors, and even physiologic processes. Albert Ellis7 and Aaron Beck6 first addressed catastrophizing as a factor that impacts the development and maintenance of depressive and anxiety disorders. Catastrophizing thoughts are irrational beliefs that one’s current or anticipated situation is exaggerated to be far worse than it actually is. Michael Sullivan8 later developed the Pain Catastrophizing Scale to assess for catastrophizing beliefs in chronic pain patients. His measure is widely used in both clinical and research settings to assess for catastrophizing beliefs in chronic pain patients. Beverly Thorn9 has also been instrumental in developing cognitive interventions for chronic pain patients.

EVIDENCE FOR COGNITIVE-BEHAVIORAL THERAPY FOR CHRONIC PAIN There is significant evidence that CBT-CP is effective for a number of chronic pain conditions, including headache, rheumatic diseases, chronic pain syndrome, chronic low back pain, and irritable bowel syndrome.10–12 In 2016, Centers for Disease Control and Prevention (CDC) published an update to their “Guidelines for Prescribing Opioids for Chronic Pain.”13 4333

Their first recommendation that the authors emphasized as being of primary importance was “nonpharmacologic and nonopioid pharmacologic therapy are preferred for chronic pain . . . .” This recommendation was based on a contextual review of nonpharmacologic and nonopioid therapies,14 which cites 13 guidelines and 18 systematic reviews of randomized or quasi-randomized trials of nonpharmacologic and nonopioid therapies, including studies with follow-up periods from 2 weeks to 6 months (with some CBT studies “assessing outcomes at 6 months or longer”). The overall quality of the evidence as informally rated by study authors was felt to be “moderate.” The contextual review found that CBT had significant positive effects on disability and catastrophizing with effects lasting up to 6 months in back pain and osteoarthritis, and biopsychosocial rehabilitation was effective for both pain and disability.14 The authors concluded that these approaches should be considered first-line treatments for chronic pain.

Components of Cognitive-Behavioral Therapy for Chronic Pain Several widely used CBT treatment protocols have been developed to bring together the various psychosocial interventions into a coherent approach for treating chronic pain.15,16 Treatment involves a comprehensive psychosocial assessment that is used to guide treatment planning. The assessment focuses on an individual’s pain history, along with psychosocial factors that may be impacting their pain experience. Providers use this assessment as an opportunity to tailor their treatment approach to the needs of the patient. The main components of CBT-CP typically include the following: • Chronic pain psychoeducation to inform patients about the biopsychosocial model of chronic pain, to introduce the components of treatment, to address common barriers to treatment, and to increase self-efficacy for engaging in new pain self-management behaviors • Relaxation techniques for stress management and to decrease muscle tension • Behavioral activation coupled with time-based pacing to encourage 4334

increased engagement in pleasant, physical, social, and otherwise meaningful activities while reducing the likelihood of experiencing a painful flare-up and excessive fatigue • Sleep hygiene to improve sleep quality and to improve daytime alertness and activity • Cognitive restructuring to identify and address maladaptive thought patterns and develop strategies to promote adaptive cognitions • Communication skills to help improve and increase positive social interactions and reduce solicitous pain behaviors from family and friends • Maintenance and relapse prevention to increase self-efficacy for using the pain self-management techniques developed in treatment, to address potential barriers and specific difficulties to using these techniques over time Treatment protocols for CBT-CP are most often tailored for individual therapy, although it has also been adapted into a group therapy approach, as is employed in some pain rehabilitation programs (PRPs). Family members and close friends may also be engaged in treatment to address communication skills and reinforce behavioral activation. Adaptations have also been developed to increase access to CBT for pain, such as delivery via telehealth.

CHRONIC PAIN PSYCHOEDUCATION The dilemma of chronic pain and its often intractable nature is that it is poorly understood, frustrating, isolating, and confusing for patients, families, and medical providers. A paramount structural element of CBTCP is psychoeducation. Like many educational approaches, this can be efficiently and effectively accomplished in a group setting. The interaction with other group members, realizing one is “not alone” in their chronic pain, hearing similar questions and concerns, and the repetition of complex material are invaluable elements in the psychoeducational model. The isolation of chronic pain and the feeling that no one else has similar struggles is directly eliminated with this group-based approach. In addition to normalizing the patient’s symptoms and experience, the major benefit of the psychoeducational approach is that it can foster motivation and 4335

sustained change.17–20

Education about the Neurobiology of Chronic Pain Successful psychoeducational approaches incorporate information about the neurobiology of pain. This includes description of the differences between acute pain and chronic pain and an explanation of central sensitization. Central sensitization is the process by which many chronic symptom conditions are thought to be (1) precipitated and (2) maintained in the central nervous system.21 The primary goal is to convey to the patients, in an understandable format, how their pain transitioned from acute to chronic, a rationale for how to manage the problem and direction for improving future functioning. Beginning with the physical origins of their problem can remove the stigma that chronic pain is purely psychological or “made up.” For example, starting with education about central sensitization followed by an explanation of how treatment can be delivered in the following simplified format: “The main precipitating factor to the development of central sensitization is a pain signal that lasts longer than it should or greater than 3 months (definition of chronic pain).” This causes an upregulated pain signal from the body and a sensitized pain receiver in the brain. As a result of these changes, four responses to chronic pain logically follow: (1) physical deconditioning, (2) emotional distress, (3) behavioral dysregulation, and (4) chemical use. Pivoting from the causative focus and instead looking at these four factors begins to shape the emphasis of the CBT model. All patients benefit from physical reconditioning to improve endurance, strength, and ability to do daily activities. Treating the emotional distress of chronic pain incorporates CBT strategies for stress, anxiety, depression, and anger management. Reducing emotional distress has obvious psychological and social benefits but is also associated with reduced symptom burden.22 Two major behavioral issues are also introduced during the psychoeducational sessions: overactivity followed by prolonged recovery (“pushing and crashing”) and pain behaviors. Patients are educated that addressing both of these behavior patterns yields less distress and fewer symptoms.

Resetting Expectations about the Outcomes of Chronic Pain 4336

—the A-B-C Model It is not uncommon that a patient with chronic pain will lament, “I wish I could go back to the way I was before having chronic pain.” In fact, the current medical approach to chronic pain (i.e., offering repeated trials of medications, interventions, and surgeries to “cure” chronic pain) actually fosters this belief that somehow, with enough trials, a cure for one’s pain is waiting to be found. For many patients with chronic pain, this will not be the case. The Mayo Clinic’s Pain Rehabilitation Center, Florida (MCPRCF) uses the A-B-C model of the chronic pain experience (Table 84.1). This model illustrates and validates the patient experience and serves as a foundational explanation of the way people change as they experience the suffering of chronic pain. The “A” version is the person’s functional status before his or her pain symptoms became chronic. This version is generally characterized by independence, productivity, fitness, and social engagement. The “B” version is the patient’s functional status with chronic pain. This version is characterized by “pushing and crashing,” reliance on medication or interventions, decreased independence and productivity, deconditioning, and more emotional distress. The goal of CBT for pain is to help the patient move toward the “C” version of functioning. The “C” version is characterized by increasing fitness, independence, productivity, and mood, with additional emphasis on acceptance, moderation, flexibility, and stability.23 TABLE 84.1 A-B-C Versions of a Patient with Chronic Pain A—Pre-Pain

B—Pain

C—Post–CBT-P

Active Productive Social Motivated Independent

Depressed Deconditioned Discouraged Drugged Dependent

More active More productive Stable Moderation More independent

CBT-P, cognitive-behavioral therapy for pain.

This model has been an effective clinical tool to educate patients, providers, and family members about the trajectory of treatment. When teaching this model, specific emphasis is placed on the linearity and intentional movement from the “B” version to the “C” version. This 4337

concept allows for the discussion that returning to the “A” version is no longer possible, and continued emphasis and expectations in that direction are counterproductive.

Changing Behaviors—SMART Method One final element from a behavior therapy perspective is the implementation of goal setting. Using the A-B-C model outlined previously, patients can be shown how their goal setting behaviors were likely altered by their chronic pain. Persons who could previously set and achieve goals easily often find themselves at a loss for how to effectively do so in their “B” version. With the unpredictability of symptoms and decreased functional capacity, goal setting can become frustrating and futile. One common method to reinstitute effective goal setting is to use the SMART method.24 The SMART acronym stands for Specific, Measurable, Attainable, Relevant, and Time bound. Adapted from business management, this model is easy to explain and translates well to the needs of a chronic pain patients. This model can be implemented during treatment and then modified as needed after treatment has ended. The element patients seem to struggle with the most is M—Measurable. Often, a brief explanation about behavioral coding and having the patient determine if the goal is a discrete activity or an ongoing one (i.e., posture, attitude). If it is an ongoing activity, then instructing them in the use of time sampling can be helpful. Although comprehensive, psychoeducation is a critical foundation for CBT-CP. In our current health care model, patients with chronic pain are often fearful and skeptical about trying an intervention that does not involve medications or interventions and concerned that engaging in CBTCP will mean that their pain is “in their head.” Spending the time to provide education to the patient about chronic pain and how CBT-CP can address the neurobiology of pain is essential for getting patients engaged in this evidence-based treatment.

RELAXATION TECHNIQUES Relaxation training was one of the earliest techniques to be integrated into CBT-CP treatment protocols. Clinicians use relaxation training to help 4338

individuals become more aware of sympathetic arousal that likely increases their pain severity and then induce a relaxation response to counter the effect of this arousal. Although these techniques may be used with biofeedback, it is important for individuals to recognize that they can be used independent of costly equipment or the assistance of a biofeedback specialist. Relaxation techniques should be presented as an active pain management strategy that individuals should practice regularly and utilize when needed. It is important for the clinician to explain relaxation training as a specific technique that actively induces a relaxation response because some people may interpret relaxation as just passively resting. It is often very easy for individuals with chronic pain to recognize life stressors that relate to their chronic pain experience, although it may be more challenging for them to recognize the mind–body connections that impact physical sensations through sympathetic arousal (i.e., muscle contraction, dilation of the pupils, constricted blood flow to many parts of the body, and increased heart and breathing rates). Individuals will often see how prolonged stress can lead to fatigue, poor sleep, and tension in their muscles. Having individuals experience a relaxation response is often a helpful step in helping them recognize that they can take an active role in managing their chronic pain complaints. Although there are many relaxation techniques used in clinical settings, we focus on some of the most commonly used techniques in this section. Herbert Benson25 is often credited with popularizing relaxation techniques with his book The Relaxation Response in 1975. He systematically looked at ways to counter the sympathetic arousal through meditation. His work has promoted relaxation techniques such as diaphragmatic breathing, progressive muscle relaxation, guided imagery, autogenic training, and other meditation techniques. There are several useful guidelines for individuals engaging in these techniques to follow. It is often recommended that individuals beginning this practice should find a quiet location that is free from distractions. Individuals new to these techniques often benefit from being guided through the induction by someone else. Although this was traditionally done by a clinician, there is a wide array of audio and video recordings that are also helpful. It is often helpful to instruct individuals to begin using these techniques at a quiet 4339

time when they are more likely to experience the relaxation response. Later, they might try to use the relaxation techniques in more challenging situations. Diaphragmatic breathing is a simple technique that most individuals can master with regular practice. Individuals practicing this technique learn to recognize the sensation of contracting their diaphragm by engaging in slow, deep breaths paired with stomach and chest expansion. The parasympathetic drive is thought to override the sympathetic as the individual becomes more relaxed. In 1938, Edmund Jacobson26 published Progressive Relaxation to introduce his work with progressive muscle relaxation. This is a technique developed to increase neuromuscular awareness based on the idea that muscles respond to stressors with tension. Many chronic pain patients recognize muscle tension, stiffness, or chronic guarding of their muscles. This may lead to tension headaches, low back pain, temporomandibular joint disorder, and misaligned posture. Progressive muscle relaxation consists of a series of isometric muscle contractions followed by efforts to completely relax the muscles by focusing on one muscle group at a time. It is also common for individuals to combine diaphragmatic breathing techniques while doing progressive muscle relaxation. This process is thought to intercept the stress response through a direct and conscious inhibition of the excitatory neural drive to muscle fibers. Guided imagery is another commonly used relaxation technique. Individuals are instructed to close their eyes and use their cognitive skills to imagine a peaceful and relaxing place. Individuals are instructed to use each of their senses when creating this setting to include the sensory perceptions of sight, sound, touch, smell, and even tastes if possible. Individuals often benefit from a discussion of the place they intend to use prior to using this technique for the first time. Mindfulness meditation is another technique that has been effectively applied to chronic pain. Jon Kabat-Zinn27 first popularized the use of this technique for health conditions with his book Full Catastrophe Living. The purpose of this technique is to assist the individual to bring their attention to the present moment without having a specific judgment about the experience. This can be particularly challenging when an individual 4340

perceives his or her experience in that moment to be negative, such as focusing on the pain sensation. The body scan meditation is often a useful technique for chronic pain patients as it allows the individual to practice focusing attention on different areas of the body, including painful areas, without judgment. Mindfulness meditation is also a component of acceptance and commitment therapy (ACT), reviewed at the end of this chapter.

BEHAVIORAL ACTIVATION AND TIME-BASED PACING Many individuals with chronic pain come to treatment having developed a pervasive pattern of behavioral avoidance. Perhaps, the most important aim of CBT-CP is reducing this behavioral avoidance by enhancing individuals’ level of daily functioning and activity. To accomplish this goal, the behavioral activation component of treatment involves gradual exposure to previously avoided physical, recreational, and social activities. Behavioral activation has been most frequently used as a treatment approach for depression and generally involves increasing contact with valued and pleasurable environments and activities in order to provide more opportunities for reward and enjoyment.28 In chronic pain treatment, increasing activity engagement can help disconfirm negative expectations about pain and harm and disrupt the harmful cycle involving fear, avoidance, pain, and low mood.29 In order to help patients understand why increasing their activity level is important, they are first introduced to the concept of hurt versus harm. Many chronic pain patients believe that activities will lead to increased physical damage and increased pain. Although this belief is typically true for acute pain, it is almost always inaccurate when it comes to chronic pain. Patients are taught about kinesiophobia, or the fear of movement, and the negative impacts of avoiding activity on maintenance of pain and distress. The chronic pain cycle is reviewed in detail. Patients are encouraged to begin an exercise program (once they have been cleared by their primary care physician or other treating medical provider) in order to begin to reduce the unhelpful cycle of pain and avoidance. They are taught about the benefits of exercise in improving 4341

flexibility and strength, decreasing pain, and enhancing mood. Walking is the most commonly chosen physical activity because it is low impact and accessible to almost everyone. Swimming, biking, yoga, and other forms of exercise are also encouraged if preferred by the patient. Patients are asked to set a specific goal for walking (or other exercise program) and monitor their progress. For the patient suffering with chronic pain, it is important to couple behavioral activation with time-based pacing. Time-based pacing is a practical behavioral technique to help individuals to engage in physical activity while reducing the possibility of a painful flare-up or excessive fatigue. This technique is often introduced when a patient is first engaging in a rehabilitation program such as physical or occupational therapy, although it can be applied to any physical activity where a painful flare-up may occur. Individuals are encouraged to identify specific physical activities that are likely to lead to a painful flare-up and then develop timebased pacing schedules to use with these activities. The total time for the activity is interrupted by episodes of rest so that muscle groups can recover before resuming the activity again. It is also important to note that some patients who experience flare-up while sitting or lying down for extended periods of time can also apply time-based pacing. Individuals with chronic pain often decrease physical activity due to the negative consequences of a painful flare-up. The perception that future activity will then lead to a flare-up will often result in avoidance of physical activity. Time-based pacing can be used in a useful way to expose patients to reengaging in a physical activity. Individuals can build on the SMART goals that they set earlier in treatment to choose an activity and then develop a schedule that is achievable so that the activity is likely to be repeated (i.e., positive reinforcement). Time-based pacing builds on William Fordyce’s30 original behavioral modification techniques for physical activity where physical activity is rewarded, whereas prolonged inactivity is disregarded. In addition to physical activity, a later component of treatment involves increasing engagement in pleasurable activities. Due to pain and associated distress, many individuals begin avoiding social and recreational activities that they used to enjoy, which can further contribute to the cycle of 4342

decreased mood, reduced activity level, and increased pain. Patients are asked to consider pleasurable activities they would be willing to begin engaging in more frequently. To explore options, they are given a list of pleasant activities to choose from, or they can choose their own. They then create a specific plan for implementing these activities while utilizing their pacing skill to maintain a balanced approach to activity. For most individuals, getting back to valued and enjoyable activities that were previously avoided due to pain contributes to mood improvement and increased energy and motivation to stay active.

SLEEP HYGIENE Patients with chronic pain often report poor sleep due to their pain or associated anxiety. Chronic poor sleep contributes to low energy and reinforces the reduction in functioning often seen in the chronic pain cycle. The sleep hygiene component of treatment involves reviewing current sleep habits and providing basic education about sleep hygiene principles. Patients are encouraged to create a sleep-conducive environment, including minimal noise, a comfortable temperature, and appropriate light. They are guided to use the bed only for sleep (and sex), establish a calming bedtime routine, and set a regular sleep/wake schedule. Sleepinterfering behaviors are introduced and discouraged, including daytime napping, drinking caffeine after midday, consuming alcohol or a large meal prior to bedtime, and watching television or utilizing a laptop (or tablet/cell phone) in bed. Patients are taught to avoid clock watching and get out of the bed if unable to sleep. The use of relaxation techniques (introduced earlier in treatment) prior to sleep is encouraged, with a goal of reducing tension and inducing sleepiness. Additionally, the benefits of exercise are further reinforced by discussing the positive impact of daytime exercise on sleep quality. Finally, the connection between stress and sleep problems is reviewed. For many individuals, worries surface in the context of a quiet bed, which can interfere with sleep onset, so patients are encouraged to set aside time earlier in the day to engage in problemsolving and planning. After reviewing healthy sleep habits, patients select a few sleep behaviors to change and are instructed to monitor these behaviors and their impact on sleep over the next week. 4343

COGNITIVE RESTRUCTURING Cognitive therapy approaches are grounded in the theoretical and clinical work of Albert Ellis7 and Aaron Beck6 and were initially developed to treat anxiety and depressive disorders. These approaches are based on the premise that thoughts, emotions, and behaviors are interrelated. When individuals experience dysfunctional thoughts, they are very likely to then experience related negative emotions and maladaptive behaviors that lead to a mood disorder. Applications were later developed to address dysfunctional thoughts specific to the experience of living with chronic pain. Beverly Thorn’s9 work has been central in forwarding cognitive therapy as a treatment for individuals with chronic pain through her book Cognitive Therapy for Chronic Pain: A Step-by-Step Guide, second edition. Individuals with chronic pain may experience dysfunctional thoughts and beliefs related to their experience with chronic pain that impact their engagement in treatment. They may experience avoidance behaviors, catastrophizing, or become excessively focused on a cure. Cognitive therapy for chronic pain often begins by working with individuals to develop techniques to better identify dysfunctional or inaccurate thoughts related to their chronic pain experience. These thoughts are referred to as automatic because they happen so quickly that individuals are often not fully aware of their presence. In fact, it is more likely that individuals are aware of the shifts toward negative emotions that accompany these automatic thoughts, so they are asked to identify their thoughts that accompany strong negative emotions such as sadness, despair, guilt, fear, or anxiety. Thought records are a valuable tool for identifying automatic negative thoughts, and they are designed to be used outside of the therapy session where individuals are engaged in their daily routines. Individuals are first taught to begin by writing down their stressful events. They will then want to identify the subsequent physical and emotional changes that happen in connection to these events. Finally, they will record the automatic negative thoughts. It is important for individuals to have a reference to common dysfunctional thoughts to provide a reference for them to record their own experiences. A list of common dysfunctional thoughts and associated adaptive thoughts are listed in Table 84.2. 4344

TABLE 84.2 Common Pain-Related Thoughts Types of Unhelpful Thoughts

Examples of Unhelpful Thoughts

Examples of Helpful Thoughts

Catastrophizing: Believing something is the worst it could possibly be Should statements: Thinking in terms of how things should, must, or ought to be All or none thinking: Seeing things as “either or” or “right or wrong” instead of in terms of degrees Overgeneralization: Viewing one or two bad events as an endless pattern of defeat

When my pain is bad, I cannot do anything.

Even when my pain is bad, there are still some things I can do. There is no cure for chronic pain, but I can use skills to cope with my pain. Even if I am in pain, I can still be happy. There is always something that I can do to have a better quality of life. Although physical therapy did not help much before, maybe this time, it will help. I might as well try. Hurt does not equal harm.

Jumping to conclusions: Making negative conclusions of events that are not based on fact Emotional reasoning: Believing how you feel reflects how things really are Disqualifying the positive: Focusing on only the bad and discounting the good

My doctor should be able to cure my pain. I can only be happy if I am pain free.

I tried doing exercises for my back pain before, and it did not help. So, it is not going to help now. When I move, my back hurts, so it must be bad for me to move. I feel useless, so I am useless.

So what if I am doing more, I am still in pain.

Even though I cannot do all the things I used to do, it does not mean I cannot do anything. Doing more is important for me to live the life I want to live.

Used with permission from KM Phillips, PhD.

Cognitive restructuring is the next phase in this approach, and this is usually done in the subsequent visit. Once patients have better identified dysfunctional thoughts and beliefs related to their pain experience, they can begin to develop techniques to better test the reality of these thoughts and beliefs. Developing more adaptive thoughts will then lead to shifts in negative emotions and maladaptive behaviors. Individuals are asked to evaluate their thoughts to better determine the extent that their thoughts are correct or inaccurate. It is often important to note that there will likely be some degree of truth in their thoughts, although the thought becomes dysfunctional once the negative beliefs are overexaggerated. The individual can then come to a more balanced conclusion. Individuals are often encouraged to develop coping statements based on their adaptive 4345

thoughts that might help them remember this exercise when they experience stressful situations in the future.

COMMUNICATION SKILLS Communication style and content are important in CBT-CP, in the general management of chronic pain, and in the interactions between patients with chronic pain and their families. Much of the literature in this area focuses on physician–patient communication, but the themes conveyed in this literature apply to the management of the patient in general, including themes that may arise in CBT-CP regarding communication with and between family members and support system. It is known that words used to communicate with people suffering with chronic pain about their pain affect their outcomes. For example, words that carry strong, negative connotations have been hypothesized to increase probability that acute pain will progress to chronic pain.31 It has also been shown that expressed or perceived spouse criticism or hostility can worsen chronic pain symptoms, especially among women and patients with depression.32 Conversely, positive communication can also be a vital component of effective pain management and relief. For example, it has been shown that improvement in communication between a patient and his or her partner can improve pain severity and relationship discord.33 Approaches to improving family communication and support around chronic pain can be done formally not only through family therapy with specific feedback about communication styles and language33 but also through modeling provided from in-office patient–provider interactions and communication with the family member present. Modeling motivational interviewing strategies including the use of open-ended questions, questions that incite reflection, empathic statements, affirming change talk, and asking permission to share information is suggested and can be successfully adopted by family members.33 It is therefore important that the provider treating the patient with chronic pain utilizes and models effective communication during treatment. It has been shown that providing clinicians with communication training in the area of chronic pain increases patient satisfaction and that improved communication predicts improved patient satisfaction more than 4346

an actual decrease in pain score.31 When evaluating effective components of provider communication with patients with chronic pain, it has been shown that it is vital for a provider to listen to the patient’s pain history and show empathy in order to communicate that the patient’s pain is “real” and important. It is also helpful to couple validation of the patient’s pain experience with the acknowledgment that the provider may not have all the answers for how to manage chronic pain and working with the patient to gently accept that chronic pain may be an ongoing part of his or her life (e.g., there might not be a “cure”).34

MAINTENANCE AND RELAPSE PREVENTION Maintaining Treatment Gains An integral part of any CBT intervention is helping the individual maintain the therapeutic changes. This includes a strong emphasis on selfmonitoring and self-management as well as planning for future difficulties and setbacks. This is especially important for individuals with chronic pain. Their struggle with a diverse and complex set of issues makes maintenance planning essential. Whether done individually or in a group setting, there needs to be sufficient time and effort dedicated to maintaining treatment gains. For the sake of illustration, a group-based PRP is discussed. As mentioned elsewhere, a comprehensive pain rehabilitation approach includes physical therapy, occupational therapy, medication reduction, and CBT. The strength of this interdisciplinary approach is that the patient is exposed in an organized program to the elements that need to change for there to be an improvement in functioning. One of the core elements of successful maintenance is to help the individual be as independent as possible. This can be achieved by linking the active elements of treatment with how they translate to the home environment. The schedule and intensity of a PRP cannot and should not have to be replicated when the patient is discharged. However, incorporating elements of the program in the home is essential. What follows are examples from a CBT perspective of maintenance tools. There are three tools that are extensions of treatment goals that are 4347

addressed during the PRP: time management, exercise, and managing symptom flares. Before dismissal, the patient is asked to establish a 2week plan. This plan is designed to ensure continued engagement in moderation, exercise, daily activities, and self-care. They are also given a home-based physical therapy program that is a continuation of the exercises and behavioral activation done during treatment. The patient is asked to maintain this program for 3 months before advancing exercise. Finally, the patient is asked to make a plan for how to handle future symptom flares. This is done for several reasons: to normalize the possibility of flares after treatment, to have a preexisting plan and schedule to maintain functioning, and so the patient’s friends and family know what to do during the flare. The second set of maintenance strategies are more universal CBT principles that are applied to this population: stimulus control, social support, and reinforcement strategies. The use of stimulus control is a behavioral strategy to help an individual not return to previous behavior patterns by limiting exposure to “tempting” stimuli. An example would be having an ex-smoker “pay at the pump” for gas rather than go into the clerk where there are ample smoking-related cues. For pain patients, stimulus control could include avoiding retail pharmacies, limiting internet use (no more symptom/cure searches), and not returning to practitioners who were solely focused on symptom relief. Social support as a maintenance strategy is extremely important. Patients need several types of support to ensure ongoing treatment success. The primary support group, friends, and family are coached and encouraged to support the behavioral changes, stop symptom-focused talk, and remain neutral to any remaining maladaptive behaviors. In addition, patients are encouraged to increase community involvement, volunteering, school, work for distraction, other focus, and opportunities for new relationships. Finally, it is recommended that patients establish someone to be accountable to regarding adherence to the exercise and activity management. Lastly, incorporating some form of reinforcement for treatment adherence is strongly recommended. Having the patient set up a reward system (e.g., weekly cash deposits to a vacation/gift account for every 4348

week that exercise was done) can add some incentive to the maintenance process.

THIRD-WAVE THERAPIES—ACCEPTANCE AND COMMITMENT THERAPY Third-wave interventions include such treatments as ACT, mindfulnessbased cognitive therapy (MBCT), and dialectical behavior therapy (DBT), among others. As applied to chronic pain, third-wave interventions focus less on controlling pain or changing maladaptive pain-related thoughts and emotions and more on mindful awareness of internal processes and living well despite pain. ACT,35 which can be considered a treatment within the family of CBT, is one of the more commonly employed and well-studied third-wave intervention for chronic pain.36 In general, ACT focuses on behavior change and psychological flexibility rather than symptom (i.e., pain) reduction. Psychological flexibility is broadly defined as the ability to remain in contact with present moment experiences (both internal and external) in a way that allows behavior to continue or change consistent with one’s goals and values.37 When applied to chronic pain, ACT aims to help individuals respond more flexibly to pain and distress, reduce unhelpful attempts to control pain, and increase engagement in behaviors that are consistent with one’s goals and values.38 Thus, individuals are guided to alter their expectations from pain elimination to living a “valuesbased” life despite pain. Important components of treatment typically include exploration of personal values, examination of the ways in which struggling with pain prevents engagement in values-based behaviors, and choosing specific behavioral goals in line with one’s values. Mindfulness practices are employed with an aim of enhancing present moment awareness of thoughts, sensations, emotions, and behaviors in order to enhance psychological flexibility. With regard to the cognitive component of treatment rather than teaching patients to challenge and change irrational thoughts about their pain or abilities, which is often difficult, patients are guided to mindfully notice and “defuse from” these thoughts in a way that allows them to engage in values-based activities anyway. In other words, the focus is less on trying to control thoughts and more on 4349

disallowing thoughts from controlling them, whether that process involves a natural restructuring of the thought or not. Additionally, ACT typically involves less of a didactic approach and more experiential, or practicebased, components within sessions.36 A recent systemic review and meta-analysis of 11 clinical trials found that ACT for chronic pain is effective in increasing pain acceptance, improving functioning, and reducing depression and anxiety.39 Research comparing CBT and ACT is limited but has generally found few differences, suggesting that either approach is appropriate. One randomized clinical trial comparing ACT to CBT found that both treatments decreased depression, anxiety, and pain interference (i.e., improved functioning), and those assigned to the ACT condition reported higher levels of satisfaction.40

TREATING COMORBID CONDITIONS Chronic pain and mental health disorders frequently co-occur,41 and it is important to manage both conditions in order to optimize recovery for patients with chronic pain.

Depression and Anxiety The link between chronic pain and depression has been well established in the literature.42 In fact, chronic pain and depression are the most commonly occurring physical and psychological conditions, respectively, with co-occurrence rates of 30% to 50%.43 Their link is sometimes referred to as the depression–pain dyad, or depression–pain syndrome,44 given their frequent co-occurrence, tendency to respond similarly to medical and behavioral treatments, and overlap in neurobiologic underpinnings.42 The link seems to be particularly strong for pain conditions without a specific origin; for example, individuals with fibromyalgia are 3 times as likely to have a major depression diagnosis than individuals without fibromyalgia.45 Research has also demonstrated a link between pain and anxiety, with 35% of chronic pain patients having an anxiety disorder diagnosis compared to 18% of the general population.46 Unfortunately, depression and anxiety have historically been associated with poorer pain treatment outcomes.47–49 4350

As discussed earlier in this chapter, CBT was originally developed and evaluated as a treatment for emotional disorders.6 Thus, the treatment is well suited for chronic pain patients with depression and/or anxiety, as the intervention directly targets cognitions and behaviors that influence affect. The link between physical and emotional factors is explained to patients from the onset of treatment through education about the pain cycle and is repeatedly reinforced throughout treatment. Accordingly, meta-analyses have demonstrated that CBT-CP has a significant impact on both pain outcomes as well as depression and anxiety symptoms.10 Aggressive treatment of both depression and anxiety to remission is important, as coping with chronic pain can be particularly challenging among patients with active mood disturbance.

Posttraumatic Stress Disorder Chronic pain also frequently co-occurs with posttraumatic stress disorder (PTSD). Studies have shown that 34% to 50% of patients seeking pain treatment also have PTSD,50 and 45% to 80% of patients seeking PTSD treatment also have chronic pain.51,52 The conceptual relationship between PTSD and pain has been explained via the “shared vulnerability” model, which proposes that the fear of physical symptoms predisposes patients to both pain and PTSD as well as the “mutual maintenance” hypothesis, which suggests that pain triggers traumatic memories, and traumatic hyperarousal worsen pains.53 The link between pain and PTSD has been widely studied in the military veteran population in particular, given the physical and emotional trauma that is often endured in battle.54 Thus, many veterans, including those from the most recent Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn (OEF/OIF/OND) era, return from deployment with both physical pain and posttraumatic stress symptoms.55 Given the frequent co-occurrence and shared fear-avoidance-based vulnerabilities of PTSD and chronic pain, CBT-CP can be appropriately utilized with patients who also have PTSD.56 Although the specific trauma is not specifically processed or targeted in traditional CBT-CP, the cognitive restructuring, emotional processing, and behavioral skills patients learn in the treatment can be generalized to aid in recovery from 4351

PTSD along with chronic pain.56 Recently, integrated cognitive-behavioral treatments have been developed to concurrently address both PTSD and chronic pain among veterans,54 and preliminary data shows therapies incorporating behavioral activation can benefit both pain and PTSD.

COGNITIVE-BEHAVIORAL THERAPY WITHIN INTERPROFESSIONAL PAIN PROGRAMS AND PAIN REHABILITATION PROGRAMS The broad and diverse impact of chronic pain on physical impairment, emotional distress, and social dysfunction can make chronic pain management overwhelming for individual health care providers. This phenomenon has been recognized from the earliest days of pain medicine and has led to the development of the interprofessional team-based approach as the standard of care for chronic pain management. PRPs, which employ an interprofessional approach (psychology, physical therapy, occupational therapy, medical treatment) in an intensive outpatient setting, are reviewed separately,17 but it is worth noting the recent renewed interest in PRPs in the midst of this nation’s opioid crisis. Historically, the number of interprofessional pain programs dramatically decreased from over 1,000 programs in the United States in 1999, when they were at their highest number, to approximately 90 programs in 2015 (this number does not include military and the veterans’ administration centers).57 Much of this decrease can be attributed to the rise in the use of opioid analgesics and economic forces favoring interventional pain management.58 The culture of diagnostic and interventional pain management at the time had as its premise, “help the patient to feel better so they can function better.” This message has inadvertently led to frustration, patient blaming, and assumptions of psychosomatics and has directly fed the opioid epidemic we are currently battling. As prescriptions for opioid analgesics are now being curbed across the nation, there is now a renewed national interest in PRPs. In fact, the CDC guidelines for pain in 201613,14 cited PRPs as an evidence-based alternative to using opioids for chronic pain.

Effectiveness of Interprofessional Pain Management 4352

Programs and Pain Rehabilitation Programs The treatment outcomes of the interprofessional pain programs and PRPs have been well documented and studied and have been shown to improve pain,59–64 mood,59 physical functioning,60 and return to work18,59,65 and have been shown to decrease medication use59 and health care utilization and costs.20,59,66,67 There have been multiple meta-analytic and systematic review types of studies summarizing the effects of interdisciplinary programs and PRPs and their effects on different chronic pain conditions,61,68,69 and showing effects were durable on pain, mood, employment, and general health, evident even after 13-year follow-up.19

COGNITIVE-BEHAVIORAL THERAPY TO PREVENT THE TRANSITION FROM ACUTE TO CHRONIC PAIN Close to one-third of acute low back pain patients report continued moderate to severe pain 1 year later.70 Given the high morbidity and health care costs associated with chronic pain, identifying interventions helpful in reducing the progression of acute to chronic pain could greatly reduce burden of disease, disability, and associated health care costs. There has been appreciable literature identifying psychosocial risk factors for developing chronic pain, such as pain catastrophizing,71,72 fear-avoidance beliefs,72–75 and depression.76,77 Additionally, the complex interaction between pain and disability can be associated with additional risk factors, such as self-reported pain and disability, personality traits, and worker’s compensation or personal injury status.78 The definition of acute and subacute pain varies in the literature from control for majority of outcomes. Group = individual for depression and most other measures. Larger effect sizes for group compared to individual at f/u.

Session duration not specified

6 mo

Rose et al.13

84 with chronic low back pain

RCT

Part 1: group CBT (N = 26) vs. individual CBT (N = 24) Part 2: compared 15h (N = 22), 30-h (N = 22), or 60-h duration treatments

Education, cognitive therapy, graded aerobic exercise, relaxation

15, 30, or 60 h duration

VAS pain severity scale (0 to 100), RolandMorris Disability Questionnaire, Modified Somatic Perception Questionnaire (MSPQ), Modified Zung

Individual = group treatments on outcome measures. Individual treatment more strongly associated with changes in disability and on MSPQ. No differences in program

No control for baseline differences on some variables

6 mo

4444

Depression Inventory, Pain Locus of Control Scale, Pain SelfEfficacy Questionnaire

duration on outcome.

Johnson and Thorn14

22 with headache

RCT

Group CBT (GCBT) (N = 7) vs. individual CBT (ICBT) (N = 7) vs. wait-list control (WLC) (N = 8)

Psychoeducation, cognitive coping strategies, relaxation

5 weekly 90min sessions

McGill Pain Questionnaire (MPQ), Brief Symptom Inventory (BSI), selfmonitoring cards (for pain intensity, number of prescribed medications, number of OTC medications, number of prescribed pills consumed, number of OTC pills consumed)

Improvement in pain ratings and decrease in anxiety across groups from Times 1 to 2. Decreases in number of times individuals took medication and in number of different medications taken. GCBT = ICBT overall

Small sample size, limited power

1, 3, and 6 mo

Spence15,16 (2-y f/u)

45 chronic workrelated pain of the upper extremity (19 followed at 2 y)

RCT

GCBT (N = 13) vs. ICBT (N = 14) vs. WLC (N = 15)

Goal setting, cognitive restructuring, relaxation, cognitive skills training, dealing with sleep problems, assertiveness training

9 weekly sessions at 1.5 h

BDI, STAI, Coping Strategies Questionnaire (CSQ), McGill Pain Rating Index (PRI), Sickness Impact Profile (selfreport and otherreport) Daily SelfMonitoring

GCBT and ICBT > WLC for reductions on all outcome measures. Improvements maintained at f/u. GCBT = ICBT 2-y f/u: less relapse for GCBT for pain ratings and interference, GCBT = ICBT for other outcomes

Small sample size, limited power

6 mo, 2 y

aInformation

obtained from English abstract only. CBT, cognitive-behavioral therapy; ITT, intention-to-treat; NRS, Numerical Rating Scale; OTC, over-the-counter; PCS, Pain Catastrophizing Scale; QOL, quality of life; RCT, randomized controlled trial; TAU, treatment as usual; VAS, visual analog scale.

One of the earliest RCTs comparing group to individual treatment14 found no differences in outcome between the two modes of treatment for headache patients with the exception that at the 6-month follow-up, participants in the group condition showed less of a tendency to drift back toward baseline levels of pain ratings. Because participants knew prior to treatment that they would be randomly assigned to group or individual treatment formats, posttreatment interviews queried their perceptions regarding the treatment modality to which they were ultimately assigned. Patients in group treatment highlighted the benefit of being able to share 4445

openly with other headache sufferers and to discuss their progress with others in the group. Patients in individual treatment valued the personalized attention given via the dyadic therapeutic relationship and expressed concern that group treatment would not have offered sufficient therapist time for each individual. Thus, patients who participated in each treatment modality seemed to highlight the positive aspects of the treatment modality to which they were assigned as the reasons why this would be the preferred mode of treatment. Another early RCT focusing on patients with pain in the upper extremities also demonstrated minimal overall differences between individual and group treatment.15 At 6-month and 2-year follow-up, those who received the group treatment reported less pain-related interference than those who were treated individually, and treatment outcome was otherwise equally efficacious.15,16 It is interesting to note that posttreatment satisfaction ratings were higher for individually treated patients, and individual treatment was more effective than group treatment on the outcome measure of self-reported coping strategies. One limitation of these early RCTs, however, was the relatively low number of participants in each condition, which limited the statistical power. A benefit of the studies was the collection of patient satisfaction data. Several later trials confirmed these general findings. In patients with chronic low back pain, Rose et al.13 reported few differences in an RCT comparing patients treated individually and those treated in groups. Another RCT by Kääpä et al.10 examined group-delivered multidisciplinary treatment compared to individual physiotherapy for chronic low back pain and found few differences in outcome immediately following treatment and at 6-, 12-, and 24-month follow-up; however, this study was limited by design features with the two conditions receiving different treatment doses and intervals. In a sample of patients with mixed chronic pain, Frettlöh and Kröner-Herwig12 also found few statistically significant differences in treatment outcome between individual and group modalities, although the effect sizes in improvement at follow-up suggested that group treatment may have been superior to individual treatment.12 In another RCT of individuals with mixed chronic pain, Turner-Stokes 4446

et al.11 compared outpatient group and individual therapies and found that both treatments resulted in improvements on measures of depression, anxiety, medication consumption, general activity, and pain severity. Those treated in a group showed greater initial gains than those treated individually, but these treatment differences were not sustained over time. Patients treated individually showed slower initial gains but evidenced the same benefits as those who had been treated in a group at the end of treatment. These authors also reported less of a tendency for the treatment gains made by individually treated patients to drift back toward baseline over time. In this study, however, group treatment was delivered for more hours at a time and over a shorter duration (8 weeks) than individual treatment (spread over 16 weeks), and this difference could explain the slower treatment gains witnessed with the individually treated patients. Finally, one recent RCT compared group-delivered, in-person CBT to individual, Internet-delivered CBT.9 The results showed that both formats resulted in significant improvements across a number of important painrelated outcomes, with the Internet-delivered condition outperforming group therapy on some domains in the completer analyses, although the longevity of these effects was not fully examined. Other research now in progress is examining the utility and efficacy of group-delivered telepain management programs that implement videoconferencing interfaces; these innovative delivery platforms have the potential to improve access to CBT in the future.17 Overall, the research comparing group to individually delivered treatment has generally concluded that there are very few meaningful differences between outcomes resulting from group and individually administered treatments for chronic pain.

GROUP COGNITIVE-BEHAVIORAL THERAPY VERSUS WAIT-LIST, TREATMENT AS USUAL, OR OTHER GROUP TREATMENTS Table 87.2 summarizes the controlled studies that have compared the effects of group-administered CBT to wait-list control conditions, treatment as usual conditions, or other group treatments such as relaxation, education, or supportive/expressive group therapy.18–64 Trials comparing CBT to MBIs and ACT are reported in Tables 87.3 and 87.4, respectively. 4447

There are an impressive number of controlled trials that have been carried out by different research groups focusing on different populations of individuals with pain that together establish the efficacy of CBT for chronic pain. Systematic reviews of these trials have been conducted that include both individual and group-delivered CBT formats across pain types and in children and adult populations; due to space limitations, not all of the studies reported in these reviews are included here.7,8,65,66 In most cases, RCTs that compared group CBT to other types of group treatments also included a wait-list condition to control for the natural progression of the chronic pain disorder. In the following text, we highlight findings from select studies reported in Table 87.2 comparing group CBT to other types of group treatment because they have played an important role in identifying the effects of CBT; later in this chapter, we also describe a selection of studies that have examined the mechanisms underlying CBT treatment efficacy.

4448

TABLE 87.2 Group Cognitive and Behavioral Therapy Studies Treatment Type

Treatment Components

RCT

Literacyadapted CBT (n = 95) vs EDU (education) (n = 97) vs. treatment as usual (TAU) (n = 98)

CBT: psychoeducation, cognitive restructuring, activity pacing, relaxation, motivational reinforcement EDU: painrelated information provided, no specific skillsbuilding exercises

Ten 1.5-h weekly sessions

111 with knee osteoarthritis, aged 35– 75 y

RCT

CBT (n = 55) vs. medical TAU (n = 56)

CBT: psychoeducation on pain, problemsolving skills, relaxation, scheduling activities, cognitive appraisals and beliefs, assertiveness training

Linden et al.20

103 with chronic low back pain

RCT

CBT (n = 53) vs. unspecified occupational therapy (OT; n = 50)

Semino -wiczet al.21

13 with mixed chronic pain vs. 13

Nonrandomized trial

CBT (n = 13)

Authors

N

Study

Thorn et al.18

290 with mixed chronic pain

Helminen et al.19

Duration

Outcome Measures

Follow up (f/u)

Results

Limitations

Brief Pain Inventory intensity and interference, Patient Health Questionnaire-9

CBT = EDU at posttreatment, both > TAU on pain intensity and physical function; gains in intensity maintained at f/u for EDU but not CBT, gains in physical function maintained for both CBT and EDU. No significant changes in depression.

Participants were recruited from a single health care system, so a selfselection bias was possible.

6 mo

Six 2-h weekly sessions

Western Ontario and McMaster Universities Osteoarthritis Index Pain Scale, Pain Self-Efficacy Questionnaire, RAND36 emotional well-being, Pain Catastrophizing Scale, Tampa Scale for Kinesiophobia (TSK), Beck Depression Inventory (BDI)

CBT = TAU on pain and function; CBT > TAU on well-being, TAU > CBT on selfefficacy. No significant differences at f/u.

Lack of fidelity monitoring, low recruitment to enrollment rate; baseline selfefficacy was high at baseline for both groups.

3 mo 12 mo

All participants treated for 21 d in an inpatient interdisciplinary rehabilitation unit. In addition: CBT group: gate control theory, stress reduction, problem solving, selfmonitoring, cognitive restructuring, reducing avoidance, increasing activities, relaxation OT: additional OT sessions, playing games, motivated to engage in activities

Six 90-min sessions (3/wk)

Symptom Checklist-90, Rating of Health Locus of Control Attributions, Fear Avoidance Belief Questionnaire, VAS pain

All outcomes significantly improved in both groups; CBT > OT on pain and fear avoidance beliefs.

Lack of fidelity monitoring; effect of CBT in isolation from other interdisciplinary treatments not established; no f/u

—

Self-regulatory skills such as relaxation, cognitive coping

Eleven 1.5-h weekly sessions

Structural neuroplasticity (i.e., gray matter, GM), McGill Pain

Increased GM post-CBT in the bilateral dorsolateral prefrontal,

Small sample size; no comparison or randomization; lack of

—

4449

healthy and agematched controls (baseline only)

strategies such as cognitive restructuring, attention diversion methods, activity pacing, scheduling pleasant events, exercise, methods for enhancing social support

Questionnaire -ShortForm, Treatment Outcomes in Pain Survey, ShortForm Health Survey (SF36), BDI, Coping Strategies Questionnaire

posterior parietal, subgenual anterior cingulate/ orbitofrontal, and sensorimotor cortices as well as hippocampus; reduced GM in supplementary motor area. Most increases in GM became significantly greater than GM in controls. CBT-related reductions in pain catastrophizing and increases in pain control were correlated with several of these regional GM changes.

f/u

SlavinSpenny et al.22

147 with mixed headaches

RCT

Anger awareness and expression training (AAET; n = 50) vs. relaxation (n = 48) vs. WL (n = 49)

AAET: psychoeducation on stressheadache connection, experiential exercises for emotional awareness, assertive communication Relaxation: psychoeducation on stressheadache connection, progressive muscle relaxation, deep breathing, brief relaxation

Three 1-h weekly sessions

Self-Assessment Manikin, Headache Management Self-Efficacy Scale, Toronto Alexithymia Scale, Rathus Assertiveness Schedule, Emotional Approach Coping Scales, Migraine Disability Assessment Scale, headache frequency, severity and duration, Brief Symptom Inventory

AAET = relaxation on self-efficacy and headache outcomes, both > control. AAET significantly improved alexithymia, emotional processing, and assertiveness, compared to the other two conditions.

Lack of f/u; lack of fidelity monitoring; use of a college sample limits generalizability; no headache diagnostic information obtained; no daily diaries of headache outcomes

—

Heutink et al.23

61 with neuropathic pain after SCI

RCT

CBT (n = 31) vs. WL (n = 30)

CBT: psychoeducation, ABC model, stress, movement and pain, assertiveness, relaxation, goals, social aspects; significant other attended first 2 sessions

Ten 3-h sessions over 10 wk and booster session 3 wk posttreatment

Chronic Pain Grade Questionnaire, Hospital Anxiety and Depression Scale, Utrecht Activities List, Life Satisfaction Questionnaire

CBT = WL on intensity and disability; CBT > WL on anxiety and participation in activities

Small sample size

3 and 6 mo

Thorn et al.24

83 with mixed chronic pain

RCT

Literacyadapted CBT (n = 49) vs. EDU (n = 34)

CBT: stresspain connection, automatic thoughts, challenging automatic thoughts and beliefs, relaxation, coping statements,

Ten 1.5-h sessions over 10 wk

Brief Pain Inventory, RolandMorris Disability Questionnaire (RMDQ), Pain Catastrophizing Scale, Center for Epide-

CBT = EDU; completer analysis showed CBT > EDU on catastrophizing and depression. Gains maintained at 6-mo f/u

Higher dropout rate in CBT; underpowered to detect effects of CBT compared to active treatment

6 mo

4450

expressive writing, assertive communication EDU: psychoeducation on chronic pain treatment, gate control theory, costs of pain, acute vs. chronic pain, sleep, mood changes, pain behaviors, communication, working with health providers

miologic Studies Depression Scale, Quality of Life Scale

Lamb et al.25

701 with subacute or chronic low back pain

RCT + costeffectiveness

Active management consultation + CBT (n = 468) vs. active management consultation only

Active management: active advice on remaining active, avoiding bed rest, medication/ symptom management, also provided with The Back Book CBT: challenging negative thoughts and beliefs, pacing, graded activity, relaxation, activity, and avoidance

Active management: 15 min CBT: an individual 1.5-h assessment, six 1.5-h CBT sessions

Change in RMDQ and modified Von Korff scores at 12 mo

Consultation + CBT > consultation only on both primary outcomes; inclusion of CBT > costeffectiveness

CBT delivered by a range of professionals with a 2d training (physiotherapists, nurses, occupational therapists, psychologists)

12 mo

Van Koulil et al.26

158 with fibromyalgia (FM)

RCT

Tailored CBT + exercise training vs. wait-list control

Pain avoidance or pain persistence treatment based on baseline cognitivebehavioral pattern Patient’s significant other attended 3rd, 9th, and 15th sessions

16 sessions of CBT (2 h) + exercise training (2 h) over 10 wk and 1 booster session at 3 mo

Pain, fatigue, functional disability, negative mood, and anxiety scales of the Impact of Rheumatic Diseases on General Health and Lifestyle (IRGL), Pain Coping Inventory

CBT + exercise > WL on all primary outcomes, with large effect sizes

Did not compare “tailored” to nontailored treatment; inert comparison

6 mo

Falcão et al.27

60 females aged 18– 65 y with FM

RCT

CBT (n = 30) vs. TAU (n = 30)

CBT: relaxation training, cognitive restructuring, stress management

CBT: 10 weekly 3-h sessions

VAS for pain, SF-36, StateTrait Anxiety Inventory, BDI, Fibromyalgia Impact Questionnaire, paracetamol

CBT > TAU on improved depression, mental health, and paracetamol. Both groups showed significant improvements on all indicators over time.

Dropouts were excluded from the analyses; limited f/u; participants had not received any prior treatment.

3 mo

Ersek et al.28

256 with noncancer pain, ≥65 y

RCT

Pain selfmanagement (n = 133) vs. EDU (n = 123)

Selfmanagement: education about persistent pain, problem solving, exercise for pain, relaxation training,

Self-management, 7 weekly 90min group sessions

Primary: RMDQ. Secondary: Geriatric Depression Scale, Brief Pain Inventory (intensity and interference)

Pain selfmanagement = EDU at post-treatment and 6- and 12mo f/u. Use of relaxation and exercise/ stretching significantly increased in

The number of strategies covered in self-management may have limited effectiveness.

6, 12 mo

4451

pacing and activity scheduling, challenging negative thoughts, medication management, hot/cold packs EDU: read an assigned book, The Chronic Pain Workbook or Managing Your Pain Before It Manages You

selfmanagement

Thorn et al.29

34 with headache

RCT compared order of treatment modules

CBT (N = 22) vs. WLC (N = 11)

Cognitive restructuring, cognitive coping, relaxation, assertiveness, behavioral pacing, homework

Ten 90-min group sessions

Pain Catastrophizing Scale (PCS), Pain Anxiety Symptoms Scale (PASS), Beck Depression Inventory–II (BDI-II), Headache Management Self-Efficacy Scale (HMSE), pain and medication via pain diaries; no difference in outcome based on order of treatment

CBT > WLC for improvements in catastrophizing, anxiety, headache management self-efficacy. 50% treated patients showed clinically significant reductions in headache frequency, medication use.

Small sample size rendered limited power to detect potential differences in order of treatment modules.

6, 12 mo

Li et al.30

64 with workrelated injuries

RCT

Training on work readiness (T) (N = 34) vs. control (C) (N = 30)

T: individual vocational counseling (3 sessions), CBT, pain and stress management, relaxation, stages of change assessment, job acquisition, preemployment training

T: 3 weekly group sessions at 2–3 h, three 1-h individual sessions

Spinal Function Sort (SFS), Loma Linda University Medical Centre Activity Sort (LLUMC), Chinese Lam Assessment of Stages of Employment Readiness (CLASER), Chinese State Trait and Anxiety Inventory (CSTAI), SF-36

T > C for improvements in anxiety, work readiness, readiness to change, and perceived health status T: within-group improvements from baseline for most SF-36 subscales and physical capacity

Lack of f/u, stages of change may require longer time period for assessment

None specified

Linton et al.31

185 workers with back/ neck pain

RCT

CBT (N = 69) vs. CBT and physical therapy (CBT PT) (N = 69) vs. minimal treatment (N = 47)

CBT: problem solving, homework, skills training, stress management, relaxation CBT + PT: CBT plus personalized exercise program Minimal: medical visit and advice, educational booklet

6 weekly 2-h sessions

Sick absenteeism, health care visits, Outcome Evaluation Questionnaire, VAS pain ratings, HAD, PCS, TSK, activities of daily living (ADLs), RMDQ

CBT + PT = CBT for most measures. CBT + PT > Minimal for reductions in health care visits. At f/u: CBT + PT fewest sick days, followed by CBT and Minimal. Both treatment groups 5 times less likely to be on long-term sick leave than Minimal.

Different intervention lengths

1y

Gold et al.32

185 with vertebral

RCT

Part 1: Intervention

I: exercise, coping skills

Part 1: I: 5 weekly

Trunk extension strength,

Part 1: I > EC for improve-

Different session lengths for I

6 mo

4452

fracture

(I) (N = 94) vs. education control (EC) (N = 91) Part 2: Crossover: EC becomes I group after 6 mo. Initial I group selfmaintenance

(relaxation, stress reduction) EC: education of health issues for women

exercise and coping sessions (225 min) EC: 1 weekly session at 45 min Part 2: I: selfmaintain EC = I group

Functional Status Index (FSI), Global Severity Index of Hopkins Symptom ChecklistRevised

ment in trunk extension and psychological symptoms EC: worse for all three outcomes Part 2: EC showed withingroup improvements in trunk extension and psychological symptoms after intervention I: decrease in back strength from posttreatment, improvement in psychological state maintained

and EC, no control group at f/u. I group did not receive education in cross-over design.

van Lankveld et al.33

59 with rheumatoid arthritis (RA)

RCT compared couples to patientonly group

Couples (C) (N = 31) vs. patientonly (P) (N = 28)

Education, cognitive restructuring, encouragement to use active coping skills

C: 2 weekly 1.5-h sessions for 4 wk

Disease Activity Score (DAS): swollen joint count IRGL, Coping with Rheumatoid Stressors Questionnaire (CORS), Maudsley Marital Questionnaire (MMQ)

Sample improvements in disease activity, cognitions, coping, physical and psychological function (C = P). At f/u: C > P for improvements in diseaserelated communication with spouse.

Possible selection bias of highly invested couples because of study design

6 mo

Ersek

45 elderly with chronic pain

RCT

Self-management (SM) (N = 17) vs. educational booklet (control) (EB) (N = 23)

SM: education, selfmonitoring, communication, relaxation, individualized goals, homework EB: booklet with information about pain, medications, instructions for selfmanagement, and pain resources

SM: 7 group sessions at 90 min

SF-36, Graded Chronic Pain Scale, Geriatric Depression Scale, Survey of Pain Attitudes (SOPA), survey assessing use of pain management strategies, treatment usefulness scales

SM > EB for improvements in pain intensity and physical role function (preto postchange); clinically significant improvement in 43% SM and 13% EB; SM = EB at f/u.

Brief f/u

3 mo

Tkachuk et al.35

28 with irritable bowel syndrome (IBS)

RCT

CBT (n = 14) vs. homebased symptom monitoring with weekly telephone contact (SMTC) (n = 14)

CBT: education, relaxation, cognitive restructuring, assertiveness training SMTC: daily symptom monitoring, discussion of symptom patterns

Ten 90-min sessions for 9 wk

Daily monitoring IBS scores, BDI-II, cognitive emotional distress (CSFBD), trait anxiety (STAI-T), discomfort with assertion (AQ), quality of life (SF-36)

CBT > SMTC for pain relief ratings, improvement in GI symptoms, quality of life. Maintained at f/u. One-third treated patients experienced clinically significant improvement.

Brief f/u

3 mo

Mishra

94 with

Urn method

CBT (n = 22),

CBT: self-

12 sessions of

Characteristic

CBT =

Combined

—

et al.34

4453

et al.36

chronic TMD

of assignment

biofeedback (n = 23), CBT + biofeedback (n = 24), no treatment (n = 25)

change plain; relaxation training; distraction; pleasant activity scheduling; cognitive restructuring; social skills and assertive communication. Biofeedback: 15 min of temperature feedback and 15 min of electromyography (EMG) biofeedback Combined: include components of both of the above

1.5 h, except for combined treatment which was 2 h; 2/wk for first 4 wk, 1/wk for other 4wk

Pain Intensity (CPI), Graded Chronic Pain Score (GCPS), Profile of Mood States (POMS)

biofeedback = combined and all 3 greater than no treatment on CPI and POMS. No significant pre- to posttreatment change was observed for GCPS across any group. Biofeedback improved the most compared to the no treatment control on CPI.

treatment was a higher dose. Lack of f/u

Leibing et al.37

55 with RA

RCT

CBT (N = 19) vs. TAU (N = 36), change in medicationmatched control group (CN) (N = 20)

CBT: education, relaxation, cognitive restructuring, pain management, pleasant activity scheduling

CBT: 12 weekly sessions at 90 min

C-reactive protein (CRP), blood sedimentation rate (Westergren), swollen joint count, Hannover Functional Ability Questionnaire (HFAQ), medication types, VAS pain intensity, affective pain score, pain diary, STAI, Depression Scale (DS), Arthritis Helplessness Scale (AHI), Bernese Coping Modes

Overall increase in disease activity across sample CBT less progressive inflammation than TAU. CBT > CN for pain reduction, improvements in depression, anxiety, helplessness; CBT: improved depression, helplessness, positive coping from baseline

Potential type I error from multiple significance tests; lack of f/u

None specified

Potts et al.38

60 with noncardiac chest pain

RCT

CBT (N = 34) vs. WLC (N = 26)

CBT: education, relaxation, biofeedback, graded exercise, challenging automatic thoughts, homework WLC: delayed treatment

6 sessions at 2 h

HADS, Nijmegen hyperventilation scale, Sickness Impact Profile (SIP), Nottingham Health Profile (NHP), chest pain diaries, hyperventilation: portable carbon dioxide monitor, exercise electrocardiography (ECG)

CBT > C for improvements in chest pain frequency, pain-free days, anxiety, and depression, disability, and exercise tolerance. Similar results for delayed treatment group once treated. Overall, 76% had improvements in chest pain. Maintained at f/u.

Lack of control group at f/u

6 mo

Cole39

113 with mixed chronic pain

NonRCT

CBT (N = 88) vs. TAU (N = 25)

Coping skills, pain selfmanagement, adjustment, stress management, relaxation, self-esteem,

75 min, 1 per week for 16 wk

Multidimensional Pain Inventory (MPI), Minnesota Multiphasic Personality Inventory-2

CBT: decreases in BDI and MPI scores, and health care visits from baseline, increase in return to work

Patients not randomly assigned. No direct comparison between CBT and control groups.

1y

4454

positive thinking

(MMPI-2), BDI Reported narcotic medication usage, health care visits, work status

f/u: medication decreased from 75% at baseline to 44%, health care visits decreased from 5/mo to 1/mo. Work status increased from 10% to 31%.

Keel et al.40

27 with FM

RCT

CBT (N = 14) vs. autogenic (N = 13)

CBT: stress inoculation, cognitive restructuring, activities for pain diversion, information, relaxation, group discussion, stretching, aerobic exercise Autogenic: practice relaxation

15 weekly sessions lasting 1–2 h

Freiburg Personality Inventory, Locus of Control Scale, Rosenzweig PictureFrustration Diary (of active hours, resting hours, sleep index, pain intensity, and medication consumption), General Symptom Checklist

2 CBT clients vs. 1 autogenic had clinically significant improvement in medication consumption, physical therapies, sleep, pain scores, general symptoms At f/u, CBT > autogenic for improvement in pain ratings. 4 CBT vs. 0 autogenic had clinically significant improvements at f/u.

Small sample size; statistical analyses not described

3 mo

Keel et al.41

411 with low back pain

NonRCT

Experimental (E) (N = 243) vs. standard physiotherapy (S) (N = 168)

E: coping strategies, stress management, relaxation, simulated work situations fitness training, education and group activity, individual physiotherapy or psychotherapy for acute pain S: mostly individual physiotherapy

E: 4-wk (27 d) inpatient program S: 3-wk (20 d) inpatient program

Work situation, physical activities, pain history, VAS pain rating, pain drawing, RMDQ, Psychological General WellBeing Index (PGWB), health costs, quality of life, impairment

E = S for improvements in functional ability, limitations in daily life, health care visits E: higher proportion of individuals in work rehabilitation (23% work incapacity decrease), E > S daily hours worked, decrease in professional handicaps; at f/u, larger proportion of S worsened

Preexisting differences between groups on demographic variables; different predominant treatment modalities in each condition (E = group, S = individual)

3 mo, 1 y

Basler

94 with low back pain

RCT

CBT (N = 36) vs. TAU (N = 40)

Education, relaxation, modifying thoughts and feelings, pleasant activity scheduling, postural training

12 weekly sessions at 150 min

Pain diary (pain intensity, control over pain, medication consumption), Heidelberg Coping Scale (HCS), Dusseldorf Disability Scale (DDS)

CBT: decreases in pain intensity, improvements in coping with pain, mental performance, and disability Gains maintained at 6-mo f/u TAU: little or no change

High attrition rate at f/u

6 mo

45 with IBS

NonRCT

CBT (N = 25) vs. WLC (N = 20)

Patient education (e.g., roles of cognitions, behaviors, in IBS),

8 weekly sessions lasting for 2h

Diary (duration of pain, daily avoidance behavior, GI complaints),

CBT > WLC for improvement in Daily Abdominal Complaint

No WLC at f/u, wide range of f/u assessment times (6 mo–4 y)

Mean = 2.25 y

et al.42

van Dulmen et al.43

4455

homework, discussion, progressive muscle relaxation

Abdominal Complaint Inventory, Symptom Checklist 90 (SCL-90)

Score (DAC), duration, avoidance, and number of successful coping strategies delayed treatment group: decreases in DAC; improvements maintained at f/u

Vlaeyen et al.44

131 with FM

RCT

Cognitive educational intervention (ECO; N = 47) vs. attention control condition of education and discussion (EDI; N = 39) vs. WLC (N = 40)

ECO: imaginative transformation of pain, relaxation and biofeedback, homework EDI: education, sharing thoughts with group members, listening to music, homework

ECO and EDI = 12 90min sessions conducted in 6 wk

Pain cognition list, Coping Strategies Questionnaire (CSQ), Behavioral Approach Test, Pain Behavior Scale, McGill Pain Questionnaire (MPQ), Multidimensional Pain Locus of Control Scale, Checklist for Interpersonal Pain Behavior, Fear Survey Schedule, BDI

ECO = EDI for improvements in pain coping and knowledge EDI > WLC on knowledge and pain control. At 12-mo f/u, ECO = EDI, although ECO had an increase in pain intensity.

Potential confounding of treatment (EDI group shared thoughts, completed homework). Low education level of participants may have made ECO difficult.

12 mo

NewtonJohn et al.45

44 with chronic back pain

RCT

CBT (N = 16) vs. electromyographic biofeedback (EMGBF; N = 16) vs. WLC (N = 12)

CBT: education, goal setting, relaxation, cognitive restructuring, homework EMGBF: education, diaphragmatic breathing, adaptation, homework

8 sessions at 1 h (2 sessions per week)

BDI, STAI, CSQ, Pain Disability Index, Pain Beliefs Questionnaire (PBQ)

CBT and EMGBF > WLC for improvements in intensity, disability, adaptive beliefs, and depression. Improvements maintained at f/u, along with improvements in anxiety and active coping

Small sample size per group

6 mo

James

33 with headache

RCT

CBT with goals (goal group) (N = 13) vs. CBT with no goals (open group) (N = 13) vs. WLC (N = 7)

Both CBT groups: education, coping, developing appropriate self-talk, generalization of skills, relaxation Goal: specific time goals for coping with pain/stress Open: instructions to cope as long as possible

6 weekly sessions at 90 min

Goal specificity: coping with daily stressors and pain, daily selfmonitoring, pain index, medication intake, downtime, Pain Behavior Questionnaire, SCL-90, SIP, BDI, STAI, Cognitive Coping Index

Goal and open groups > WLC for improvements in pain coping skills, goal group > open and WLC group for reduction of headache and nonnarcotic medication use

Lack of f/u period

None specified

102 with low back pain

RCT

Relaxation (R) (N = 17) vs. cognitive therapy (C) (N = 21) vs. cognitive therapy and relaxation (CR) (N = 16) vs.

R: imagery, progressive muscle relaxation (PMR) C: identify negative thoughts, counter negative

6 weekly sessions at 2h

VAS pain ratings, SIP, BDI, Observed Pain Behaviors, Cognitive Errors Questionnaire, BDI

R, C, and CR > WLC for improvements in pain ratings and disability. At f/u: all three patient groups improved. At both f/u,

No comparison to control group at f/u, attrition rates for control condition

6, 12 mo

et al.46

Turner and Jensen47

4456

WLC (N = 18)

automatic thoughts CR: combined treatment

patients in all groups improved R = C = CR.

Kneebone and Martin48

35 with headache

NonRCT Compared couples to standard noncouple and control groups

Partners involved (PI) (N = 12) vs. no partners (NPI) (N = 10) vs. no treatment control (NTC) (N = 13)

PI and NPI: selfmonitoring, relaxation, cognitive restructuring, assertiveness, group process (e.g., support), homework PI: partners educated in reinforcement principles

10 weekly sessions at 1.5–2 h

Headache activity, intensity, medication usage, relaxation practice, Partner Involvement Questionnaire, Dyadic Adjustment Scale (DAS), selfmonitoring forms

PI = NPI for relaxation time, PI > NPI for partner involvement: spouse assisted with relaxation PI: decrease headache activity from baseline NPI: decreased medication usage from baseline. NTC increased medication usage. At f/u: NPI > NTC for reductions in medication. Other measures: PI = NPI at f/u.

Potential for type 1 inflation; low motivation across treatment groups to practice relaxation

2, 12 mo

Nicholas et al.49

58 with low back pain

RCT

Cognitive therapy (CT) + relaxation (N = 8) or CT (N = 10) vs. behavior therapy + relaxation (N = 9) or BT (N = 10) vs. attention (ATC; N = 10) and no attention control (N = 11)

All groups: physiotherapy, education, exercise CT: cognitive restructuring, distraction, imagery, selfmonitoring BT: activity pacing, medication reduction, reinforcement Relaxation: PMR ATC: group discussion about back pain

Five 1.5- to 2h sessions twice per week

Pain Rating Chart STAI, PBQ, CSQ, SIP, SIPOthers (SIPO), medication intake, report of alternative treatments, visits to health care facilities

Sample improved on affective distress, functional impairment, medication use, and active coping. Both CBT groups and both BT groups > ATC and control for improvements in pain intensity, selfreported disability, pain beliefs, and active coping. BT > CBT for improvements in impairment. Improvements somewhat maintained at f/u.

Physiotherapy included as part of all treatments Small sample size

6, 12 mo

Subramanian 50,51

39 with mixed chronic pain Longterm f/u = 22

RCT

Structured group therapy (N = 19) vs. WLC (N = 20)

Therapy: stress management, relaxation cognitive restructuring (coping thoughts, selfdefeating, self-enhancing thoughts), assertiveness training

8 weekly 2-h sessions

SIP, Pain level (0–10 scale) used a control variable Profile of Mood States (POMS), Social Support Questionnaire

Therapy > WLC for improvements in physical and psychosocial dysfunction, negative mood states. Within-group improvements also apparent. Long-term f/u: improvements maintained, improvement in pain severity observed, 77% improved from posttreatment to

No comparison group at longterm f/u

6 mo Long-term: 18–22 mo

4457

f/u, 36% reduction in prescription medication usage Peters and Large52

68 with chronic pain

RCT

Group inpatient program (IPMP) (N = 29) vs. Group outpatient program (OPMP) (N = 23) vs. control (C) (N = 16)

IPMP: education, pain management, relaxation, cognitive restructuring, exercise, vocational counseling, reinforcement OPMP: education, activity goal setting, exercise, medication and stress management, relaxation

Inpatient: 4 wk Outpatient: 9 weekly sessions at 2h

BDI, MPQ, General Health Questionnaire (GHQ), SIP, Pain Behaviour Checklist, pain drawings, VAS ratings, VAS stair climbing test, physiologic measures, physical endurance

Sample improvements in disability, GHQ scores, BDI, and MPQ scores IPMP and OPMP > control for improvements in disability, VAS pain ratings, and pain behavior

Results may have been influenced by timing of the assessments; lack of f/u

None specified

Turner et al.53

96 chronic low back pain patients

RCT

Group behavioral and aerobic exercise (BE) (N = 18) vs. behavioral therapy only (B) (N = 18) Aerobic exercise only (E) (N = 21) vs. WLC (N = 23)

BE: behavioral intervention followed by exercise in each session B: reinforcement role-playing, discussion, homework, communication E: Exercises 5 times per week

BE and B: 8 weekly 2-h sessions E: 5 weekly sessions

MPQ, SIP, Pain Behavior Checklist (PBC), PBCspouse ratings, Physical Work Capacity (PWC), Center for Epidemiologic Studies — Depression Scale (CESD), recorded pain behaviors

All three groups improved more than the WLC from pre- to posttreatment, BE > WLC from pre- to posttreatment on self-report and observer rated pain behavior measures, BE > E on PBC Spouse ratings F/u: all treatment groups improved over time

Interaction with therapists varied by condition

6, 12 mo

Linton et al.54

66 nurses with back pain

RCT

Physical and behavioral preventive intervention (PBI) (N = 36) vs. WLC (N = 30)

PBI: physical therapy, “low back school,” relaxation, pain control instruction, goal setting, problem solving, coping, identifying high-risk situations

PBI: 8 h/d for 5 wk

Daily pain diaries, VAS intensity, fatigue, anxiety, sleep, pain behavior, ADLs, BDI, AHI, marital satisfaction, absenteeism, medication intake

PBI > WLC for improvements in pain intensity, fatigue, pain behavior, sleep, ADLs, helplessness Most differences maintained at f/u

Use of nonstandardized measures of sleep quality, ADLs, marital satisfaction

6 mo

Puder55

69 with mixed chronic pain

RCT

Stress inoculation training (SIT) (N = 31) vs. WLC (N = 38)

SIT: explaining treatment, reviewing progress, problem solving

10 weekly 2-h group sessions

Daily pain diary, nontreatment technique usage: psychological support, exercise, heat/cold, massage, TENS, injections

SIT > WLC for improvements in pain interference, coping, decreased analgesic intake, discontinuation of heat/cold, and home traction technique. No difference according to age. Improvements maintained at f/u.

Use of nonstandardized measures

1, 6 mo

Bradley et al.56

53 with RA

RCT

Biofeedbackassisted CBT (N = 17) vs.

CBT: thermal biofeedback, education, relaxation,

CBT: 5 thermal sessions, 10 family/

STAI, Depression Adjective Checklist

CBT > SGT and NAT for decreases in pain behavior,

Session duration not specified

6 mo

4458

structured group social support therapy (SGT) (N = 18), no adjunct treatment (NAT) (N = 18)

behavioral goal setting, self-rewards SGT: education, discussion of coping strategies, encouragement to develop improved strategies

friend meetings SGT: 15 sessions family/ friends

(DACL), Health Locus of Control Scale (HLCS), AHI, pain behaviors, rheumatologist ratings of disease activity level, rheumatoid factor titers, sedimentation rate (Westergren)

pain ratings, rheumatoid activity (RAI), NAT: lower RAI scores than SGT SGT and NAT increased in depression and rheumatoid factor titer across assessments CBT and SGT > NAT for improvement in anxiety CBT maintained improvement at f/u

Larsson et al.57

36 high school students with tension/ migraine headaches

RCT

Self Help Relaxation (SHR) (N = 12) vs. Problem Discussion Condition (PDC) (N = 10) vs. Untreated SelfMonitoring Condition (SM) (N = 12)

SHR: relaxation programs, rapid cuecontrolled strategy, homework, help solving problems during relaxation PDC: discussion of conflicts in everyday life, role-play, identifying stressors, assertiveness

5 weekly sessions SHR = 3 h PDC = 7 h

Headache diary: frequency, duration headache free days, peak intensity, modified Depression Scale for Female adolescents, Children’s Manifest Anxiety Scale, Social RelationshipCompetence Questionnaire (SRCQ)

Headache activity: Greatest reductions for SHR group, SHR > SM and PDC Headache sum and peak intensity: SHR > PDC during pre-f/u interval Headache duration and headache -free days: SHR > SM and PDC

Small sample size, different therapist interaction for two interventions

5 mo

Bradley et al.58

33 with RA

RCT

Thermal biofeedback and group cognitive behavioral (CB = 11) vs. social support (SS = 10) vs. NAT (N = 12)

CB: thermal biofeedback, education, skills acquisition, selfinstructional training, application SS: education, support, encouragement to develop own coping strategies NAT = control

CB: 5 individual thermal sessions, 10 family meetings SS: 15 family meetings

STAI, DACL, VAS ratings of pain intensity, unpleasantness, severity of morning stiffness, pain behaviors, HLCS, rheumatoid factor titers, Westergren, rheumatologist ratings of disease activity

CB > NAT group for significant decreases in pain intensity, pre- to posttreatment: CB less pain behavior from pre- to posttreatment, less rheumatoid activity, and rheumatoid factor titer. CB and SS less anxiety and depression. SS increase in sedimentation rate NAT: significant reduction in morning stiffness.

Small sample size, lack of f/u

None specified

Linton et al.59 and

28 with heterogeneous chronic pain 26 with heterogeneous chronic pain

RCT Longterm f/u

Regular treatment (RT) vs. applied relaxation and operant activities (RT + BT) vs. WLC

RT: prescribed treatment plan RT + BT: plan and relaxation training, operant training, reinforcement of well behaviors, decrease in medication

12 sessions

BDI, Activities of Daily Living questionnaire, selfmonitoring of pain, medication consumption, sleep f/u measures also included pain, health, activity, level, sleep,

RT + BT > RT and WLC for improvements in pain level and leisure activity Improvements maintained at f/u

Small sample size Long-term f/u: WLC group received individual treatment prior to assessment

14–16 mo

Melin and Linton60

4459

occupation Moore and Chaney61

43 with mixed chronic pain

RCT

Couples group therapy (CBT) (N = 17) vs. patientonly group therapy (N = 14) vs. WLC (N = 12)

Couples and patient only: education, goal setting, problem solving, relaxation and controlled breathing, direct pain reduction method, coping strategies, homework

16-h program, couples: 8 biweekly 2h sessions

VAS pain severity (patient and spouse) MMPI Hs, D, and Hy scales only, SIP, PARS IV Community Adjustment Scale (spouses), LockeWallace Marital Adjustment Test (LMAT), utilization of medical resources medication usage

Couples and patientonly groups > WLC for improvements in VAS ratings, pain severity and pain behavior ratings, somatization, and PARS (spouse rating) Patient-only groups > controls on LMAT and SIP scores Treatment gains maintained at f/u Couples = patient-only therapy

Small sample sizes for each condition

3, 7 mo

Cohen et al.62

25 with chronic low back pain

RCT

Behavioral intervention (BT) (N = 13) vs. physical therapy (PT) (N = 12)

PT: pain control strategies, relaxation, exercise, pool therapy, use of body mechanics BT: goal setting, activity pacing, problem solving, assertiveness

10 weekly 2-h sessions

Physical Abilities and Walking Abilities testing, Knowledge and Functional Measure of Body Mechanics, CES-D, Psychological Adjustment to Role Scale (PARS-V)

PT: greater low back control and decreases in CES-D score. BT and PT: lower anxiety and depression per patients and significant others on PARS-V, others. Decreases in physical and activity limitations for both groups

Small sample size, validity data for some instruments not provided

None specified

Figueroa63

15 tension headache patients

RCT

Behavior therapy (BT) (N = 5) vs. psychotherapy (P) (N = 5) vs. selfmonitoring (SM; N = 5)

BT: problem solving, relaxation, anxiety management training, stress inoculation P: discussion, conflict resolution, discussion of stressful events

BT: seven 90min sessions P: seven 90min sessions (twice weekly)

Headache questionnaire, headache checklist (e.g., level of relaxation, number of headaches, duration, severity, medication usage, disability), selfmonitoring forms

Pre to f/u: B > P and SM for improvements in perceived disability BT > SM for reductions in headache frequency and duration, medication usage, level of relaxation, and pain severity

Small sample size, use of nonstandardized measures

Time not specified

Turner64

36 chronic low back pain patients

RCT

CBT (N = 13), vs. relaxation (N = 14) training, WLC/ attention conditions (N = 9)

CBT: stress inoculation, behavioral goals, cognitive and affective responses to pain, coping selfstatements, relaxation Wait-list/ attention: gave daily pain ratings to therapist in weekly phone calls

5 weekly 90min sessions

SIP, SIP Significant Other (SIP-O), VAS ratings, self-ratings of improvement, BDI, work hours, health care usage

CBT and relaxation groups > WLC for improvements in pain, depression, disability, and spousal ratings of physical and psychosocial function At f/u: CBT improved on SIP, SIP-O, pain severity, relaxation: worse pain severity 1.5- to 2-y f/u: both groups

Small sample size

1 mo, 1.5– 2y

4460

retain improvements, CBT > in hours worked per week

AQ, Assertiveness Questionnaire; CBT, cognitive-behavioral therapy; CSFBD, Cognitive Scale for Functional Bowel Disorders; GI, gastrointestinal; HADS, Hospital Anxiety and Depression Scale; IPMP, inpatient pain management program; OPMP, outpatient pain management program; RAI, Rheumatoid Activity Index; RCT, randomized controlled trial; SCI, spinal cord injury; STAI-T, State-Trait Anxiety Inventory–Trait Scale; TMD, temporomandibular disorder; VAS, Visual Analog Scale; WL, wait-list; WLC, wait-list control.

CBT is a generic term used to describe a complex and multifaceted treatment, and the included treatment components within group CBT protocols vary across studies and research groups. However, the general principles associated with CBT are typically consistent across studies (i.e., that one’s thoughts and feelings influence one’s ability to cope with pain and teaching pain self-management strategies). An overarching component of CBT includes strategies to educate patients about how the brain processes pain and psychological factors affecting pain perception. Furthermore, training in specific pain management skills almost always includes one or more modules on recognizing and modifying maladaptive or distorted pain-related automatic cognitions and beliefs, enhancing cognitive coping, learning relaxation strategies (including one or more types of relaxation techniques such as biofeedback, autogenic relaxation, progressive or passive muscle relaxation, meditation, and/or selfhypnosis), and completing regular homework assignments such as thought records or guided relaxation for skills acquisition. Frequently, but less consistently, CBT includes modules focusing on stress management (sometimes referred to as stress inoculation), paced physical activity, assertive communication, pleasant activity scheduling, and coping selfstatements. Because of the varied approaches that have all been subsumed under the label of CBT in the literature, it has historically been difficult to identify the specific treatment components that account for treatment efficacy, and this continues to be the case. There are a limited number of dismantling studies that have evaluated specific CBT components for pain management. However, controlling for nonspecific treatment effects (e.g., attention from therapist, expectations of health care provider and patient) 4461

is an important step toward determining the specific components of treatment efficacy as well as for elucidating specific and shared treatment mechanisms. Comparing patients receiving group treatment for chronic pain to those on a wait-list does not allow for this type of analysis, although wait-lists do control for the natural progression of the disorder over time and potential reactivity associated with self-monitoring or keeping pain diaries (if included as part of the study). The social context in which the treatment is administered is of particular relevance for the study of the active components of group treatment approaches. Therefore, studies comparing one type of group treatment to another type of group “attention control” treatment (e.g., support group) provide better evidence for disentangling the specific versus nonspecific treatment effects of CBT. Furthermore, comparing CBT to other active treatments demonstrates the relative effects and also allows for examination of whether the treatments exert benefit for the reasons proposed by the respective theory. Although there is strong evidence for CBT delivered in nongroup formats in nonadult populations, most of the group CBT research to date has been conducted within adult populations with chronic back pain, headache, orofacial pain, or arthritis-related pain and to a lesser degree across an array of other pain conditions.67 Systematic reviews of the CBT literature typically collapse across most pain types (indicative that the treatment approach and effects are sufficiently similar across these conditions to do so); however, headache and migraine are usually reviewed separately due to differences in the overall approach as well as history.8 More recently, the treatment of neuropathic pain was isolated within a systematic review and results showed that compared to nociceptive pain, neuropathic pain is particularly recalcitrant to treatment.7 The primary focus here is on adult populations; the specific type of pain investigated in each study is reported in the corresponding Table 87.2. There continues to be a limited number of studies in which one group treatment for pain has been compared to another. One study in patients with fibromyalgia, for example, compared group education plus CBT versus group education plus group discussion (which controlled for the effects of attention).44 These authors found that both groups showed equal improvements in pain coping and knowledge, and both were superior to a 4462

wait-list control condition. An economic evaluation of the treatments resulted in the authors’ suggestion that the extra health care costs associated with the addition of the CBT modules were not warranted based on the outcomes.44,68 It is important to note that the education modules that were offered to all participants included structured physical fitness training after each of 12 sessions, and this behavioral component may have served to increase the overall outcome efficacy of both groups. Furthermore, the discussion modules (attention control) included weekly homework assignments, which is typical of CBT groups but atypical of control conditions. The authors suggest that the homework assignments may have served as a form of graded exposure for the fearful participants, thereby resulting in treatment gains in the control group. It is also important to mention that both treatment groups in the mentioned study used limited therapist time in an effort to reduce treatment costs. It may be that the principles associated with cognitive-behavioral change require some threshold amount of therapeutic intervention in order to be successfully implemented. These findings and others led Vlaeyen and colleagues44 raise the important point that the active components of group treatment need further careful study. Another study assessed the efficacy of group CBT for pain using education booklets as the control condition34 and found significant pre- to posttreatment differences in favor of the CBT self-management groups. Although the use of education booklets does not control for the nonspecific treatment effects of group interaction or support, this study suggests that merely offering facts about pain and pain management outside a therapeutic context does not appear to be efficacious. However, another study that compared cognitive-behavioral pain self-management to a condition that was assigned a book to read on managing chronic pain found that both conditions similarly showed clinically significant changes over time.28 A limitation of such an approach is that to read a book requires a certain level of literacy, as does participating in a traditional CBT program. Thorn and colleagues addressed the literacy treatment barrier via developing literacy-adapted CBT and education programs and tested their relative efficacy in a series of two RCTs within low-literacy, low4463

socioeconomic status (SES), predominantly minority populations.18,24 Results of the initial RCT24 showed that delivering education within a therapeutic context (i.e., that included factors such as therapeutic rapport and group support, as opposed to bibliotherapy) was particularly beneficial and both groups improved significantly across a number of outcomes; no significant differences between the literacy-adapted CBT and pain education treatment were observed in the intent to treat sample. In Thorn and colleagues’ most recent trial18 that included a larger sample size and several methodologic enhancements, again, both the literacy-adapted CBT and education interventions performed similarly on the primary outcome of pain intensity and the secondary outcome of pain interference, with both significantly outperforming the treatment as usual control. Maintenance of gains in pain interference was observed in both groups; although benefits in pain intensity were maintained in education at follow-up, this was not the case for CBT. However, participants in CBT were less likely to be depressed at follow-up. Comparison of effect sizes and clinically meaningful improvement (>30% reductions in pain intensity, pain interference, and depression) suggested a slight advantage of CBT over education, but overall, these findings suggest that both literacy-adapted CBT and pain education are suitable for implementation in highly disadvantaged populations. Patient workbooks and therapist supplements for these literacy-adapted treatments are freely available at pmt.ua.edu/publications.html. Several other studies have compared group CBT to relaxation training or another group condition. In one study of patients with low back pain, patients receiving group CBT and those receiving relaxation training improved compared to wait-list controls, although at follow-up, those who received CBT showed greater treatment gains than those receiving relaxation training.64 In a similar study with individuals with fibromyalgia, those who received group CBT showed greater improvement in pain ratings than those who received autogenic relaxation training.40 Focusing on high school students with migraine and tension-type headaches, Larsson et al.57 compared self-help relaxation groups to problem discussion groups and untreated self-monitoring groups and found selfhelp relaxation to be superior to the other two conditions. Contrary 4464

findings were reported by Mishra and colleagues36 who compared CBT versus biofeedback versus CBT + biofeedback versus no treatment in a temporomandibular disorder population and found that although all three active treatments significantly outperformed the no treatment arm, there were no significant differences in outcomes across the active treatments. Together, these studies suggest tentative evidence supporting CBT groups as conferring greater benefit than relaxation-only groups and that relaxation groups alone may be superior to groups offering only education or discussion in some settings. A specialized subset of studies comparing one type of group treatment to another are those that have compared group CBT offered only to the patient, to group CBT offered to both the patient and his or her partner. Moore and Chaney61 found that among patients with mixed chronic pain syndromes, couples group therapy and patient-only group therapy were both superior to a wait-list control group, but the patient-only groups showed significant improvement on more outcome variables than did the couples groups. Another study found similar improvements in physical and psychological functioning, cognitions, and coping among both couples groups and patient-only groups, although at 6-month follow-up, patients in the couples groups reported greater improvement in communication with their spouse than did patients in the patient-only groups.33 Patients with chronic headache differ in some ways from those with other chronic pain syndromes, and therefore, it is interesting to note that one study found that partner involvement in chronic headache management groups actually reduced efficacy compared to nonpartner involvement.48 Further research is necessary to determine whether this finding is unique to individuals with chronic headache pain or if other variables are associated with this outcome. Another line of research has examined potential algorithms for tailoring CBT to the specific baseline symptom profiles of individuals entering treatment. van Koulil and colleagues26 conducted an RCT within a fibromyalgia sample and compared tailored CBT + exercise to a wait-list control. Specifically, patients were classified at baseline into two groups, (1) pain avoidance (i.e., individuals who avoid activities due to fear of pain) or (2) pain persistence (i.e., individuals who persist in activities 4465

despite pain), and were then randomized. Those in the intervention condition received treatment that was tailored to their cognitive-behavioral pattern. Specifically, individuals with a pain-avoidance profile received group-delivered treatment theorized to explicitly target increasing daily activities, reducing pain and avoidance behaviors, and increasing physical condition. Whereas those individuals with a pain persistence profile received group treatment targeted toward regulating daily activity, increasing activity pacing, restructuring pain-persistence cognitions, and increasing physical condition. Results showed that the tailored treatment resulted in large effect sizes and significantly greater improvements across all primary outcomes as compared to the wait-list control. Unfortunately, this study did not include a “mismatched” arm; hence, the utility of matching patients to these tailored treatments is not fully known. However, in a recent study by Kerns et al.69 that examined individually delivered tailored CBT to standard CBT, no significant outcomes were observed; to the best of our knowledge, no research has examined similar research questions in a group setting. Future research identifying the optimal approach to tailoring group-delivered CBT to specific profiles is needed as this has the capacity to more efficiently and effectively engender positive changes. Finally, one promising study by Seminowicz and colleagues21 showed that group-delivered CBT resulted in increased gray matter in several areas of the brain related to pain processing following an 11-week treatment. Many of these increases were correlated with treatment-related reductions in pain catastrophizing, suggesting that successfully targeting this cognitive mechanism may be a powerful way to harness neuroplasticity and potentially reverse a selection of brain-related changes associated with central sensitization and worse pain outcomes. Although the sample size was small and the design lacked randomization and follow-up, these promising results provide preliminary evidence to support CBT as an intervention that effectively retrains the brain to enhance top–down control of pain and cognitive reappraisal of pain as well as alters the perception of noxious signals. Although reduced pain catastrophizing was found to be a critical correlate of these changes, it is not clear if cognitive change in catastrophizing is a mechanism specific to CBT. 4466

BEHAVIORAL VERSUS EXERCISE AND PHYSICAL THERAPY GROUP TREATMENTS Physical therapy has long been considered an essential component of chronic pain management, and as a result, it is important to consider its role in treatment groups for chronic pain. Although most studies have focused on the efficacy of physical therapy and exercise in an individual context, we located two RCTs specifically comparing group behavioral approaches to group physical therapy. In one study, individuals with chronic low back pain who received group behavioral treatment and those who received group physical therapy both showed significant decreases in activity limitations, anxiety, and depression.62 In another study, Turner et al.53 examined the differential efficacy of group behavioral therapy alone, group aerobic exercise training alone, group behavioral therapy plus group aerobic exercise, and a wait-list control group. The three treatment groups showed greater improvement than the wait-list control group, and all groups showed increasing improvement over the 6- and 12-month followups. It is important to note that in this study, the combined behavioral plus exercise group treatment showed the greatest improvement overall, suggesting that physical activity may be an important component to incorporate into group treatment for chronic pain. However, in another study by van der Roer et al.70 that compared a combined exercise therapy, back school and operant-conditioning behavioral principles condition to physiotherapy, no significant differences in outcome were observed on any outcome measure during the complete follow-up period. Similarly, in an RCT by Smeets and colleagues,71 the advantage of combining cognitive and behavioral interventions (primarily graded activity) with active physical therapy was also not observed; this study found no significant differences in outcomes between the combined treatment and the individual components, but all three significantly outperformed the wait-list control.71 The van der Roer et al.70 study and research by Smeets et al.71 was not included in Table 87.2, however, as the treatments compared in these studies entailed both individual and group delivery components. To summarize, converging lines of evidence described earlier and in Table 87.2 provide strong evidence that individuals with chronic pain 4467

benefit significantly more from group CBT than from being on a waiting list or receiving medical treatment as usual. The specific mechanisms of treatment efficacy have yet to be clearly identified, but studies to date have shed some light on these mechanisms, which are described in more detail later in this chapter. As efficacy research moves from open trials to RCTs designed specifically to compare group CBT to other active group treatments, future studies are likely to emerge that will help identify the active components of CBT treatment.

MINDFULNESS-BASED APPROACHES TO PAIN MANAGEMENT The past decade has witnessed an exponential growth in the amount of research directed toward understanding the effects of MBIs for chronic pain management.72 Although this body of research continues to be limited due to common methodologic issues such as small sample sizes, and lack of randomization and comparison conditions, the number of quality RCTs on mindfulness-based pain and stress reduction or other meditative therapies for chronic pain is steadily increasing. A recent meta-analytic review by Veehof and colleagues73 examined the evidence of mindfulnessand acceptance-based interventions for pain. Nearly all of the studies reporting on the effects of MBIs for various chronic pain conditions that were included in this review involved group-delivered treatment, except for a small selection that examined modes of online delivery in an individual format. Regarding group meditation treatments specific to chronic pain, we were able to locate 17 RCTs74–90 and 3 non-RCTs91–93 (see Table 87.3 for a summary). Most of these studies compared group meditation (usually in integrated packages such as MBSR and more recently, MBCT) to standard care and found meditation to be more beneficial with respect to pain interference, pain perception, pain coping, and measures of affect immediately posttreatment and also at follow-up. However, most follow-up periods were relatively short (i.e., 3 to 6 months), and although pain interference is the recommended primary outcome for MBIs, a number of studies did not include a measure of this outcome.96 Furthermore, there is a large range in the size of the groups examined in the MBI for chronic pain literature, ranging from as small as 4 4468

all the way up to 25 group members; although yet to be empirically examined, this variability in group size is likely an important factor influencing potential differences in outcomes observed across studies. TABLE 87.3 Mindfulness Based Group Interventions Treatment Type

Treatment Components

RCT

MBSR (n = 116) vs. CBT (n = 113) vs. usual care (n = 113)

MBSR: training in mindfulness meditation (MM) and yoga CBT: training to change maladaptive pain-related thoughts and behaviors Usual care: continuation of what is typically received

143 with rheumatoid arthritis (RA)

RCT

CBT (n = 52) vs. MBI (n = 48) vs. EDU (n = 44)

Cash et al.78

91 women with fibromyalgia (FM)

RCT

Cathcart et al.79

58 with chronic tensiontype headache

RCT

Authors

N

Study

Cherkin et al.94,95

342 with chronic low back pain

Davis et al.77

Outcome Measures

Results

Limitations

8 weekly 2-h sessions

Percentage of participants with ≥30% improvement on RolandMorris Disability Questionnaire (RMDQ), and 0– 10 back pain bothersome scale

MBSR = CBT; both MBSR and CBT > usual care; however, at the 2-y f/u, CBT > usual care in function, whereas MBSR = usual care at 2-y f/u.

Participants were recruited from single health care system and were highly educated— limits generalizability; 20% in MBSR and CBT lost to f/u

26 wk, 52 wk; then a 2-y f/u

CBT: training in cognitive reappraisal, relaxation, pacing MBI: training in mindfulness skills and skills to boost affective engagement such as savoring positive events EDU: information on etiology, pathophysiology and treatment of RA, healthy lifestyles and patient– physician communication

8 weekly 2-h sessions

Daily diary of pain and fatigue NRS, morning disability, interpersonal distress, pain catastrophizing and pain control, serene and anxious affect (PANAS items)

MBI > CBT and EDU in daily pain-related catastrophizing, morning disability, and fatigue and greater reductions in daily stressrelated anxious affect. On days of high pain, CBT showed less pronounced declines in daily painrelated perceived control than MBI or EDU.

Sample was mostly white and female, so generalizability may be limited; lack of fidelity monitoring; differences between conditions were small in magnitude; lack of f/u

—

MBSR (n = 51) vs. WL (n = 40)

MBSR: formal and information mindfulness practice, and yoga

8 weekly 2.5-h sessions and a halfday meditation retreat after session 6

BDI, Perceived Stress Scale, VAS Pain, Stanford Sleep Questionnaire, Fatigue Symptom Inventory, Fibromyalgia Impact Questionnaire, neuroendocrine function (salivary cortisol)

MBSR > WL on perceived stress, sleep disturbance, symptom severity with gains maintained at f/u; no significant differences in pain, physical functioning, or cortisol profiles

Sample was all female and predominantly well-educated, so generalizability is limited; lack of fidelity monitoring; attrition rate; brief f/u

2 mo

MBI (n = 29) vs. WL (n = 29)

MBI: MM

Six 2-h sessions over 3 wk

Five facet mindfulness questionnaire, headache diary (intensity, frequency, duration), Depression

MBI > WL on reduction in headache frequency and increase in mindfulness observe facet

Lack of f/u

—

Duration

4469

Follow up (f/u)

Anxiety Stress Scales Garland et al.80

115 with chronic pain

RCT

MBI (n = 57) vs. support/ EDU (n = 58)

MBI: mindfulness training, positive psychology Support: discussion/ information on topics of chronic pain, longterm opiate use, dimensions of pain, coping with pain and emotions, stress, acceptance

Eight 2-h weekly sessions

Brief Pain Inventory Intensity and Interference, Current Opioid Misuse Measure, Five Facet Mindfulness Questionnaire nonreactivity scale

MBI > support on pain intensity and interference at posttreatment and f/u; stress arousal and desire for opioids reduced at posttreatment but not maintained

Lack of quantitative fidelity monitoring, attrition rate

3 mo

Day et al.81

36 with primary headache

RCT

MBCT (n = 19) vs. delayed treatment (DT) (n = 17)

MBCT: MM, mindful walking and movement, cognitive therapy– oriented exercises, pleasant and stressful event monitoring

Eight 2-h weekly sessions

Daily headache diary, Brief Pain Inventory, Pain Catastrophizing Scale, Mindful Attention Awareness Scale, Chronic Pain Acceptance Questionnaire, Headache Management SelfEfficacy Scale

MBCT > DT in self-efficacy, pain acceptance; in completers, MBCT > DT also on pain interference and pain catastrophizing

Lack of f/u, small sample size

—

ParraDelgado and LatorrePostigo82

31 females with FM

RCT

MBCT (n = 17) vs. TAU (n = 16)

MBCT: MM, yoga, psychoeducational activities on anxiety and depression, cognitive therapy– oriented content on automatic thoughts

8 weekly 2.5-h sessions

Beck Depression Inventory (BDI), Fibromyalgia Impact Questionnaire, VAS Pain Intensity

MBCT > TAU on Fibromyalgia Impact Questionnaire and BDI, maintained at f/u; no significant changes in pain intensity

Limited measures of pain-related outcomes; small sample size; brief f/u

3 mo

Brown and Jones83

28 with musculoskeletal pain

RCT

MBI (n = 15) vs. TAU (n = 13)

MBI: MM and mindful movement, pacing, kindness meditation

8 weekly 2.5-h sessions

SF-36, Pain Stages of Change Questionnaire, Survey of Pain Attitudes, ShortForm McGill Pain Questionnaire, Mindful Attention and Awareness Scale; EEG and experimental pain manipulation

MBI > TAU on mental health, perceived control of pain, anticipatory and pain evoked eventrelated potentials to experimental pain

Lack of f/u

—

Wong et al.84

99 with chronic pain

RCT

MBSR (n = 51) vs. multidisciplinary pain intervention (MPI; n = 48)

MBSR: training in MM and yoga MPI: educational instructions on management of chronic pain

8 weekly 2.5-h sessions and a 7-h retreat

NRS Pain Intensity and PainRelated Distress, Profile of Mood States, Center for Epidemiologic Studies Depression Scale, State-Trait Anxiety Inventory, ShortForm Health Survey 12 (SF-12)

MBSR = MPI on pain intensity and painrelated distress; both improved significantly

Fidelity was not monitored in the study.

3, 6 mo

Schmidt et al.85

177 females with FM

RCT

MBSR vs. control of nonspecific effects versus WL

MBSR: training in MM and yoga Control: progressive muscle relaxation

8 weekly 2.5-h sessions and allday retreat for MBSR

Quality of Life Profile for the Chronically Ill, Fibromyalgia Impact Questionnaire, Center for Epide-

MBSR = control = WL on primary outcome, all improved significantly. On secondary outcomes,

Fidelity was not monitored in the study; brief f/u

2 mo

4470

and FMspecific gentle stretching exercises

miologic Studies depression inventory, StateTrait Anxiety Inventory, Pittsburgh Sleep Quality Index, Pain Perception Scale, Freiburg Mindfulness Inventory, Giessen Complaint Questionnaire

MBSR significantly improved 6 of 8 outcomes vs. the control condition improved 3 and WL 2 out of 8.

Morone et al.86

40 with low back pain, ≥65 y

RCT

MBI (n = 20) vs. EDU (n = 20)

MBI: MM and walking practice EDU: session topics on pain medications, complementary treatments, types of back pain, role of physical therapist, nutrition, Alzheimer

8 weekly 90min sessions

McGill Pain Questionnaire ShortForm, Chronic Pain SelfEfficacy Scale, SF-36, RolandMorris Disability Questionnaire, Mindfulness Attention Awareness Scale, global impressions of change

MBI = EDU for disability, pain, psychological function at posttreatment and f/uboth conditions significantly improved

High functioning at baseline leading to possibility of ceiling effects; sample was predominantly high functioning, white and welleducated, limiting generalizability

4 mo

Zautra et al.87

144 with RA

RCT

CBT (n = 52) vs. MBI (n = 48) vs. EDU (n = 44)

EDU: information on ways to manage RA CBT: psychoeducation, relaxation training; activity pacing; cognitive coping; problem solving MBI: mindfulness and model of emotion; awareness; emotional well-being; acceptance and reframing; pleasant even scheduling; social relations; intimacy; stress

8 weekly 2-h sessions

NRS daily pain; Positive and Negative Affect Schedule; depressive symptoms; coping efficacy; pain catastrophizing; perceived pain control; laboratory outcomes.

CBT > MBI and EDU on selfreported pain control and IL6; CBT and MBI > EDU on coping efficacy. Participants with recurrent depression benefited most from MBI for negative and positive affect and physicians’ ratings of joint tenderness.

Low to moderate baseline levels of pain—not clear if results generalize to more impaired populations; multiple analyses raises issue of potential α inflation.

6 mo

Morone et al.88

37 with low back pain, ≥65 y

RCT

MBI (n = 19) vs. WL (n = 18)

MBI: MM and walking practice

8 weekly 90min sessions

McGill Pain Questionnaire Short-Form, Chronic Pain Acceptance Questionnaire, SF-36, RolandMorris Disability Questionnaire

MBI > WL on Chronic Pain Acceptance Questionnaire total score and Activity Engagement subscale, SF-36 Physical Function

No f/u data on WL as immediately crossed over to treatment

3 mo

Pradhan et al.89

63 with RA

RCT

MBSR (n = 31) vs. WL (n = 32)

MBSR: MM and yoga, mindful walking

8 weekly 2.5-h sessions with 3 booster sessions over following 4 mo

Symptom Checklist90-Revised, Disease Activity Score 28, Psychological Well-Being Scales, Mindful Attention Awareness Scale

MBSR = WL at posttreatment; MBSR > WL at f/u on psychological distress and well-being; no change on RA disease activity

Possible floor effect as sample had low distress and RA activity at baseline

6 mo

Grossman et al.91

58 females with FM

NonRCT

MBSR (n = 39) vs.

MBSR: mindful-

8 weekly 2.5-h

Quality of Life Profile for the

MBSR > support for

Unequal n limits statistical power

3y

4471

Active Social Support (n = 13)

ness practice, awareness during yoga, stressful situations, social interactions, homework Support: social support, relaxation training, stretching exercises, discussion, homework

sessions plus 1 allday session

Chronically Ill (QoL), Hospital Anxiety and Depression Scale (HADS), Pain Perception Scale (PPS), Inventory of Pain Regulation (IPR), visual analog ratings (VAS)

improvements in VAS pain, QoL subscales, pain coping, depression, and somatic complaints Improvements maintained at f/u

Carson et al.74

43 with low back pain

RCT

Lovingkindness meditation (Medi) (N = 18) vs. standard care (TAU) (N = 25)

Medi: silent mental phrases to direct positive feelings toward others attend to feelings of love instead of anger/ resentment, discussion, practice

8 weekly 90min sessions

McGill Pain Questionnaire (MPQ), Brief Pain Inventory (BPI), State-Trait Anger Expression Inventory (STAXI), Anger Expression and Control, Brief Symptom Inventory (BSI), diary, VAS ratings of pain and anger, affect, pain, and fatigue

Medi: improvement in pain intensity, usual pain, psychological distress, and anxiety from baseline TAU: little change Pre to f/u: Medi improved in usual pain, anxiety, psychological distress, and the phobia scale of the BSI

No direct comparison between intervention and TAU group

3 mo

Plews-Ogan et al.75

30 with musculoskeletal pain

RCT

MBSR (N = 10) vs. massage (N = 10) vs. standard care (TAU) (N = 10)

MBSR: meditation and yoga, nonjudgmental awareness, practice Massage: Swedish, deep tissue, neuromuscular, pressure point

MBSR: 8 weekly 2.5-h sessions Massage: 8 weekly 1h sessions

Pain intensity, pain unpleasantness, SF-12

Posttreatment: Massage > TAU for improvements in unpleasantness and mental status. MBSR = TAU At f/u: MBSR > TAU for improvement in mental health score

Small sample size limits statistical power

4 wk

Sagula and Rice93

57 with mixed chronic pain

NonRCT

MM (N = 39) vs. Control (C) (N = 18)

MM: 20-min daily meditation (body scan, mindfulness on breath, Hatha yoga), meditation log, development of resources for selfhealing

8 weekly 90min sessions

Response to Loss Scale (RTL) (e.g., Growth, Cope/Awareness), BDI, STAI

MM > C for reductions in depression, state anxiety, and intensity of grief from loss associated with pain. Growth: MM = C

Unequal sample sizes limits statistical power lack of f/u

None specified

Astin et al.90

65 with FM

RCT

MBSR + Qigong (n = 32) vs. EDU/ support (n = 33)

MBSR + Qigong: MM training and Qigong practices EDU: information on stress, exercise, pain/ emotions, sleep, work, intimacy

8 weekly 2.5-h sessions

Pain via SF-36, BDI; Fibromyalgia Impact Questionnaire; 6min walk test; tender point count

MBSR + Qigong = EDU at both posttreatment and f/u

High attrition

6 mo

Kabat-Zinn et al.92

90 with mixed chronic pain

NonRCT

Stress reduction and relaxation (SR and RP) (N = 69) vs. Pain Clinic

SR and RP: meditation training, Hatha yoga, homework, 45-min daily meditation

10 weekly 2h sessions

McGill-Melzack Pain Rating Index (PRI), Body Parts Problem Assessment (BPPA) scale, medically oriented symptom

Sample improvements in pain indices, mood, and psychological symptoms. SR and PR > PC for

Wide range in f/u assessments

2.5–15 mo

4472

control group (PC) (N = 21)

checklist (MSCL), Profile of Mood States (POMS), revised Hopkins Symptom Checklist (SCL90R)

improvements in anxiety, hostility, and somatization. SR and PR: larger proportion of individuals with clinically significant improvements. Maintenance at f/u

CBT, cognitive-behavioral therapy; EDU, education; EEG, electroencephalogram; IL-6, interleukin 6; MBCT, mindfulness-based cognitive therapy; MBI, mindfulness-based intervention; MBSR, mindfulness-based stress reduction; NRS, Numerical Rating Scale; RA, rheumatoid arthritis; RCT, randomized controlled trial; SF-36, Short-Form Health Survey; STAI, State-Trait Anger Inventory; TAU, treatment as usual; VAS, visual analog scale; WL, wait-list.

Given the promising preliminary evidence of group-delivered MBIs for chronic pain as compared to inert comparison conditions, a more recent focus has been on comparing MBIs to attention control conditions (such as social support), psychoeducation, and to other active treatments— primarily to CBT, given this is the “gold standard” treatment in the field.67 In one of the largest RCTs conducted to date, Cherkin and colleagues94 compared MBSR versus CBT versus usual care in a population with chronic low back pain. The results found that MBSR was as effective as CBT (both of which were significantly better than the control) for improving back pain and associated functional limitations, and the benefit in both active treatment conditions was maintained at the 52-week longterm follow-up. In a 2-year follow-up, participants in CBT compared with usual care showed greater improvement in function, whereas MBSR did not differ from usual care at 2 years.95 Clearly, further well-controlled trials comparing MBIs to other active treatments with adequately powered samples and long-term follow-up assessment time points are needed. However, the literature to date suggests that group-delivered MBIs are efficacious approaches for chronic pain management and, although not typically superior to CBT, do provide a viable alternative.

ACCEPTANCE-BASED APPROACHES TO PAIN MANAGEMENT As with MBIs, the body of research devoted to acceptance-based interventions such as ACT97 and contextual cognitive-behavioral therapy (CCBT)98 has rapidly increased since the prior edition of this book. In the 4473

aforementioned review by Veehof and colleagues,73 several of the included ACT studies entailed group treatment delivery; in total, we identified six RCTs99–104 that examined group-delivered acceptance-based approaches for heterogeneous chronic pain conditions (see Table 87.4 for a summary). Across these studies, the most consistently reported benefits of group-based ACT applied to chronic pain include improved physical and emotional functioning and increased pain acceptance, and although followup periods were short, the benefits observed were maintained. TABLE 87.4 Group Acceptance and Commitment Therapy Treatment Type

Treatment Components

RCT

Acceptance and commitment therapy (ACT) (n = 16) vs. TAU (n = 15)

ACT: psychoeducation on pain, acceptance, values, goals and committed action, mindfulness

Six 90-min sessions

104 with fibromyalgia

RCT

ACT (n = 51) vs. Pharmacologic treatment (n = 52) vs. wait-list (n = 53)

ACT: problem of control, acceptance vs. resignation, values, avoidance, mindfulness, committed action Pharm: pregabalin + duloxetine for those also with major depression

Wicksell et al.101

40 females with fibromyalgia

RCT

ACT (n = 23) vs. WL (n = 17)

McCracken et al.102

73 with fibromyalgia or depression or chronic

RCT

ACT (n = 37) vs. TAU (n = 36)

Authors

N

Study

Clarke et al.99

31 with knee or hip osteoarthritis

Luciano et al.100

Duration

Outcome Measures

Follow up (f/u)

Results

Limitations

Intermittent and Constant Osteoarthritis Pain Scale, General Health Questionnaire, Pain Anxiety Symptoms Scale, NRS Pain Intensity, Chronic Pain Acceptance Questionnaire

ACT > TAU on NRS, constant and intermittent pain, painrelated anxiety, sleep and wellbeing at 4 mo; ACT > TAU on activity engagement at 2 mo but not 4 mo

Small sample size, brief f/u, lack of fidelity monitoring, low recruitment: enrollment ratio

2 and 4 mo

Eight 2.5-h weekly sessions

VAS Pain Intensity, Hospital Anxiety and Depression Scale, Fibromyalgia Impact Questionnaire, Pain Catastrophizing Scale, Chronic Pain Acceptance Questionnaire, EuroQol

ACT > pharm and WL at both posttreatment and f/u for functional impairment, catastrophizing, anxiety, depression, subjective pain, pain acceptance, and quality of life

Lack of formal fidelity monitoring and therapist allegiance

6 mo

ACT: avoidance, valued living, clarification of values, acceptance, values-based committed action and behavioral goals, acceptance, cognitive defusion

12 weekly 90-min sessions

Pain Disability Index, Fibromyalgia Impact Questionnaire, SF-36, SelfEfficacy Scale, BDI, Spielberger StateTrait Anxiety Inventory, NRS Pain, Psychological Inflexibility in Pain Scale

ACT > WL on pain disability, fibromyalgia impact, mental health– related QOL, selfefficacy, depression, anxiety, psychological flexibility at posttreatment and f/u

Brief f/u: inclusion of only females limits generalizability

3 mo

ACT: acceptance, cognitive defusion, values-

Four 4-h sessions, 3 sessions in week 1 and 1

Roland-Morris Disability Questionnaire, Patient Health Questionnaire-

ACT > WL on depression at posttreatment; ACT > WL on depression,

Fidelity not reported; brief f/u; large number of analyses for

3 mo

4474

pain

based committed action with experiential exercises and metaphors

session a week later

9, SF-36 Physical Function, NRS Pain Intensity, Chronic Pain Acceptance Questionnaire, Acceptance and Action QuestionnaireII

pain acceptance, and disability at f/u.

small sample

Mo’tamedi et al.103

30 females with primary chronic headache

RCT

ACT (n = 15) vs. TAU (n = 15)

ACT: problem of control, engagement in meaningful activities, avoidance, values, mindfulness

8 weekly 90-min sessions

Short-Form McGill Pain Questionnaire, Migraine Disability Assessment Scale, StateTrait Anxiety Inventory

ACT > TAU on disability and affective distress; no change in pain

Lack of f/u, small sample

—

LoebachWetherell et al.104

114 with mixed chronic pain

RCT

Cognitivebehavioral therapy (CBT) (N = 57) vs. ACT N = 57)

In CBT: monitoring of thoughts, feelings, behaviors and pain; challenging negative thoughts; relaxation training; pain–fatigue cycle; pacing; problemsolving skills; assertive communication; and pleasant event scheduling. In ACT: limits of control, focus on experience; values; cognitive defusion; mindfulness of raisin exercise; committed action

Eight 90min, weekly group sessions

Brief Pain Inventory (BPI) ShortForm Interference Scale, ShortForm Health Survey (SF12), Multidimensional Pain Inventory; Beck Depression Inventory–II (BDI-II); Pain Anxiety Symptoms Scale ShortForm (PASS20), Client Satisfaction Questionnaire, Chronic Pain Acceptance Questionnaire, Survey of Pain Attitudes

CBT = ACT at both posttreatment and f/u; both led to significant improvements on interference, depression, and pain-related anxiety that were maintained at f/u. ACT > CBT on client satisfaction; CBT > ACT on treatment credibility

Lack of long-term f/u; generalizability may be limited as sample was predominantly veterans with higher levels of medical and psychiatric comorbidity, on a high number of medications

6 mo

BDI, Beck Depression Inventory; NRS, numerical rating scale; QOL, quality of life; RCT, randomized controlled trial; SF-36, Short-Form Health Survey; TAU, treatment as usual; WL, wait-list.

Several other nonrandomized trials of interdisciplinary treatment outcomes where the orientation was ACT-based have also found support for this approach; these studies were not included in Table 87.4 as it was not possible to determine the effect of group-based ACT as a standalone (i.e., ACT in the absence of combined physiotherapy, activity/exercise, nursing and anesthesiology, etc.).98,105–109 However, these studies do provide further preliminary evidence for the potential efficacy of groupdelivered ACT across a range of chronic pain conditions. To summarize 4475

these findings, results generally found interdisciplinary ACT resulted in significantly improved physical performance and quality of life; fewer sick days; and reduced pain intensity, disability, medical utilization, daytime rest, distress, depression, and pain-related anxiety, with these benefits typically maintained at follow-up. Similar to the mindfulness literature, the research examining groupdelivered ACT approaches for chronic pain has more recently transitioned to comparing ACT to other active treatments. Within a fibromyalgia sample, Luciano and colleagues100 reported that ACT resulted in significantly greater improvements across a number of pain-related outcomes in comparison to both the recommended pharmacologic treatment for fibromyalgia, as well as a wait-list control; these effects were maintained at 6-month follow-up. One RCT by Loebach-Wetherell et al.104 compared ACT to CBT in a mixed chronic pain sample and reported similar significant benefits for both treatments across physical and emotional functioning outcomes immediately following treatment and at 6month follow-up; however, ACT outperformed CBT in terms of client satisfaction, whereas treatment credibility ratings were significantly higher for CBT than ACT. Moreover, in a secondary analysis, it was found that although older adults were more likely to respond to ACT, younger adults were more likely to respond to CBT, both immediately following treatment and at follow-up.110 Across the group-delivered acceptancebased literature as a whole (including open trials), there is a large amount of variability in the number of sessions delivered, and the frequency and length of sessions per week, and much of the research has examined ACToriented interdisciplinary programs as opposed to ACT as a stand-alone psychosocial approach. However, the evidence to date is particularly promising and suggests that group-delivered ACT (especially as delivered within an interdisciplinary context) may perform as well as CBT for chronic pain management.

Factors Affecting Psychotherapeutic Outcome Although evidence for the efficacy of a number of group-delivered psychosocial treatments is accumulating, the approach with the most well 4476

developed body of research to support its use continues to be CBT. Thus, here, we focus on examining the literature that has investigated the mechanisms underlying the well-documented effects of CBT for chronic pain. Although there are many potential factors affecting group CBT treatment outcome for pain management, we have chosen to highlight four: the importance of changing cognitions, the importance of practicing skills to maintain treatment gains, the need for sufficient therapist contact to promote change, and the role of the group process itself.

THE IMPORTANCE OF COGNITIVE CHANGE The CBT approach is based on the underlying theoretical assumption that emotions and behavior are largely determined by cognitive perceptions of the world. Based on this premise, although there is no “standard” CBT protocol, a critical component of CBT for chronic pain is promoting more adaptive and realistic appraisals of pain and stress. Specifically, the basis of cognitively focused CBT for pain is on helping patients become aware of, examine, and gain control over the thoughts that influence their feelings, coping behavior, and physiology.111 Given the plethora of research that has consistently found that pain catastrophizing is a robust predictor of a range of negative outcomes (above and beyond other factors such as disease severity, pain intensity, anxiety, and neuroticism), this construct represents a key cognitive mechanism targeted in many CBT programs.112–119 Research has found that treatment-related reductions in pain catastrophizing during CBT-oriented interdisciplinary treatment correlate with improvement in pain-related outcomes.120,121 In another study by Thorn and colleagues,29 it was found that tailoring CBT specifically toward the reduction of catastrophizing is particularly effective for headache pain, with treatment-related reductions in pain catastrophizing correlating with improvement in several treatment outcome variables. Furthermore, Burns and colleagues122,123 used lagged and cross-lagged analyses and found that early treatment reductions in pain catastrophizing predicted late-treatment improvements in pain-related outcomes, but not vice versa during CBT-oriented interdisciplinary treatment programs. Additional cognitive variables that have been found to correlate with improved outcomes during CBT include self-efficacy,29,124 4477

perceived pain control,120,125 pain helplessness,126 and other pain-related beliefs.120 Other research has also shown CBT to shift implicit pain selfassociations, and this shift was correlated with improved self-esteem.127 More recent research has identified that changes in cognitions, such as pain catastrophizing is likely not a mechanism specific to group CBT for pain, however. For example, Thorn and colleagues conducted secondary analyses of the RCT described earlier128 (within the low-income population with low health literacy skills24) and found that the observed similar efficacy between group CBT and education might have been accomplished through similar mechanisms, with pain catastrophizing found to account for pre- to posttreatment differences in outcomes across both conditions. Smeets et al.129 found that treatment-related changes in pain catastrophizing similarly mediated outcome across both CBT as well as physical treatments for chronic low back pain. Turner et al.130 also found that pain catastrophizing similarly improved across both groupdelivered CBT and MBSR.130 Moreover, this same study by Turner’s group identified similar effects on mindfulness, acceptance, and pain management self-efficacy for both CBT and MBSR. Consistent with this, other research examining group CBT-based multidisciplinary pain programs has found that pain acceptance (which is a treatment target theoretically specific to acceptance-based treatments) was correlated with improvement in pain outcomes,131,132 and another study showed CBTrelated changes in mindfulness was associated with improved pain outcomes.133 Taken together, this research suggests that beneficial outcomes during group-delivered CBT (as well as other psychosocial treatments) might be due to widespread changes across a range of both theory-specific and theory-nonspecific, as well as adaptive and maladaptive, pain-related cognitions of which pain catastrophizing is just one (albeit potent) factor.134 These findings have led some researchers to posit that global changes in cognitions associated with CBT (e.g., the way one relates to and conceptualizes chronic pain, appraisal processes, confidence in one’s ability to cope, altered pain self-associations) may be more important to positive outcome than increases in the performance of specific skills taught in CBT per se.135,136 However, this view is yet to be empirically tested, and as discussed in more depth in the next section, it is 4478

more commonly theorized that skills practice is a necessary but perhaps not sufficient factor (i.e., cognitive change is also needed) for improving outcomes.

COMPLIANCE WITH HOMEWORK AND SKILLS PRACTICE TO MAINTAIN TREATMENT GAINS The CBT approach is designed to be an empowering intervention that teaches patients skills that they themselves can continue to use to selfmanage pain, long after completion of treatment delivery. Thus, when considering whether a valid clinical trial of CBT has been conducted, there must be some demonstration that patients are independently practicing these coping skills at an adequate level as this is theorized to be a key precipitating factor in engendering the earlier described cognitive changes. Treatment enactment refers to the extent that clients actually apply what they have learned out of the treatment session. Homework or practice of skills learned in treatment is one way to measure treatment enactment. Scharff and Marcus137 found that individuals with headache pain who practiced the skills taught in treatment (which included physical therapy, headache-free diets, and relaxation) were more likely to maintain their treatment gains when measured at follow-up. Likewise, completion of homework assignments were significantly related to treatment outcome in patients with irritable bowel syndrome (IBS) participating in group CBT.35 Vlaeyen et al.44 compared group education plus CBT to group education plus attention control (group discussion) and noted that in the CBT group, compliance with completion of homework assignments was quite low, which might increase risk for relapse long-term. Indeed, research underscores the problem of relapse following CBT and other psychosocial pain interventions.138 Although it has been assumed that posttreatment variability in maintenance trajectories depends at least in part on the maintenance of coping skills practice, few studies have empirically examined if this is the case. One important study comparing individually delivered CBT to treatment as usual that examined a 2-week posttreatment epoch identified that on average, continued use of active cognitive and behavioral coping, positive affect, self-efficacy, and perceived control over pain was associated with maintenance of gains, and 4479

pain catastrophizing and negative affect were associated with loss of gains.139 Although innovative approaches to enhancing skills practice have been applied, the beneficial effects of these maintenance model approaches has been somewhat limited.140,141 The less than optimal efficacy of these relapse prevention interventions may stem from a lack of understanding of the mechanisms of posttreatment improvement, maintenance, and relapse, and future research in this area is critically needed.

IMPORTANCE OF THERAPIST SKILL AND ADEQUATE TIME WITH THERAPIST Given the lack of compelling evidence to date in regard to change in cognitions being specific to CBT, it has been postulated that beneficial effects may be wrought via change in nonspecific factors.134,142 From the inception of CBT, Beck and colleagues143 ascribed importance to the presentation of a convincing treatment rationale in the first CBT session. In this context, it has been argued that more experienced/skillful therapists will deliver a more credible and persuasive rationale and will more likely be perceived as “experts.” Importantly, this treatment rationale also functions to foster a collaborative therapeutic alliance and generate positive expectations—factors which have repeatedly been demonstrated to influence outcome across a range of studies and population types.69,144,145 Furthermore, although trials specifically designed to evaluate the contribution of therapist expertise/skill in group CBT for chronic pain in relation to outcomes are lacking, in the CBT for depression literature, it has been found that compared to those treated by less experienced clinicians, patients of experienced clinicians tend to show more improvements.146 Within the group CBT for chronic pain literature included in Table 87.2, there was a large amount of variability across studies regarding the professional discipline of the delivering interventionist (i.e., psychologist, nurse, physiotherapist, etc.), the length and form of therapist training procedures specific to the study protocol, the degree of therapist expertise/experience (i.e., graduate student, postdoctoral student, licensed clinical psychologist), and the amount of time therapists spend with patients (i.e., treatment dose) as well as in the number of therapists in the 4480

room leading any one group. Moreover, treatment fidelity (also known as treatment integrity) was not routinely reported, and when fidelity ratings were reported, there was also variability in what precisely was coded and described (i.e., adherence, appropriateness and quality, or any combination of the three). Thus, the specific role of therapist factors along with the “dose” of time a patient spends with the therapist is not well quantified in group CBT for pain research.67 However, available evidence across other population types suggests such therapist factors play a critical role in outcomes, and it will be important for future research to establish the size of these effects in the context of group CBT for chronic pain.

IMPORTANCE OF GROUP PROCESS Research across various populations (i.e., not specific to pain) has shown that group processes developed during treatment, such as cohesion and social learning, have the capacity to become agents of change in and of themselves.147 In our review of the group pain management literature, we located one open clinical trial and one RCT that offered interesting qualitative information regarding the importance of group process. Moore et al.148 identified that failure to improve during a multidisciplinary treatment depended in part on whether other members of the same treatment group also failed to respond (or left the program prematurely due to dissatisfaction). In another study by Day et al.,149 qualitative data from recorded semistructured interviews with participants who completed either group CBT or pain education (as a component of Thorn et al.’s24 earlier described RCT among low-income patients who generally had low health literacy) were thematically analyzed. Group cohesion emerged as one of the most robust themes identified across both CBT and education, and within this overarching theme, subtheme processes of “learning together/sharing” and a “feeling of not being alone” were identified as exceptionally valued aspects of both treatments. A sense of “feeling like a family” was a further subtheme reported by participants who completed CBT but not education. More research is needed to clarify the role of such nonspecific treatment factors in treatment outcome. However, the earlier studies highlight the importance of social factors in chronic pain and underscore the caveat that group treatment should be designed to capitalize 4481

on these social influences.

Advantages of Group Treatment EFFICIENCY AND COST-EFFECTIVENESS Given the general lack of difference in treatment outcomes between group and individual CBT, it could reasonably be argued that group treatment is a more efficient modality of therapy for chronic pain disorders. Certainly, group treatment is cheaper in terms of practitioner time and patient expense. Indeed, in a study by Bruns and colleagues150 that used Medicare reimbursements rates to compare the cost of a typical lumbar spinal fusion to the cost of a 10-session group-delivered CBT program, it was found that the surgical costs alone were 168 times greater than the costs of delivering the CBT program. However, cost-effectiveness depends not only on cost but also on relative effects. Reviews of the literature have identified that psychosocial approaches such as CBT are at least as efficacious as surgery and medication management for pain.151,152 Other research153 has examined the costeffectiveness of adding CBT to an inpatient rehabilitation program compared to standard rehabilitation without CBT; there were no significant differences between direct medical or nonmedical costs, and CBT showed lower indirect costs. Furthermore, 6 months following treatment, those who additionally received CBT were absent from work an average of 5.4 days less than those who received standard care.153 Similar results were reported in an outpatient setting by Lamb and colleagues25 who examined the cost-effectiveness of adding six sessions of group CBT to a standard active management advisor consultation versus the consultation alone; over 1 year, the group who had additionally received CBT had a sustained benefit in pain-related disability at low-cost to the health care provider. However, “more is not always better,” as described by Smeets and colleagues154 who compared the cost-effectiveness of active physical treatment versus graded activity and problem solving versus a combination of these treatments; the combination treatment did not result in significantly greater improvements in quality adjusted life years or disability as compared to the single treatment modalities, and it 4482

was not deemed cost-effective.

SOCIAL PROXIMITY AND SUPPORT There are several other advantages to using a group modality with patients who have chronic pain-related conditions: A group approach provides social interaction and support from others who share common distressing experiences including the pain itself as well as secondary stressors associated with the pain such as frustrating interactions with the health care system, economic hardship, and deteriorating family relationships. Individuals struggling with chronic pain often feel isolated and misunderstood. Disclosing thoughts and feelings to others who share similar concerns offers patients a greater sense of legitimacy than might be experienced by sharing thoughts and feelings with a therapist or significant other who does not experience pain. More times than not, other patients in the group will have had similar experiences that they also share, which is validating to the person who originally disclosed their concerns, leading to a sense of “not being alone.” Qualitative studies of people who have previously completed group-delivered CBT have found that sharing experiences and learning together, as well as being listened to, understood, accepted, tolerated, and affirmed, were highly valued perceived benefits of the group approach for pain management.149,155 Beyond the social support provided by others who share similar concerns (which is considered a nonspecific treatment factor), group CBT seems to offer additional benefits. Studies have shown group CBT to be superior to group relaxation sessions64 and to group discussion sessions,57 both of which offer the type of social support received in group CBT. Maunder and Esplen156 reported that a supportive-expressive group for patients with inflammatory bowel disease did not improve symptoms of gastrointestinal (GI) distress/pain, patient quality of life, anxiety, or depression, and they concluded that, at least for this population, supportive-expressive group therapy alone is not efficacious.

VICARIOUS LEARNING AND MODELING OF COLLABORATIVE APPROACH Group treatment provides clinicians with multiple scenarios to choose 4483

from and build on during group discussions, which is helpful when illustrating a particular teaching point. Taking advantage of a salient example and using it for the benefit of the entire group maximizes the likelihood that patients will understand the intervention through vicarious learning (i.e., other group members observing a therapeutic interaction between an individual patient and the therapist). Moreover, group treatment provides a fertile venue for modeling a collaborative approach to treatment between the patient and the practitioner. Early in the group process, the leader establishes the expectation that patients will actively participate in group discussions, selfmonitor their activities, and complete homework assignments. Through selective reinforcement of patients who actively engage in their treatment by participating in the group and completing the homework assignments, the leader can strive to increase active coping in all of its members. A qualitative study of group CBT treatment with women suffering from chronic pelvic pain revealed that this collaborative approach facilitates a therapeutic progression beginning with developing self-knowledge, followed by assuming responsibility for self-management, and ending with increasing self-control and personal mastery of emotions.157 Similar results were found by Day and colleagues149 in their qualitative analysis of literacy-adapted CBT versus pain education in a rural, minority population. Participants reported valuing the collaborative rapport and group learning environment, and many found that working through thought record homework activities in session on a flip chart with the therapist was particularly important for acquiring the cognitive restructuring skill set.149

INTERPERSONAL GROUP PROCESS A final potential advantage of group treatment is the use of group process to facilitate treatment gains (i.e., utilizing the interpersonal exchange between group members in addition to the exchange between therapist and the patient). A group of patients provides an opportunity to capitalize on the moment-by-moment interchanges among group members as well as the interpersonal relationships that develop over time. It is noteworthy that group members will often accept positive feedback, negative feedback, 4484

and confrontation from other group members better than from the group leader. This may not only be due in part to feeling more understood by a fellow patient (someone who has “walked in my shoes”) but may also be due to the power of the interpersonal process that occurs in group settings.

Practical Issues OPEN VERSUS CLOSED GROUPS Most controlled studies in the literature have focused on time-limited, closed groups. In research, this is a necessity to control for a number of confounding variables that ongoing, open groups would introduce into a research design. There are also clinical advantages to running a closed group where all members start and end group treatment at the same time. From a practical perspective, however, running closed groups can prove difficult in some clinical settings because new patients would be required to wait until a new group starts to begin treatment. In response to this concern, Thorn111 adapted her 10-session CBT manual so that the modules were less dependent on each other, with an introductory session provided to any patient just starting out (i.e., before he or she joins an ongoing group). The feasibility and effectiveness of such an approach has not been tested but may hold particular importance for patients such as injured workers, who are under pressure to return to work. Furthermore, such practical adaptations, if found to be effective, would also increase the probability of implementation in real-world settings.

LENGTH OF GROUP The length of the groups varied in the RCTs reviewed for this chapter, ranging from 5 to 12 sessions, with a modal number of 10 sessions. Most RCTs reported meeting weekly for 90-minute sessions. Time-limited groups are the accepted standard in research trials because treatment manuals are usually highly structured, and demonstrating fidelity of treatment through therapist adherence to the protocol is an important component of treatment implementation.158 Furthermore, treatment groups of varying lengths would introduce variance that would reduce the statistical power required to detect real differences between treatment and 4485

control groups. On the other hand, clinical realities often necessitate varying the length of a particular treatment component based on whether or not the intervention has been understood by the group members. In clinical settings, there may indeed be some situations in which it would be well advised to repeat a particular unit, continue coverage of a particular topic, or adapt the treatment protocol in some other way. An example of this is Thorn’s research described earlier, where the CBT and pain education materials were adapted for patients attending low-income clinics, many of whom also had low health literacy.18,24

NUMBER OF PARTICIPANTS A group composed of approximately five to six members is of sufficient size to facilitate interaction among group members, accommodate the absence of a member without jeopardizing group cohesiveness, and provide enough time to attend to each patient during the individual sessions. Most CBT groups will have more women than men because women have more chronic pain problems, present more frequently for pain treatment than men,159 and may be more receptive to group interventions based on their tendency to cope via a communal support process.160 Indeed, one study found that women improved more than men on a number of pain-related outcomes during a multimodal pain management program that included both individual as well as group therapy components.161 Differences in age, ethnicity, and cultural background do not appear to jeopardize the group process perhaps because chronic pain serves as a unifying factor, making other potentially divisive issues less important. We were unable to identify any studies addressing the issue of whether it is important to racially match group leaders with participants. In an unpublished follow-up qualitative study using posttreatment key informant interviews with African American members of a CBT headache management group 2 years after the RCT had been completed,29 those interviewed thought that including therapists of different racial and ethnic backgrounds as group leaders would enhance the comfort level of participants and thus increase both their willingness to participate and their chances of treatment completion. In mixed race groups, it is probably preferable to have at least one of the cotherapists be a person of different 4486

racial and/or ethnic background.

INDIVIDUALS WHO MAY BE INAPPROPRIATE FOR GROUPS Almost anyone deemed appropriate for individual CBT for pain management is appropriate for group treatment, but there are a few exceptions. Patients with moderate to severe dementia or other cognitive impairment, psychosis, or chronic interpersonal relationship problems have typically been considered inappropriate for group treatment. However, a published protocol by Kennedy et al.162 described a mixed methods controlled trial that they were conducting to investigate an adapted group CBT program for women with mild to moderate intellectual disabilities and menstrual pain; to the best of our knowledge, although the trial is listed as completed on the trial registry, the results have not been published. Further research to examine modified CBT programs to reduce the cognitive load and needed literacy level for effective participation is needed. In addition, it is not unusual for individuals with chronic pain to have problems managing anger, and in some cases, the degree of anger and hostility may be a contraindication for group treatment. In these cases, however, it is often possible to help the patient learn to regulate his or her anger and hostility in individual treatment and then invite him or her to participate in a group at a later date. Keefe et al.1 noted that they sometimes use a “time-out” strategy for group members whose anger is disruptive or in other ways countertherapeutic, in which patients meet individually with group leaders while continuing to attend the group but remaining silent for two to three sessions. Clearly, if a patient expresses a strong preference for individual treatment or if his or her schedule prohibits involvement at the prescribed group time, an individual approach will need to be employed.

Summary and Conclusions Group treatment approaches for pain management have been clearly established as efficacious. Although the evidence for MBIs and ACT has 4487

grown exponentially over the past decade, the vast majority of controlled research studies continue to be focused on CBT group approaches. The available research suggests that there are few differences in treatment outcome between group and individual CBT for chronic pain. Thus, because group treatment is more efficient in terms of therapist time and more economical for patients, we suggest that group treatment is generally the favored modality. Certainly, not all patients are appropriate for group pain management, and logistical difficulties in organizing and running a group prevent the universal adoption of group treatment as the only method of appropriate treatment. Relatedly, some patients may need more intensive psychotherapy than what the typical group approach has to offer. It is therefore quite appropriate to refer certain patients for individual treatment after the completion of group treatment.

Future Directions It is important to note that although the extant research literature has established the efficacy of group CBT for pain management, the external validity of research-based efficacy trials has yet to be studied (i.e., effectiveness studies). Because the efficacy studies cover a wide range of pain problems and come from a variety of research laboratories both inside and outside the United States, we may feel more confident in the generalizability of the results. Methodologically, an important next step would be to move toward pragmatic randomized controlled trials (pRCT), which would help provide information necessary for implementation in routine clinical practice. Furthermore, future research such as that initiated by Thorn and colleagues exploring appropriate adaptations for local populations with special needs will help establish the effectiveness of group approaches for real-world settings.18,24 Other important issues include enhancing access, durability of treatment effects, and identifying and facilitating reliable mechanisms for reimbursement. Recently published national clinical practice guidelines stress nonpharmacologic evidence-based alternatives to pain medications and specifically list CBT as one of those options.163–166 Notably, the 2017 MD Chronic Pain Guidelines reviewed all available high-quality research on 4488

364 treatment × condition pairs. Of these, CBT and only seven other treatments are listed as having consistent evidence of efficacy, no risk of mortality, limited or no side effects, and low cost.166 Although other formats for treatment delivery of CBT have been developed to increase accessibility (e.g., online resources), the power of group participation in patients who are socially isolated cannot be underestimated. Two other areas in need of more research are cost-effectiveness studies and research examining the specific mechanisms associated with treatment efficacy. Regarding cost-effectiveness, such research is particularly difficult to carry out in health care settings without readily available (electronic and universal) health care utilization information. Regarding the identification of specific treatment factors responsible as the agent of change, the research conducted up to this point offers a promising start that efficacious group CBT is more than simply therapeutic and social support. However, the mechanisms that may be specific to CBT versus shared across all active treatments for chronic pain need further investigation. Also lacking is well-formulated algorithms for tailoring CBT to the specific baseline cognitive and behavioral profiles of patients in order to most effectively and efficiently target change mechanisms to optimize outcomes. Although yet to be empirically tested a priori, the limit, activate and enhance model recently proposed by Day et al.,167 provides a theorydriven moderation model for guiding the matching of patients to the evidence-based treatment mostly likely to be of benefit on the basis of key baseline characteristics. The determination of the need for preparatoryoriented interventions (i.e., such as motivational interviewing to prepare readiness to change) is also integrated into this framework. This model provides the first theory-driven framework for algorithm-based interventions within the pain management context; further research testing this model is needed to further refine and optimize its tenets. Finally, there is a clear need for improvements in the reporting of groupdelivered treatments across the chronic pain literature. Current reports often omit details regarding theory, design, and delivery features that have been shown to be of importance in the group setting. Indeed, a recent review identified that only 12% of studies investigating group-based behavioral change programs for chronic musculoskeletal pain reported a 4489

theoretical basis for the intervention(s) delivered.168 The insufficient reporting of critical design, implementation, and evaluation processes impedes efforts to compare group-delivered psychological treatments across studies, reduces the capacity to replicate effective treatments, and limits the capacity to synthesize the evidence of effects.169 Although systematic reviews and meta-analysis of group treatments for chronic pain are lacking, to assist in the future conduct of such studies, it is recommended that future RCTs of group-delivered treatments follow the reporting guidelines for group-delivered interventions proposed by Borek et al.169 As health care practitioners of all disciplines become more and more reliant on systematic reviews to support evidence-based practice, comprehensive reporting of design and delivery features and a thorough systematic review and meta-analysis of group treatments for chronic pain would represent certain contributions to the literature.

Appendix 87.1: Search Strategies The search strategy implemented in the prior edition of this chapter was extended to search the updated literature published since the end point of the prior review (March 2007, dating back to 1950) until August 2017. Specifically, the Cochrane Database was searched along with MEDLINE, PsycINFO, PsycARTICLES, CINAHL Complete, and Academic Search Complete using EBSCOhost as an interface to search for group treatments for (1) gastrointestinal disorders; (2) back, facial, neck, neuralgia, and intractable pain; (3) pelvic pain, dysmenorrheal, and vulvar diseases; and (4) headache disorders. The search was limited to “human” studies published in “English.” 1. Search strategy 1. exp psychotherapy, group (15,111) 2. exp colonic diseases (208) 3. 1 and 2 (7) 2. Search strategy 1. exp psychotherapy, group/ (4,397) 2. back pain/ or facial pain/ or neck pain/ or neuralgia/ or pain, intractable/(36,108) 4490

3. 1 and 2 (186) 3. Search strategy 1. exp psychotherapy, group/ (4,689) 2. exp pelvic pain/ or exp dysmenorrhea/ or vulvar diseases (3890) 3. 1 and 2 (5) 4. Search strategy 1. exp group psychotherapy/ (4860) 2. exp Headache/ (15,574) 3. 1 and 2 (5) References 1. Keefe FJ, Beupre PM, Gil KM. Group therapy for patients with chronic pain In: Turk DC, Gatchel RJ, eds. Psychological Approaches to Pain Management: A Practitioner’s Handbook. 2nd ed. New York: Guilford Press; 2002:234–256. 2. Gamsa A, Braha RE, Catchlove RF. The use of structured group therapy sessions in the treatment of chronic pain patients. Pain 1985;22(1):91–96. 3. Blanchard EB, Schwarz SP. Adaptation of a multicomponent treatment for irritable bowel syndrome to a small-group format. Biofeedback Self Regul 1987;12(1):63–69. 4. Herman E, Baptiste S. Pain control: mastery through group experience. Pain 1981;10(1):79– 86. 5. Straus SE, Richardson WS, Glasziou P. Evidence-Based Medicine: How to Practice and Teach EBM. 3rd ed. London: Elsevier/Churchill Livingstone; 2005. 6. McKibbon A. PDQ: Evidence-Based Principles and Practice. Hamilton, Canada: B.C. Decker; 1999. 7. Eccleston C, Hearn L, Williams AC. Psychological therapies for the management of chronic neuropathic pain in adults. Cochrane Database Syst Rev 2015;(10):CD011259. 8. Williams AC, Eccleston C, Morley S. Psychological therapies for the management of chronic pain (excluding headache) in adults. Cochrane Database Syst Rev 2012;(11):CD007407. 9. de Boer MJ, Versteegen GJ, Vermeulen KM, et al. A randomized controlled trial of an Internet-based cognitive-behavioural intervention for non-specific chronic pain: an effectiveness and cost-effectiveness study. Eur J Pain 2014;18:1440–1451. 10. Kääpä EH, Frantsi K, Sarna S, et al. Multidisciplinary group versus individual physiotherapy for chronic nonspecific low back pain. Spine 2006;31(4):371–376. 11. Turner-Stokes L, Erkeller-Yuksel F, Miles A, et al. Outpatient cognitive behavioral pain management programs: a randomized comparison of a group-based multidisciplinary versus an individual therapy model. Arch Phys Med Rehabil 2003;84(6):781–788. 12. Frettlöh J, Kröner-Herwig B. Individual versus group training in the treatment of chronic pain: which is more efficacious? J Clin Psychol 1999;28:256–266. 13. Rose MJ, Reilly JP, Pennie B, et al. Chronic low back pain rehabilitation programs: a study of the optimum duration of treatment and a comparison of group and individual therapy. Spine 1997;22(19):2246–2251. 14. Johnson PR, Thorn BE. Cognitive behavioral treatment of chronic headache: group versus individual treatment format. Headache 1989;29(6):358–365. 15. Spence SH. Cognitive-behavior therapy in the management of chronic, occupational pain of the upper limbs. Behav Res Ther 1989;27(4):435–446.

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132. Baranoff J, Hanrahan S, Kapur D, et al. Acceptance as a process variable in relation to catastrophizing in multidisciplinary pain treatment. Eur J Pain 2013;17:101–110. 133. Cassidy EL, Atherton RJ, Robertson N, et al. Mindfulness, functioning and catastrophizing after multidisciplinary pain management for chronic low back pain. Pain 2012;152(3):644– 650. 134. Burns J, Nielson WR, Jensen MP, et al. Does change occur for the reasons we think it does? A test of specific therapeutic operations during cognitive-behavioral treatment of chronic pain. Clin J Pain 2015;31:603–611. 135. Sil S, Kashikar-Zuck S. Understanding why cognitive-behavioral therapy is an effective treatment for adolescents with juvenile fibromyalgia. Int J Clin Rheumatol 2013;8(2). 136. Hofmann SG, Asmundson GJ. Acceptance and mindfulness-based therapy: new wave or old hat? Clin Psychol Rev 2008;28(1):1–16. 137. Scharff L, Marcus DA. Interdisciplinary outpatient group treatment of intractable headache. Headache 1994;34(2):73–78. 138. Turk DC, Rudy TE. Neglected topics in the treatment of chronic pain patients - relapse, noncompliance, and adherence enhancement. Pain 1991;44:5–28. 139. Litt MD, Shafer DM, Ibanez CR, et al. Momentary pain and coping in temporomandibular disorder pain: exploring mechanisms of cognitive behavioral treatment for chronic pain. Pain 2009;145:160–168. 140. Naylor MR, Keefe FJ, Brigidi B, et al. Therapeutic interactive voice response for chronic pain reduction and relapse prevention. Pain 2008;134(3):335–345. 141. Keefe F, Van Horn Y. Cognitive-behavioral treatment of rheumatoid arthritis pain. Arthritis Care Res 1993;6(4):213–222. 142. Day MA, Thorn BE, Burns J. The continuing evolution of biopsychosocial interventions for chronic pain. J Cogn Psychother 2012;26(2):114–129. 143. Beck AT, Rush AJ, Shaw B, et al. Cognitive Therapy of Depression. New York: Guilford Press; 1979. 144. Jensen M, Nielson WR, Kerns RD. Toward the development of a motivational model of pain self-management. J Pain 2003;4:477–492. 145. Day MA, Halpin J, Thorn BE. An empirical examination of the role of common factors of therapy during a mindfulness-based cognitive therapy intervention for headache pain. Clin J Pain 2016;32(5):420–427. 146. Ilardi SS, Craighead WE. The role of nonspecific factors in cognitive-behavioral therapy for depression. Clin Psychol Sci Pract 1994;1(2):138–155. 147. Yalom ID, Leszcz M. The Theory and Practice of Group Psychotherapy. 5th ed. New York: Basic Books; 2005. 148. Moore ME, Berk SN, Nypaver A. Chronic pain: inpatient treatment with small group effects. Arch Phys Med Rehabil 1984;65(7):356–361. 149. Day MA, Thorn BE, Kapoor S. A qualitative analysis of a randomized controlled trial comparing a cognitive-behavioral treatment with education. J Pain 2011;12(9):941–952. 150. Bruns D, Mueller K, Warren PA. Biopsychosocial law, health care reform, and the control of medical inflation in Colorado. Rehabil Psychol 2012;57(2):81–97. 151. Eccleston C, Palermo TM, Williams AC, et al. Psychological therapies for the management of chronic and recurrent pain in children and adolescents. Cochrane Database Syst Rev 2009; (2):CD003968. 152. Morley S, Williams A. New developments in the psychological management of chronic pain. Can J Psychiatry 2015;60(4):168–175. 153. Schweikert B, Jacobi E, Seitz R, et al. Effectiveness and cost-effectiveness of adding a cognitive behavioral treatment to the rehabilitation of chronic low back pain. J Rheumatol

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2006;33(12):2519–2526. Smeets RJ, Severens JL, Beelen S, et al. More is not always better: cost-effectiveness analysis of combined, single behavioral and single physical rehabilitation programs for chronic low back pain. Eur J Pain 2009;13(1):71–81. Steihaug S, Ahlsen B, Malterud K. “I am allowed to be myself”: women with chronic muscular pain being recognized. Scand J Public Health 2002;30(4):281–287. Maunder RG, Esplen MJ. Supportive-expressive group psychotherapy for persons with inflammatory bowel disease. Can J Psychiatry 2001;46(7):622–626. Albert H. Psychosomatic group treatment helps women with chronic pelvic pain. J Psychosom Obstet Gynaecol 1999;20(4):216–225. Lichstein KL, Riedel BW, Grieve R. Fair tests of clinical trials: a treatment implementation model. Adv Behav Res Ther 1994;16:1–29. Unruh AM. Gender variations in clinical pain experience. Pain 1996;65:123–167. Lyons RF, Mickelson KD, Sullivan MJ, et al. Coping as a communal process. J Soc Pers Relat 1998;15(5):579–605. Pieh C, Altmeppen J, Neumeier S, et al. Gender differences in outcomes of a multimodal pain management program. Pain 2012;153:197–202. Kennedy S, O’Higgins S, Sarma K, et al. Evaluation of a group based cognitive behavioural programme for menstrual pain management in young women with intellectual disabilities: protocol for a mixed methods controlled clinical trial. BMC Womens Health 2014;14:107. Institute of Medicine. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Washington, DC: National Academies Press; 2011. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain— United States, 2016. JAMA 2016;315(15):1624–1645. The Opioid Therapy for Chronic Pain Word Group. VA/DoD Clinical Practice Guideline for Opioid Therapy for Chronic Pain. Washington, DC: U.S. Department of Veterans Affairs, Office of Quality and Performance, Office of Evidence Based Practice; 2017. Qaseem A, Wilt TJ, McLean RM, et al. Noninvasive treatments for acute, subacute, and chronic low back pain: a clinical practice guideline from the American College of Physicians. Ann Intern Med 2017;166(7):514–530. Day MA, Ehde DM, Jensen MP. Psychosocial pain management moderation: the limit, activate and enhance model. J Pain 2015;16(10):947–960. Keogh A, Tully MA, Matthews J, et al. A review of behaviour change theories and techniques used in group based self-management programmes for chronic low back pain and arthritis. Manual Ther 2015;20:727–735. Borek A, Abraham C, Smith JR, et al. A checklist to improve reporting of group-based behaviour-change interventions. BMC Public Health 2015;15:963.

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CHAPTER 88 Motivating Chronic Pain Patients for Behavioral Change AKIKO OKIFUJI, EMILY HAGN, CHRISTINA ELISE BOKAT, and DENNIS C. TURK Motivation is a primary determinant of human behavior, influencing its initiation, direction, intensity, and persistence.1 Historically, motivation has not been a central issue in health care as the modal approach to treat illness was believed to require very little active participation from patients beyond complying with advice. However, as our appreciation of the growing number of chronic diseases for which there are no cures, the importance of helping patients become active in a treatment has been increasingly noted. Patients have described the importance of motivation and accountability, particularly when they become discouraged or have difficulty with treatment adherence.2,3 This realization has led to motivation and motivation enhancement being given greater attention. Self-management approaches for managing health have gained in importance as potential methods to increase motivation for selfmanagement and to facilitate long-term health-relevant behaviors. There is a large volume of literature indicating that even relatively simple behaviors, such as taking medication in the prescribed manner, can be problematic. Studies have reported that depending on how it is defined and measured, the rates of nonadherence to medication in adults range anywhere from 8% to 62%.4,5 In general, one-third of patients can be expected to be nonadherent.6 Treatment nonadherence is also a significant behavioral health problem and public health concern in pediatric populations. Approximately 50% of children7 and 65% to 90% of adolescents8,9 are nonadherent across pediatric conditions. For patients with chronic pain, rehabilitation rather than complete cure is most realistic. One of the critical requirements for successful 4500

rehabilitation is that patients adopt an active, participatory role in their treatments, coping with symptoms and life changes, and adjustment to their circumstances. Literature consistently acknowledges that multidisciplinary pain care, which includes an activating therapy, is helpful for restoring functioning and improving quality of life, without complete elimination of pain.10 However, such a treatment requires patients to make significant lifestyle changes including the incorporation of various functional activities in their daily routines. Maintaining these changes over long periods of time is often difficult even for healthy individuals. For example, two-thirds of those who sign up with gyms never use the facility,11 and 50% drop out of physical activity programs within the first 6 months.12 Thus, it is hardly surprising that patients with chronic pain find it difficult to adhere to regular physical activity regimens, use of coping skills, engaging in problem solving, and modifying communication patterns with family, friends, and coworkers as well as health care providers. In the one study that directly examined the issue of adherence to pain rehabilitation recommendations, Lutz et al.13 followed patients 8 months after they had been successfully treated at pain rehabilitation and found that, based on self-report, the rates of adherence with each of the specifically recommended behaviors (e.g., progressive ambulation and stretching exercises, regular application of ice and heat, relaxation) averaged about 42% and with all of the recommendations proscribed by the treatment program was only 12.2%. Another dilemma for successful implementation of activating therapy is that it can be contrary to the very nature of pain where the motivational drive is to avoid or escape from any activities that might increase pain. Furthermore, most people including many health care providers have learned “if something hurts, don’t do it.” This approach may be appropriate for acute pain care where may pain serve a protective role. However, for chronic pain, equating hurt with harm often becomes a barrier for successful rehabilitation and even increases disability following loss of mobility, strength, and endurance from inactivity. Thus, clinicians are frequently faced with the challenge of how to motivate patients to actively engage in the treatment recommendations that may seem counter to patients’ acquired beliefs. Long-term treatment success, in particular, 4501

depends on regular adherence to recommended self-care regimens,6,14,15 although how close to the recommendations is an open question.16,17 Historically, clinicians have invested less energy in patients who show little commitment to follow through with recommended therapies. “You can lead a horse to water, but you can’t make it drink” was a typical way of conceptualizing the issue.18 However, as noted earlier, motivation to commit to the treatment plan and adherence with regimen are essential in successful pain rehabilitation (pharmacologic as well as rehabilitative).17 Thus, motivating patients for behavioral change is essential and a critical clinical issue in successful pain management. In this chapter, we review the two approaches to optimize motivation and engagement of patients: motivation enhancement therapy (MET) and implementation intentions (IIs).

Neural Mechanisms of Motivation Neural mechanisms of motivation are complex, involving multiple brain systems.19 Although motivation is a critical component of recovery from chronic pain, how specific neural factors underlie the motivational factors relevant to people with chronic pain is not well understood. However, we may consider how chronic pain itself as well as comorbid dysfunctions could contribute to the motivational state of chronic pain patients to adhere to specific recommendations. Chronic pain commonly outlives peripheral tissue injury or actual neural damage; yet, long-lasting changes in the modulations of pain due to neural plasticity and central sensitization have been well documented in various chronic pain conditions.20,21 Neuroimaging studies in humans have demonstrated alterations in the reward, motivational, emotional, and cognitive brain centers that may play a role in establishing and/or maintaining chronic pain.22–24 In addition, it has been hypothesized that some chronic pain syndromes may be maintained by dysregulation of homeostatic reward processes similar to those described in addiction neurobiology.25 Addiction and chronic pain disorders may share central reward deficiency and motivational maladaptation patterns secondary to hypodopaminergic states in the nucleus accumbens core (NAc) and medial 4502

prefrontal cortex (mPFC) and alterations in endogenous pain transmission pathways.26–28 Furthermore, a study in mice by Schwartz et al.29 suggests that chronic pain induces synaptic changes within the NAc, which plays a central role in the neural circuitry that modulates motivation.29,30 Such pain-induced synaptic changes can have a negative impact on patients’ motivation,29,31,32 which in turn could lead to difficulty in adhering to a treatment plan for their chronic pain. In addition to the painful symptoms, individuals who have chronic pain often experience a multitude of quality of life–altering symptoms such as anxiety, depression, fatigue, sleep disturbance, elevated stress levels, activity reduction, and cognitive deficits.31–34 Such comorbidities can further decrease motivation to initiate and complete goal-directed and higher order mental and physical tasks.29 Thus, individuals can experience a twofold impairment of motivation secondary to both chronic pain itself and its comorbidities.

Concept of Readiness to Change: Transtheoretical Model of Behavior Change The transtheoretical model of behavior change was developed in an attempt to understand motivation to adhere to health care regimens. The model offers an integrative framework describing the process of behavior change.35 It was originally developed to understand how people change their addictive behaviors. The model, however, has been extended to many medical problems including chronic pain.36 The basic assumptions underlying the model are the notions that people differ in their readiness and willingness to take on behavioral change and that there are certain processes of changes that facilitate the advancement of one’s readiness. The model is organized around a major construct: stages of change. According to the model, patients attempting to change health-related behavior move from one stage to another, often in a cyclic fashion (Fig. 88.1; description of each stage is in Table 88.1), although the movement through these stages is not necessarily linear or unidirectional. Some behaviors are easier to change than others; it is reasonable to assume that several attempts may be necessary to achieve significant behavioral 4503

change. A good example of the nonlinear change of stages may occur in smoking cessation where average smokers take seven to eight attempts to quit before succeeding.37 The description of each stage as well as typical patient behavior seen at each stage point is listed in Table 88.1.

FIGURE 88.1 Stages of changes.

TABLE 88.1 Stages of Change Stages

Descriptions

Precontemplation

Patient does not perceive a need to change and actively resists change. Patient begins to see a need for change and may consider making a change in the future. Patient feels ready to change and takes a first concrete (behavioral) change. Patient actively engages in behaviors consistent with regimen. Patient executes plans to sustain the changes made.

Contemplation

Preparation

Action

Maintenance

Relapse

Some patients fail to sustain the effort.

Patients’ Behaviors Unwilling to discuss “Who? Me?” Somewhat ambivalent or fearful of change “Yes, but . . . ” Sees more pros for change than cons “I’ll start this on Sunday!” Feels more confident

Feels comfortable with the change Identifies self as the changed entity Variable

The model has been adapted to chronic pain. Kerns and colleagues36 developed a self-report inventory “Pain Stages of Change Questionnaire” to assess the level of readiness to adopt self-management approach in chronic pain patients. Research has found the significant association 4504

between the stages of change and coping as well as disability of chronic pain patients.38 Furthermore, improvement of the stages corresponds with better outcomes of pain rehabilitation.39 There are three critical parameters of the model that determines the likelihood of advancing one’s readiness. 1. Processes of change are one of the dimensions of the transtheoretical model that enables understanding of how shifts in behavior may be achieved. Change processes involve both covert and overt activities and experiences that patients engage in when they attempt to change their behavioral patterns. Each process is a broad category, and an eclectic collection of techniques, methods, and interventions can be recommended to facilitate the change process. Ten processes are cluster into two groups: the cognitive-experiential cluster of processes and the behavioral processes (Table 88.2). As can be seen (right-hand column of Table 88.2), there are various strategies that come from the disparate theoretical orientations to target each process. 2. Self-efficacy is defined as personal confidence in one’s ability to change problematic situations.40 If people think that there is no way that they can perform the prescribed activities, it is highly unlikely that they will initiate or persist in the desired behaviors and that the treatment will be successful. 3. Decisional balance is defined as a personal “balance sheet” of gains (benefits) and losses (costs) for changing and not changing their behaviors.41 People are likely to advance their change stages when they (1) perceive themselves to have adequate skills to cope, (2) feel confident in executing those skills (i.e., high efficacy belief), and (3) perceive more gains of changing and losses of not changing than more losses of changing and gains of not changing (decisional balance). We discuss the decisional balance process later in this chapter as a part of reviewing some motivational enhancement techniques. TABLE 88.2 Processes of Change Processes

Therapeutic Strategies That May Help Targeting the Process

Definition

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Experiential Processes Consciousness raising Increasing information about self and problem Self-reevaluation Assessing how one feels and thinks about oneself with respect to a problem Dramatic relief Experiencing and expressing feelings about one’s problem and solutions Environmental Assessing how one’s reevaluation problems affect the physical environment Social liberation Increasing alternatives for nonproblem behaviors available in society Behavioral Processes Counterconditioning Substituting alternatives for problem and anxiety related behaviors Helping relationships Being open and trusting about problems with someone who cares Reinforcement Rewarding oneself or being management rewarded by others for making changes Stimulus control Avoiding stimuli that elicit problem behaviors

Self-liberation

Choosing and committing to act or believe in ability to change

Observations, confrontations, interpretations, bibliotherapy Value clarification, imagery, corrective emotional experience Role playing, psychodrama, grieving losses Empathy training, documentaries

Advocating for rights of repressed, empowering, policy interventions

Relaxation, desensitization, assertion, positive self-statements Therapeutic alliance, social support, self-help groups Contingency contracts, overt and covert reinforcement, self-reward Adding stimuli that encourage alternative behaviors, restructuring one’s environment, avoiding highrisk cues, fading techniques Decision-making therapy, resolution

Some of the behavioral strategies such as counterconditioning and stimulus control are generally a major part of the rehabilitation for chronic pain. The cognitive-behavioral self-management skill training that is typically a part of the pain rehabilitation also improves self-efficacy42; however, baseline levels of self-efficacy vary across patients, and there is a linear relationship between the baseline level of self-efficacy and posttreatment level of self-efficacy and subsequent treatment benefit selfmanagement skill training.43 Strategies targeting experiential processes are recommended as the primary approach to help people with low level of treatment readiness and self-efficacy.44 Thus, using the concept of the 4506

change process seems a promising way to optimize the clinical outcomes of pain rehabilitation.

MOTIVATION ENHANCEMENT THERAPY MET, developed by Miller,45 is one of the therapeutic methods to target motivation and patient engagement with therapy. This approach is based on the transtheoretical model that people vary in their readiness to adhere to treatment regimen and provides a problem-focused, patient-centered, clinician-directed approach with the aim of helping patients move through the stages-of-change readiness. Although some of the techniques and approaches overlap with those of cognitive-behavioral therapy (CBT), one of the most prevalent behavioral medicine approaches in treating chronic pain patients, the two therapy approaches have some distinct characteristics. The nature of the therapy course is no doubt variable depending on the personal styles of the clinicians, and there is a danger of oversimplification of complex therapy modalities; however, for the sake of comparison and contrast, we summarize the characteristics of MET as compared to CBT in Table 88.3. TABLE 88.3 Motivation Enhancement Therapy (MET) Versus Cognitive-Behavioral Therapy (CBT) Approaches Orientation Therapist–patient relationship Focus Therapist’s task Dealing with ambivalence Approaches to reasons for change

MET

CBT

Patient-centered Collaborative Stage change More listening Explore ambivalence Elicit reasons for change

Goal-oriented Top-down Action More talking Direct persuasion Give reasons for change

MET is nonconfrontational and patient-centered, exploring and reaching resolution of ambivalence toward behavior change. A MET clinician helps patients explore their inner phenomenology that is explored without judgment or criticism. In order to facilitate this process, MET encourages a clinician to exercise empathetic listening and to ask open-ended questions. Asking open-ended questions helps the clinician to better understand the individualized phenomenology of the patient regarding the problem that is the target of behavior change in a nonthreatening manner. It also aids the 4507

patient to achieve a clearer view on the issue. Asking open-ended questions, however, is not time-efficient; asking questions that can be responded with a short “yes” or “no” answer can save time. As you can see in the following sections describing the MET techniques, however, asking open-ended questions is vital in successful implementation of MET. Some examples of open-ended and close-ended questions are listed in Table 88.4. TABLE 88.4 Close-ended Questions Versus Open-ended Questions: Examples Close-ended Questions

Open-ended Questions

Are you having a problem exercising?

Tell me about the problem you are having about exercising. What do you do when your pain is really bad?

Do you overuse your pain medications when your pain is really bad? Would you be able to come to the clinic every week for trigger point injections?

How would you feel about coming to the clinic for trigger point injections?

The MET offers a collection of therapeutic techniques to help patients (1) clearly recognize their problems, (2) perform decisional balance work, and (3) produce self-motivational statements and internalize those motivational statements by means of improved self-efficacy. MET also provides the guidance for how to handle resistance and setbacks. In the following section, we describe the basic MET methods, including how to deal with resistance and what not to do while engaging in MET. Although MET might be a treatment within itself, it may also serve as a complement to CBT and set the stage for patients to benefit from the skills included in CBT.

Help Patients Recognize the Problems and Goals Patients come to clinics with various expectations and goals. Some patients expect to be pain-free, whereas some patients focus on improving the quality of life even if pain is not totally resolved. However, many patients are often unaware of what should happen to achieve their goals and what their role should be for meeting the expectation. The next step to help patients become more aware of what needs to happen is to delineate 4508

the gap between where they are now and where they want to be when they get better. For example, the discussion may start with questions such as: • How is your life different from your life before pain began? • How has your pain stopped you from doing what you want to do? • What are you now doing to cope with your pain problem? How is that working for you? • How do you think your pain and disability impact your relationship with your spouse/family? • What do you miss most about your life before the pain began? Then, the discussion should be turned into what patients want to see happen through treatment. For example: • What would your life look like with better pain management? • What change would you like to see most? • What are you doing now that is helping you to make these things happen? • What other things could you do, or do more of, to help achieve your goal? This line of discussion can also help identify specific discrepancy between what a patient wants from therapy (e.g., “I want to get well”) and what he or she is doing (e.g., “I can’t do my exercise because I am not well”). The process facilitates the realization of the possibility that patients’ own behaviors contribute to the maintenance of pain and prevent them from obtaining their goal of “getting better.” Such realization in turn can form a background on which motivation for behavioral change can be built. Not only can clarification of the gap between a present state and a goal state help drive the motivation to change but it also serves to create the opportunity to move to specific plans. A clinician and patient can start “brainstorming” as to what possible ways there are to make the change probable. Plans can be prioritized by patients’ preference and practical concerns as well as perceived effectiveness of the actions. Possible problems and obstacles should also be thoroughly explored to better prepare the patient. It is common to find that the patient, after years of functional impairment and other related problems, feels very helpless and convinced 4509

that there is nothing they can do to manage their plight. Such resistance can seriously arrest the process of behavioral change. We discuss some ways to deal with resistance later in this chapter.

DECISIONAL BALANCE Motivation for behavioral changes is rarely linear. Often, we may understand the need for behavioral change but remain reluctant to commit ourselves to do the things needed for the change. People experiencing persistent pain are no exception. Nearly all pain patients would want to improve, and many of them may intuitively understand how behavioral changes can help their pain. Despite this, many patients may remain feeling ambivalent or conflicted about committing themselves for behavioral change. One often hears comments like “I know I need to be more active, but . . . .” To a large extent, activating rehabilitation and self-management pain care requires daily practice of the learned skills and modification of lifestyle, aiming at the long-term, gradual improvement. Thus, activities required for these approaches typically do occur immediately despite substantial effort involved. This tends to lead patients to focus more on immediate “cost” of self-management activities, such as postexercise soreness and time commitment. Decisional balance helps people explore all sides of the story on the consequences of not only “doing” but also “not doing” activities that they think need to be done. The decisional balance procedure involves creating a personal “balance sheet” of both advantages and disadvantages of committing to change compared to not committing. For example, suppose that a clinician would like to facilitate a more active lifestyle for a patient who has dealt with pain by remaining sedentary and resting for years. The patient will be asked to list what they think are good things and not so good things about maintaining the status quo, in other words, not changing and keeping doing what they have been doing. The patient will also be asked to list good and not so good things about changing their way to be more active and keep functioning despite pain. An example of a “balance sheet” is shown in Table 88.5. The clinician can help patients explore the impact of the change and no change on various life domains and the emotional and 4510

cognitive consequences of their action (or nonaction). The sheet will help facilitate the resolution of the potential “I want to, but . . . ” conflict. The section of “not so good” things about change can also help the clinician see what areas of coping and other supportive care can be implemented to increase the sense of self-efficacy for the change. TABLE 88.5 Decisional Balance Sheet Staying in Bed or Resting Every Time I Feel Pain (Status Quo) Good Things Helps me rest I will not get tired or sore.

Not so Good Things Life has to come to a halt. I do not feel that good anyway. I may get even more deconditioned. I have to ask for help from others. Cannot participate in social things More depression May gain weight Will never be able to go back to work

Trying to Stay Active (Change) Good Things Things can get done Keep in touch with friends Feel better about the day Feel more independent May gain physical strength Less burden on family

Not so Good Things I may feel worse. I may feel stressed out.

SELF-MOTIVATIONAL STATEMENTS Self-motivational statements or “change talks” by patients represent an important step toward better readiness for behavioral change. In MET, it is critical that thoughts reflecting their intention to change are discussed and help them internalize such thoughts. There are three steps in this phase. First, such thoughts should be elicited and verbalized. Then the thoughts need to be elaborated, as such thoughts, if remaining abstract, may result in perpetual wishful thinking with no actual behavioral change. And finally, elicitation and elaboration of such thoughts need to be reinforced. Going through this process helps patients identify problems and goals, and they then explore what it would mean to change versus not change. At this point, the patients may spontaneously come up with statements reflecting their willingness and intention to commit themselves for behavioral changes. If so, the therapy can start with the second step. However, for 4511

many chronic pain patients whose maladaptive habitual patterns are so ingrained in their lifestyles, some time may be devoted to help patients feel comfortable with change talks. In order to guide a patient through this process, the clinician may ask questions such as: • What encourages you that you can change if you want to? • What do you think would work for you, if you decided to change? • What will make (engaging in exercise program, etc.) it easier for you? One of the supportive yet effective methods for the elicitation of selfmotivational statements is to review past success. By recognizing that they were able to commit to change and were successful in doing so, it breeds the ground for optimism and improves the sense of self-efficacy. For example, in the earlier phase in treatment, the clinician may ask patient to list what and how they were able to change something in their lives, and guide the patient by asking • What do you remember when you were able to . . . ? • What was it like when you changed . . . ? • When else in your life have you made a significant change? How did you do it? Some patients may have a tendency to disregard past success and instead focus exclusively on past failures. It is also common to encounter the extremely negative cognitive style in which patients generalize past failure to all or many future actions. In a case like this, it is helpful to explore their previous failures and help them reframe the experience. Provision of education regarding outcome literature and how certain behaviors increase their probability of recovery may also be beneficial as serve as a means of encouragement and facilitate persistence even when initial positive effects may be modest. It is extremely important for a clinician to recognize and acknowledge self-motivational statements. Typically, initial self-motivational statements are rather only vaguely directed toward the perceived needs (e.g., “I know I really need to take the home exercise program more seriously,” “I am wondering if I should start thinking of how I can manage my anxiety better,” “It may not be a bad idea for me to go back to work”). How such statements are responded to by the clinician can determine whether they 4512

can be transformed to more concrete motivation and actual behavioral actions. Basic responses by the clinicians should clarify the issue at hand in terms of how the change can be made based on what concerns. The statements can further be elaborated with responses like: • Tell me in what ways you think you can do that. • Sounds like you have some thoughts about it. What other concerns have you noticed about this problem? • What are some reasons why you want to do this? • How do you think you can enjoy this change? Note that these statements focus on the patient’s thoughts and not the clinicians. They are designed to engage the patient in the process of exploration. The clinician must remain cautious during the process of elaboration. It is common to see that premature or presumptuous encouragement by the clinician can result in undue pressure for the patient. A discouraged patient is likely to become resistant to change. It is important to remember that MET is clinician-directed but patient-centered. The attempts at self-motivational statements and subsequent elaborations should be positively reinforced. The clinician’s encouraging responses can significantly impact the patient’s frame of mind about the change. Simple comments such as “I think it’s a wonderful idea,” “I see how important this is to you,” “You have a point there,” and “You seem to have some useful insights” can help the process of eliciting selfmotivational statements conclude in a positive and productive manner.

What Not to Do in Motivation Enhancement Therapy One of the important aspects in MET is to avoid placing a patient in a passive role in the clinician–patient interaction. This is a very easy trap for the clinician to get in. For example: Clinician: How long have you had this pain? Patient: Seven years. Clinician: Where does it hurt? Patient: My back. Clinician: Are you working now? 4513

Patient: No. Clinician: Are you receiving disability? Patient: Yes. The process like this is counterproductive for activating rehabilitation because it sets a tone of the treatment where the clinician is the expert who can tell what to do, whereas the patient is the passive recipient of the treatment. We are not saying that a clinician should never provide advice. As an expert, a clinician can provide options and choices. What is important here is to emphasize that there are options and to help the patient achieve their own conclusion of what would work for him or her. Ultimate responsibility of behavioral change lies with the patient, and it should be communicated clearly through the MET process. Value judgment by the clinician can also be detrimental in helping the patient increase motivation for behavioral change. Consider the following interaction: Clinician: It seems that you are only interested in getting medications from us. You have not done anything we asked you to do such as exercise, habit change, and mood monitoring; no wonder you are not doing so well. Patient: Well, I need my medicine because it takes some edge off my pain. I am not doing that badly. I am doing fine. Value judgments by clinicians can elicit defensiveness, often leading patients to discount the very problem that needs to be addressed. “Oh, it’s no big deal,” and the change stage could return all the way back to the precontemplative stage (see Table 88.1 for the description of the stage). When the patients consider the problem “no problem,” it is very hard, if not impossible, to motivate them for behavioral changes.

Dealing with Setbacks and Resistance Changes are hard to make. As noted earlier, patients are likely to hold some ambivalence about committing to change, particularly when the change involves the fundamental part of their lifestyle. Resistance should be anticipated and is expected. It can occur at any phase of MET and may 4514

take various forms such as arguing, interrupting, denying, ignoring, challenging, minimizing, and sidetracking. Some example behaviors of these resistance forms are listed in Table 88.6. One of the hallmarks of MET is that a clinician does not fight resistance but works with it. Too often, an eager clinician gets overdriven to argue for the change, only to find that the patient backs off from the previous self-motivational stance and becomes reluctant to commit. MET requires a clinician to direct a patient to move toward the behavioral change without imposing, ordering, or arguing for it. How do we do this? The approach here is to stay on the same side with patients yet help them to argue for change themselves. There are several specific techniques that a clinician can employ to work with resistance. TABLE 88.6 Examples of Resistance Resistance

Behaviors

Arguing Interrupting Denying Ignoring Challenging

Contests the accuracy of information or the clinician’s expertise Interrupts the clinician in a defensive manner Shows unwillingness to admit/recognize problems Does not follow the discussion or conversational direction Challenges the accuracy, effectiveness, or applicability of what the clinician says Minimizes the risk of problem behaviors (or not doing something) or minimizing the benefit of change Changes the direction of the conversation away from the direction that the clinician was pursuing Blames others for the problem and does not acknowledge any responsibility for him or herself Gives a response that is no answer to the question asked “Yes, but . . . ”—disagrees with a suggestion without offering any constructive alternative

Minimizing Sidetracking Blaming Nonanswering Disagreeing

SIMPLE REFLECTION In simple reflection, clinicians express their acknowledgment of the patients’ comments that reflects resistance in a nonconfrontational manner. For example, patients may argue that they are too exhausted and sore to do the home exercise program after taking care of the household chores; the clinician may respond: • I see that you are frustrated for not being able to make the change you want. 4515

• It is hard for you to work out after a long day. The simple reflection method is to provide the sense that the patient is heard and understood. Notice that the reflection does not have any hint of value judgment (e.g., “It is really too bad that you cannot save any energy to exercise because we are not asking you to do that much, you know”), which would defeat the purpose of the simple reflection technique that is to be used to signal that the patient’s concern was heard and taken seriously.

AMPLIFIED REFLECTION Amplified reflection is an applied variation of simple reflection in which the clinician reflects back the patient’s comment in an overexaggerated manner. With the example of not being able to do the home exercise earlier, the clinician may respond, “You feel/believe that it is absolutely impossible for you to do the exercise.” The amplified reflection adds the core meaning or intensity of the emotion associated with the patient’s statement. By doing so, it helps patient better see the balance of their ambivalence. Facing the exaggerated form of their own statement often helps them focus more on the other side of their original comment. Consider a case where a patient complains of postexercise soreness. Patient: I am so sore after doing those exercises that I cannot do anything but lay in bed for the rest of the day. The house is a mess and I do not feel better. Clinician: There is absolutely no way that the exercise can help you get better. The amplification must be done in an empathetic manner. There can be a fine line between empathetic amplification and sarcasm. The same statement earlier, with a slightly different tone, can be delivered as a sarcastic criticism. If the patient feels that the clinician is being sarcastic or inpatient, the reflection will likely encourage further resistance and retard the process of change.

DOUBLE-SIDED REFLECTION Double-sided reflection is used to highlight the ambivalent feeling that the 4516

patient has expressed. With the example earlier, the clinician may respond, “On the one hand, you find it very difficult to incorporate exercise in your life, and at the same time, it is frustrating because you really want to do it.” Miller and Rollnick46 recommend the use of “and” rather than “but” to bridge the two sides of the ambivalence. It also seems advisable that one ends the reflection with the motivational side, perhaps reflecting the motivational statement the patient has previously used.

AGREEMENT WITH TWIST This is another variation of the reflection in which the clinician initially reflects and then reframes the patient’s statement. Initial reflection is typically presented as an empathetic agreement, affirming that the patient was well heard. Then, the clinician offers a reframed perspective on the same subject in a nonthreatening manner. For example: Patient: I know I do not do all the stuff the physical therapist wants me to do. But it is so hard, and I don’t think she [the physical therapist] understands how hard it is for me to do the program every day. Clinician: You have a point there. It is so frustrating for you not to be able to do the exercise, even though you are so anxious to find a way to do it and move forward with your program. This subtle change in the direction can help the patient move further toward change while maintaining the therapeutic relationship.

PERSONAL CHOICE AND CONTROL The psychotherapy literature suggests that one of the conditions in which resistance tends to arise is when a patient perceives a loss of, or a threat of losing, personal choice and control.47 Typically, resistance is stronger when the importance of the threatened freedom is greater, often resulting in people asserting their option by doing something counteractive to the required behavior. In MET, it is essential that the affirmation of personal choice and control be reminded throughout the course of treatment that it is ultimately their choice to follow through the treatment recommendation. For example: Patient: All of you keep telling me to do the home program, even though I 4517

keep telling you I do not want to do it. Clinician: It is your choice, of course. It is your health after all. We can only make the recommendations and the rest is up to you. Such an interaction can help the patients understand that the choice is theirs; at the same time, it fosters a sense of responsibility for the patients to commit to the treatment regimen.

SHIFTING FOCUS Some patients, particularly those with tendency to “catastrophize” (i.e., a cognitive and emotional process that involves magnification of painrelated stimuli, feelings of helplessness, and a negative orientation toward pain) and use the black–white cognitive styles, tend to get trapped into the mode of “cannot do because . . . ”; there is always a reason why they cannot do what they need or want to do. For them, obstacles and barriers to advance behavioral changes can become so great that such barriers could be the only thing on which they focus. This may become even more pronounced in the time of flare-up. Once they feel very discouraged by the flare-up episode, motivation to apply coping skills may dwindle. A clinician can defuse such intense focus and help the patient move out of the trap and onto the step necessary to make the desired change. For example: Patient: I can’t believe this! I thought I was doing so well with this program, but it must have been just all illusion! There is absolutely no way I am getting better. Pain always wins! I just should give up. Clinician: I see your frustration. Having a bad day feels like such a setback. It sounds like pain really influences your life. Tell me more about the kind of things you would like to do in your life. Shifting focus can help defuse the resistance and instead shift attention onto something that can be workable and supportive for behavioral change.

Research Outcomes A growing body of research supports the conclusion that MET is effective 4518

in promoting healthful behaviors. Past research has shown that MET has been effective for facilitating change to reduce problem behaviors, such as smoking,48,49 alcohol abuse,50,51 problem gambling,52 behaviors related to eating disorders,53 and high-risk sexual behaviors.54,55 MET has also been shown to increase wellness behaviors such as promoting exercise in myocardial infarction patients56 and cancer survivors,57 adherence with self-management regimen in diabetics,58 and attendance for mammography screening.59 MET has become a popular method to address obesity and research shows its efficacy for children60 as well as adult diabetic patients.61 MET has been shown to help normalize the lipid profiles of hyperlipidemic individuals via increased fitness.56 MET can easily be integrated in various clinical settings and with painoriented treatments such as CBT and physical therapy. Brief MET counseling in a primary care setting may reduce substance use among high-risk adolescents.62 In a busy clinical setting, clinicians may regard a full course of MET difficult to implement. There is some evidence, however, that implementing even a small part of MET can be efficacious in promoting behavioral change. A recent study has reported that a brief MET provided at the emergency room setting significantly decreased aggressive behaviors in high-risk adolescents.63 MET can also be implemented through phone counseling. Phone-based MET has been shown to help medication adherence64 and promote healthy lifestyle in diabetics.64 Unfortunately, MET has not been extensively tested for pain patients, although there are some excellent chapters describing MET,65–67 reflecting the growing awareness of the importance of motivation in pain treatment. Available evidence strongly suggests that the state of motivation for change is critical in better treatment outcomes for pain patients.68 Furthermore, a recent study suggests that implementing MET prior to the initiation of the CBT-based self-management skill training for pain patients may enhance the treatment attendance.47 A single-group study shows significant symptom reduction in fibromyalgia patients undergoing a brief exercise program with phone-based MET.69 A recent case series70 for back pain patients also showed significant pain and medication reduction following MET combined with CBT. 4519

Volitional Approach: Implementation Intentions The idea of IIs aims to address the imperfect relationship between intentions to perform a certain behavior and actual behavioral engagement.71 IIs involve practical action plans to deal with a range of contingencies; they require construction of “if-then” plans for foreseeable barriers and problems that may interfere with attaining the behavioral goal. Thus, IIs encompass a process of identifying potential barriers and situations and planning potential responses by means of resource findings and problem solving.72 IIs typically involve two types of planning: action and coping.73 Action planning involves determining when, where, and how to execute the target behavior, whereas coping planning offers a series of problem-solving exercises to handle potential barriers. Suppose that one of the therapy goals is to help a patient become more physically active. The patient is well aware of the importance of activation and would very much like to be able to tolerate a greater level of activities so she could enjoy her life with her family. In this case, her intention to be active is strong. What IIs can do for her is to fill a gap between her strong intention and actual implementation of the behavior. As suggested previously, IIs approaches have two phases: action planning and coping planning. For the action planning, all parameters of behaviors will be determined, including when, where, and how the target behaviors are executed. Action plans should be detailed, feasible, and practical. It should not be overly ambitious; starting out at the level that the patient can easily experience initial success may help foster a sense of selfefficacy. Coping planning involves identification of potential barriers and preparation to address them. A portion of the session should be spent on identifying specific barriers that may keep the actualization of the behavior from happening. Barriers in various areas need to be considered, such as pain-related issues (e.g., actual or anticipated postactivity flare-ups), lack of time or resources, or interpersonal issues (e.g., family/friends support). In order for effective coping planning, patients may benefit from acquiring basic problem solving skills. Typical problem-solving skill training74 begins with the identification of specific problems; for each 4520

problem, the patient is asked to generate as many potential solutions as they can, no matter how implausible impossible they may seem. Then, the patient in collaboration with the therapist can systematically evaluate the feasibility and potential consequence of each approach. Based on the evaluation, the patient rank-orders the options and is encouraged to start trying one at the time from the highest ranked solution. Similarly, acquisition of specific behavioral or cognitive skills that are typically included in a multimodal self-management rehabilitation for chronic pain may also be helpful. For example, self-management skill training for pain flare-ups, effective communication and social skills training, relaxation, and time management can be incorporated in the IIs coping planning to help address specific barriers. Applications of these skills should be well integrated in the coping planning by developing if (barrier)–then (coping) scenarios. For some barriers, behavioral rehearsal may be applied to help patient gain confidence for carrying out the planned behavior. Each person likely has unique barriers to his or her situation. Those unique barriers also need to be identified and addressed in advance, anticipating the most likely difficulties they will encounter in trying to implement planned behavior. Clinicians should work collaboratively with patients to explore emotional, cognitive, and physical cues that are associated with barriers. Examples of IIs outlines are described in Table 88.7. TABLE 88.7 Examples of Implementation Intentions Outlines for Specific Barriers to Activation Therapy Barriers Time management

Flare-ups

Outline Clarifying values of exercise If–then problem solving and action plans If there is not enough time to exercise because . . . Apply problem solving Develop action plans Combating procrastination How procrastination happen Apply problem solving Develop action plans Flare-up management What can we do

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Support from others

Resource management

Skill training for flare-up management If–then exercise Develop action plans Interpersonal effectiveness Effective communication training Interpersonal effectiveness to improve relation with others If–then exercise Develop action plans Available resources What are available within 10 min from home Parks, recreation centers, shopping area, trails Things that make difficult to stick with regimen Weather, pain, stress, time, low motivation If–then exercise Develop action plans using available resources

Adapted by permission from Springer: O’Donohue W, James L, Snipes C. Practical Strategies and Tools to Promote Treatment Engagement. 1st ed. Cham, Switzerland : Springer International Publishing; 2017:229–251. Table 14-2. Copyright © 2017 Springer International Publishing AG.

IMPLEMENTATION INTENTIONS: OUTCOMES The IIs approach has been used to promote the patients’ active involvement in modifying their own health behaviors including better eating habits,75 addictive behaviors,76 smoking,77 weight loss,78 medication adherence,79 cancer screening,80 vaccination,81 and dental flossing.82 A meta-analysis of 94 studies72 found that II formation had a medium-to-large effect on goal attainment (d = .65). IIs have also been incorporated in a number of trials aiming to activate people with or without health concerns. A recent meta-analysis review also showed a large effect of IIs (d = .99) for achieving the goal behaviors among those with psychiatric conditions.83 IIs may be particularly useful adjunct for activation therapy; IIs have been shown to be effective for improving physical activity levels in healthy young adults,84 sedentary women,85 obese elderly people,86 cardiac patients,87 and diabetic patients.88 The meta-analytic review of the IIs on physical activity from 24 studies shows encouraging results with a pooled effect of .31 at posttreatment and .24 for follow-up visit with a higher effects shown with a program involving specific barrier management.73 Interestingly, the coping pattern acquired through the IIs approach appears to generalize over and beyond the target behaviors,89 likely helping patients become proficient to handle a range of challenges on their own. Although there is no study yet to show the 4522

effectiveness of the IIs approach for patients with chronic pain, the available evidence strongly suggests that the approach should be beneficial for improving their ability to actively engage in the treatment and maintain their effort to perform self-management skills and is worth systematic investigation.

Conclusion In this chapter, we have described and reviewed the approaches to address patients’ motivation and engagement for treatments. Effective pain management often requires active engagement and adherence to prescribed regimens over long periods of time. We reviewed the theoretical basis of behavioral change and the basics of the therapeutic approaches to enhance motivation for change, MET and IIs. There are multiple areas of treatments that require significant behavioral, cognitive, and emotional changes for pain patients. Pain clinicians, across disciplines, often face behavioral issues, such as maladaptive behaviors related to medication use and resistance and nonadherence to exercise and other self-management behaviors, all of which become a significant hindrance for optimal treatment implementation. MET and IIs are two approaches that are designed help patients achieve behavioral goals and optimize treatment benefit. Although there is limited empirical evidence for MET and IIs in pain medicine, there are a growing number of studies in other areas demonstrating the efficacy of MET and IIs in reducing maladaptive behaviors and increasing wellness behaviors, suggesting that these approaches can be a powerful tool for pain clinicians as well. Although we present MET and IIs as stand-alone treatments, the concepts and strategies can be used to complement more traditional rehabilitation treatments. References 1. Geen R. Human Motivation: A Social Psychological Approach. Pacific Grove, CA: Brooks/Cole; 1995. 2. Matthias MS, Bair MJ, Nyland KA, et al. Self-management support and communication from nurse care managers compared with primary care physicians: a focus group study of patients with chronic musculoskeletal pain. Pain Manag Nurs 2010;11:26–34. 3. Matthias MS, Miech EJ, Myers LJ, et al. An expanded view of self-management: patients’ perceptions of education and support in an intervention for chronic musculoskeletal pain. Pain Med 2012;13:1018–1028.

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therapists. In: Twomey L, Taylor J, eds. Physical Therapy of the Low Back. New York: Churchill Livingstone; 2000:351–384. Heapy A, Otis J, Marcus KS, et al. Intersession coping skill practice mediates the relationship between readiness for self-management treatment and goal accomplishment. Pain 2005;118:360–368. Ang D, Kesavalu R, Lydon JR, et al. Exercise-based motivational interviewing for female patients with fibromyalgia: a case series. Clin Rheumatol 2007;26:1843–1849. Jerome J, Topham R, Dematatis A, et al. Treatment outcomes after combination interventional and cognitive motivational counseling on analgesic medication use in patients with chronic spine pain. Pain Physician 2015;18:287–297. Gollwitzer PM. Goal achievement: the role of intentions. Eur Rev Soc Psychol 1993;4:141– 185. Gollwitzer PM, Sheeran P. Implementation intentions and goal achievement: a meta-analysis of effects and processes. Adv Exp Soc Psychol 2006;38:69–119. Belanger-Gravel A, Godin G, Amireault S. A meta-analytic review of the effect of implementation intentions on physical activity. Health Psychol Rev 2013;7:23–54. Nezu AM, Perri MG. Social problem-solving therapy for unipolar depression: an initial dismantling investigation. J Consult Clin Psychol 1989;57:408–413. Adriaanse MA, Vinkers CD, De Ridder DT, et al. Do implementation intentions help to eat a healthy diet? A systematic review and meta-analysis of the empirical evidence. Appetite 2011;56:183–193. Webb TL, Sniehotta FF, Michie S. Using theories of behaviour change to inform interventions for addictive behaviours. Addiction 2010;105:1879–1892. Armitage CJ. A volitional help sheet to encourage smoking cessation: a randomized exploratory trial. Health Psychol 2008;27:557–566. Armitage CJ, Alganem S, Norman P. Randomized controlled trial of a volitional help sheet to encourage weight loss in the Middle East. Prev Sci 2017;18:976–983. Meslot C, Gauchet A, Hagger MS, et al. A randomised controlled trial to test the effectiveness of planning strategies to improve medication adherence in patients with cardiovascular disease. Appl Psychol Health Well Being 2017;9:106–129. Browne JL, Chan AY. Using the theory of planned behaviour and implementation intentions to predict and facilitate upward family communication about mammography. Psychol Health 2012;27:655–673. Milkman KL, Beshears J, Choi JJ, et al. Using implementation intentions prompts to enhance influenza vaccination rates. Proc Natl Acad Sci U S A 2011;108:10415–10420. Schuz B, Wiedemann AU, Mallach N, et al. Effects of a short behavioural intervention for dental flossing: randomized-controlled trial on planning when, where and how. J Clin Periodontol 2009;36:498–505. Toli A, Webb TL, Hardy GE. Does forming implementation intentions help people with mental health problems to achieve goals? A meta-analysis of experimental studies with clinical and analogue samples. Br J Clin Psychol 2016;55:69–90. Prestwich A, Perugini M, Hurling R. Can implementation intentions and text messages promote brisk walking? A randomized trial. Health Psychol 2010;29:40–49. Arbour KP, Martin Ginis KA. A randomised controlled trial of the effects of implementation intentions on women’s walking behaviour. Psychol Health 2009;24:49–65. Belanger-Gravel A, Godin G, Bilodeau A, et al. The effect of implementation intentions on physical activity among obese older adults: a randomised control study. Psychol Health 2013;28:217–233. Sniehotta FF, Scholz U, Schwarzer R. Action plans and coping plans for physical exercise: a

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longitudinal intervention study in cardiac rehabilitation. Br J Health Psychol 2006;11:23–37. 88. Thoolen BJ, de Ridder D, Bensing J, et al. Beyond good intentions: the role of proactive coping in achieving sustained behavioural change in the context of diabetes management. Psychol Health 2009;24:237–254. 89. Bieleke M, Legrand E, Mignon A, et al. More than planned: implementation intention effects in non-planned situations. Acta Psychol (Amst) 2017;184:64–74.

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PHYSICAL AND OTHER NONINTERVENTIONAL THERAPEUTIC MODALITIES CHAPTER 89 Basic Concepts in Biomechanics and Musculoskeletal Rehabilitation MAUREEN YOUNG SHIN NOH, BENJAMIN C. SOYDAN, and ANAND B. JOSHI Clinical pain training has historically focused on the following categories: type, location (usually tied to a specific offending joint), and psychological components of pain. Musculoskeletal pain generators do not neatly fit into these categories. These pain generators are often regional, a consequence of the body’s biomechanical function against Earth’s gravitational pull, and subject to the will and desire of the individual person. For example, the pain generator in medial compartment knee osteoarthritis can be viewed as the knee joint complex in which targeted treatments such as medications, injections, or surgery can be considered. Alternately (or perhaps ideally, simultaneously), the pain generator could be viewed as all the biomechanical considerations of strength, flexibility, and gait which lead the patient to place increased mechanical stress on the medial knee compartment, therefore worsening pain and joint pathology. In that light, a combination of exercise, weight loss, and specific gait training can decrease medial knee joint loads and therefore treat the painful area.1 By emphasizing biomechanical principles, the contents of this chapter represent a fundamental change from the customary emphasis on the use of passive physical therapy and physical modalities in treating musculoskeletal pain. Patients are often treated for musculoskeletal disorders with passive modalities such as hot packs, cold packs, massage, electrical stimulation, and deep heat. Unfortunately, these passive 4529

therapies are overused. Although they certainly can play an important role in providing symptomatic relief of musculoskeletal pain, passive modalities should be used only as methods to facilitate active rehabilitation. The patient most needs to become actively involved in a therapeutic exercise program specifically designed to improve musculoskeletal functioning. Musculoskeletal rehabilitation is a process whereby poor posture, muscle imbalances, and other biomechanical deficits are corrected using specific exercises to gain better static and dynamic control of the musculoskeletal system. The physical restoration process may involve passive therapeutic modalities to facilitate the exercise program. Clinicians treating musculoskeletal pain and dysfunction must identify and work to correct deficits in the patient’s biomechanics. The goal of this chapter is to provide an overview of a biomechanical approach to assessing and managing patients with musculoskeletal pain. This chapter reviews basic concepts in biomechanical assessment, followed by examples of common painful syndromes and their biomechanical considerations. Clinical applications of physical modalities are outside the intention of this chapter and are discussed elsewhere in this book.

Basic Considerations Key considerations in musculoskeletal rehabilitation include but are not limited to the following concepts: kinetic chain theory, adverse neural tension, and neuromuscular control. In addition, biomechanical considerations in the setting of common physical examination techniques can aid the clinician in evaluating ineffective movement patterns which can precipitate or reinforce pain. As the patient is an active participant in the examination, he or she too is made aware of his or her alternate movement patterns which may positively reinforce the process for correction.

KINETIC CHAIN THEORY The underpinning of modern kinetic chain theory was pioneered by Franz Reuleaux, a German mechanical engineer as well as author. Reuleaux’s 4530

works in the late 1800s, inclusive of The Kinematics of Machinery, emphasized the relationship among mechanical links or “kinematic pairings.” He theorized that any mechanistic movement could be broken down into these fundamental pairings and that the sequences of movement within and between these pairs produced a resultant “kinematic chain” directly related to constraints placed on them.2 Therefore, movements at one location directly affected movements at another location in the mechanical link.3 Although kinematics relate more strictly to description of movement, it can be assumed that kinetics (forces that cause motion) can be used to explain kinematic relationships. Arthur Steindler, an orthopedic surgeon and professor at the University of Iowa, adapted these theories into the analysis of human movement.4 Steindler was very involved in analysis of movement and pain associated with a variety of orthopedic diagnoses, including scoliosis, foot deformities, and back pain as well as upper and lower extremity reconstruction.5 Steindler proposed that the segments in the human body be thought of as rigid, overlapping units in series, where in successively arranged joints create an overlying kinetic chain and ultimately a collection of multisegmental movement patterns. He divided these movements into two categories: open kinetic (where the terminal segment moves freely) and closed kinetic (the terminal segment is restrained from free motion). It is acknowledged, however, that, unlike machines, no motion of the human body is “true” closed chain, as there always exist some component or segment that is unrestricted during movement (whether it be upper or lower body).4 Regardless of whether or not a kinetic chain is open or closed, in order to achieve a desired human movement pattern two kinetic chain variables of interest are considered: adequate range of motion (ROM) (kinematic element) and adequate force production (kinetic element). In the assessment of musculoskeletal pain, it should not and cannot be assumed that each joint has adequate freedom and/or strength to achieve the desired movement pattern (neuromuscular control plays a significant role but is to be discussed in a later section in more detail). One may present with inadequate strength and/or inadequate ROM at a particular joint, thereby lending to a compensatory faulty movement pattern (and likely undue 4531

tissue stress) at any given joint involved in the movement. A prime example of a faulty closed chain movement pattern is that of a flexible foot deformity leading to excessive subtalar joint (STJ) pronation and/or delayed return to supination during gait propulsion. In a weightbearing position, STJ pronation is correlated with a position of knee flexion, valgus, and medial tibial rotation.6 If one is unable to adequately control STJ pronation during the initial loading phase or propulsion phase of gait, the knee will be placed in a position of excessive medial tibial rotation, valgus, and flexion. This may lend to excessive stress on supporting structures such as the medial collateral ligament and patellofemoral joint. However, if tissue structures at the knee fail to control motion adequately, the femur may then incur excessive internal rotational forces, and in such cases, the hip or even the sacroiliac (SI) joint may be affected.6 In this example, the variable of concern is not a restricted ROM but rather inadequate strength or control to adequately maintain proper positions within a closed kinetic chain movement. This is one isolated example but lends insight into concerns of any multijoint movement (running, walking, bending, throwing, etc.). Although a patient may present with a localized tissue or joint insult, it is paramount that any clinician receiving a patient reporting localized pain acknowledge the role of faulty movement mechanics in the assessment of pain etiology and appropriate management.

ADVERSE NEURAL TENSION When observing an athletic contest or a performance art, one can appreciate movement of the human body. Although the primary function of the nervous system is to conduct impulses, the nervous system must also be able to move along with the rest of the body. However, in addition to movement alone, nervous system function is also dependent on normal physiology. Neurodynamics refers to the interactions between nervous system mechanics and physiology.7 Adverse neural tension is a subset of neurodynamic theory that specifically deals with abnormal mechanical responses of the nervous system as its tissues are taken through a ROM.8 Due to commonality of use, we use the term adverse neural tension (ANT) 4532

in this chapter. Literature on “nerve stretching” can be found as far back as the 1880s.9,10 Although a full review of the underpinnings of ANT theory is beyond the scope of this book, a bedrock principle for the pain clinician is that abnormalities in nervous system movement or physiology can provoke symptoms.7 Failure to engage in the protective adaptions mentioned earlier renders the nervous system vulnerable to edema, ischemia, fibrosis, and hypoxia.11,12 Testing for ANT can be made a part of the clinical evaluation based on the patient’s presentation. The best known test is the straight-leg raise (SLR). However, evaluations for many other peripheral nerves are possible and should be considered when a patient presents with limb pain or paresthesia with movement, or restricted ROM. The nervous system’s sensitivity to movement can be considered as a proxy of its physiology, including blood flow, ion channel activity, and inflammation.13 Therefore, the aim of a neural tension evaluation is to test the mechanics and physiology of the nervous system.13 Findings of ANT may suggest the need for neural mobilization, which aims to facilitate nerve gliding, reduce nerve adherence, disperse noxious fluids, increase nerve vascularity, and improve axoplasmic flow.11 Shacklock7 has elegantly summarized the connection between the musculoskeletal and nervous systems: Very simply, the musculoskeletal system is felt to be the mechanical interface to the nervous system. This interface occurs at both central and peripheral levels. Centrally, the mechanical interface consists of the cranial and spinal canals, which contain the central nervous system, cranial nerves, and spinal nerve roots. Peripherally, the nervous system interfaces with bone, muscle, joints, and other tissues. The critical concept for the clinician to recollect when evaluating pain is that as the body moves, the mechanical interface between the musculoskeletal and nervous systems changes dimensions, placing force and deformation on nerve structures, which may potentially generate pain or other symptoms.7 The nervous system must be able to adapt to mechanical loads and may undergo a variety of adaptations in order to do so, such as nerve elongation, sliding, cross-sectional change, angulation, and compression.11 4533

As an example, the SLR is a commonly used provocation test that has been shown to displace not only the lumbar nerve roots14,15 but more proximal structures such as the conus medullaris as well.16–18 During elbow flexion, the ulnar nerve will lengthen while the median and radial nerves will shorten.12 Additionally, sliding movements are also possible. The median nerve has a mean displacement of 2.09 mm with fist motion of healthy volunteers.19 Median nerve displacement is reduced in patients with carpal tunnel syndrome (CTS) when compared to normal volunteers, with smaller amounts of median nerve motion seen when comparing mild to severe CTS.20 Several physical examination maneuvers are available to assist the clinician in determining whether ANT is present and related to the patient’s presenting complaints. Commonly used neural tension tests are detailed in the following text (images courtesy of Michael Schmidt, PT, DPT, and Preston Roundy, PT, DPT).

Lower Limb Straight-leg raise: The SLR is among the most commonly performed evaluations of patients with neuropathic leg pain. Performance is straightforward: The patient is positioned supine. The knee of the symptomatic leg is kept extended, and the leg is flexed at the hip (Fig. 89.1).

FIGURE 89.1 Straight-leg raise.

A positive response will provoke the patient’s typical leg pain, frequently cited as being between 30 and 70 degrees.13 4534

Upper Limb Neurodynamic testing of the upper limb can be likened to straight-leg raising of the arm. The median, ulnar, and radial nerves can all be evaluated. Although passive positioning of the patient is possible, patients actively positioning themselves is most straightforward. If provocation of symptoms is not achieved with limb positioning alone, additional stress may be incorporated through neck or shoulder positioning. Median nerve: Neurodynamic testing of the median nerve may be considered when upper limb pain is speculated to be neuropathic and possibly localized to the median nerve pathways, provoked with forearm pronation or supination, or nerve conduction testing suggests median nerve injury.13 The patient can be asked to look at the palm, extend the elbow, and then extend the arm until it comes level to the head. A positive test would provoke the patient’s typical arm symptoms at any step of this test (Figs. 89.2 and 89.3).

FIGURE 89.2 Median nerve A.

FIGURE 89.3 Median nerve B.

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Radial nerve: Neurodynamic evaluation of the radial nerve may be considered when the patient presents with lateral elbow pain or a diagnosis of lateral epicondylitis. A very straightforward way to perform this test is for the patient to actively perform it. The patient can be instructed to hold the arm to the side, flex the wrist, internally rotate the arm, and look at the palm over the shoulder. Subsequently, the patient should be asked to depress the shoulder girdle (by “pushing the wrist to the floor”) and to laterally flex the neck (by “looking away”). A positive test would provoke typical lateral arm symptoms (Fig. 89.4).13

FIGURE 89.4 Radial nerve.

Ulnar nerve: Neurodynamic testing of the ulnar nerve is best performed with the elbow in flexion. The patients can be asked to look at their hand and hold it up as if they were carrying a tray of food at their shoulder. Additional provocation may be added by asking the patient to look away, add more elbow flexion, or depress the shoulder girdle (Figs. 89.5 and 89.6).13

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FIGURE 89.5 Ulnar nerve A.

FIGURE 89.6 Ulnar nerve B.

NEUROMUSCULAR CONTROL Motor control is often overlooked in musculoskeletal rehabilitation. A muscle or muscle group may be quite strong, but if it does not fire at the appropriate time (within a synergistic movement pattern), the proper movement pattern is already forfeited. The muscle might as well not fire at all. Neuromuscular control is a combination of sensory feedback from the body part, premotor planning, and motor execution.21,22 Impairments in any of these pathways can lead to altered mechanics of movement with a resultant musculoskeletal dysfunction and pain. This is commonly seen in persistent pain after ankle inversion injuries as well as patellofemoral pain. Normal neuromuscular control can be lost through injury or disuse and but can be regained through appropriate retraining.23 In addition, the effects of neuromuscular training can be seen in those without pain, in the setting of sports performance enhancement independent of strength gains.24 4537

Proprioceptive neuromuscular facilitation uses predictable patterns to facilitate efficient muscle movement. These exercises are often prescribed as balance or proprioceptive in nature. Proper movement patterns require properly timed muscle activation. For example, when lifting an object, a person must first fire the foot and ankle muscles to stabilize the feet on the ground. Then, one must fire the thigh muscles to stabilize the knee. Next, the hip girdle muscles must stabilize the pelvis before the spine extensors can elevate the torso. If the gluteus maximus fails to fire before the erector spinae fires, the pelvis will remain anteriorly tilted and abnormal motion will occur in the lumbar spine. Corrective technique focuses on the pattern of movement rather than the overall strength gains, which can explain why traditional gym exercises do not necessarily correlate to improvement in pain. This is a key concept in explaining why use of physical and occupational therapy for pain syndromes can be helpful even in the active population.

BIOMECHANICAL CONSIDERATIONS IN THE SETTING OF COMMON PHYSICAL EXAMINATION TECHNIQUES In the setting of pain, the goal of any proper patient examination is to not only elucidate the painful complaint but also hypothesize causation of pain. In doing so, one must consider the biomechanical nature of musculoskeletal pain syndromes. Basic tenets such as inspection, palpation, and ROM may be highly informative and help achieve a more comprehensive interventional plan. Inspection: Evaluation of the patient begins with visual inspection. Pattern of shoe wear, assistive device usage, brace needs, general posture, and habitus as well as gross movement patterns during standing, walking, and transfers are significant considerations. These observations provide an overall view of how the patient moves about his or her environment and help the clinician to discern what may be gross mechanical abnormalities. Palpation: Palpation provides the clinician with information about generalized tenderness, potential targets for injection, tissue texture, and also pain patterns. Kinetic chain abnormalities will often present with palpable pain patterns. For example, patellofemoral pain has been 4538

associated with iliotibial band, hamstring, and gastrocsoleus restrictions as well as leg length discrepancies, hip muscle dysfunction, overpronation, patellar malalignment, and patellar hypermobility.25 Given these biomechanical correlations, a patient with patellofemoral pain has the potential to demonstrate tenderness about the ipsilateral SI joint, greater trochanter, iliotibial band, pes anserine, or medial tibial structures as well. The clinician is thus cued to treat distant areas of dysfunction in order to affect pain at the site of concern. Range of motion: Lack of adequate ROM may be the most common biomechanical deficit seen and one of the easiest to address. Deficits in ROM can cause pain directly or may lead to pain elsewhere. The musculoskeletal clinician must have knowledge of normative values, employ adequate examination skills to identify major ROM limitations, decide which of these contribute most significantly to the patient’s symptoms, and implement appropriate therapies to correct the deficits. For example, during gait, an ankle plantar flexion contracture can cause excessive knee extension and resultant increased hip flexion and forward trunk lean. According to kinetic chain theory, one must address ankle mechanics to normalize the dysfunction at the knee, hip, and spine. This may be required to facilitate adequate pain intervention.26 ROM restrictions can be due to shortening of muscle-tendon units, restrictions in joint capsule distensibility, ANT, or bone-on-bone contact at joint interfaces. The first three conditions are almost always amenable to specific stretching techniques. ROM deficits due to bone-on-bone contact are generally not improved with therapeutic exercise or physical modalities but at times can be addressed by compensatory strategies. In addition, quality of ROM can be assessed in the setting of functional movements. For example, functional forward bending is a combination of hip, pelvis, and a spinal movement. This is often clinically evaluated by having a patient bend forward and measuring the distance between the patient’s fingertips and the floor. A subject with restricted hamstrings and gluteal muscles will present with increased lumbar and thoracic flexion to reach as low as a subject with highly flexible hamstrings and gluteal muscles. This second subject may exhibit minimal motion through the spine as he or she is able to achieve the required amount of “bend” using 4539

predominantly hip flexion. Strength: Strength assessment is another part of comprehensive patient examination. Whether it is through manual muscle testing (MMT), or a more formal dynamometric assessment, the goal of strength testing is threefold: (1) determining etiology of strength deficits (i.e., deconditioning, pain inhibition, poor neuromuscular control; these often improve with repeated cueing) or neural deficit, (2) painting a clinical picture of overall strength, and (3) demonstration/determination of kinesiophobia (an important factor in chronic pain). As a general rule, the patient should be examined with regard to muscles surrounding the region that is painful and in the regions immediately proximal and distal to the painful region. For example, in a patient with elbow pain, the clinician should evaluate strength in the shoulder, elbow, and wrist. Given that strength deficits are relative, contralateral strength values should be used as an internal control. Additionally, because many pain complaints are concerning for an underlying spine etiology (e.g., a radiculopathy), it is often useful to examine the key myotomes in the affected region. Using the same example of elbow pain, the clinician would evaluate muscle strength of the C5–T1 myotomes bilaterally to assess for focal weakness. These have been covered earlier in this book. Admittedly, MMT is a faster method than more formal strength measurement such as dynamometry or manual sphygmomanometry. However, one must acknowledge that the MMT grading scale of 0 to 5 consists only of ordinal values. These values represent directional relationship only and should not be used as replacement for interval or ratio measures, such as torque, force, or percentage of muscle activity. In fact, Beasley27 noted that a knee extensor strength loss of 50% is needed before clinicians reported a grade change within MMT. With regard to kinetic chain theory and altered neuromuscular control, the testing of muscles distant to the presenting complaint becomes important during the development of a rehabilitation plan. Just as patients with patellofemoral pain present with distant palpable tender sites, they will often demonstrate weakness as well, typically about the hip abductors, hip extensors, and hip external rotators.28 This evaluation process is a joint 4540

experience, one undertaken by both the clinician and the patient, which may ultimately improve patient compliance in a physiotherapy program. Two primary factors contribute to relative strength deficits in ambulatory patients without major nerve or muscle injury. The first might be considered a relative disuse weakness. In relative disuse, the body part is not immobilized but is infrequently used in a manner that develops strength. Triceps weakness in sedentary office workers is a good example of this. Although these individuals may be “pushing papers” all day long, they may go for decades without ever performing elbow extensions against enough resistance to prevent gradual weakness from developing. The second primary factor that contributes to relative strength deficits in ambulatory patients without major nerve or muscle injury is a process sometimes referred to as muscle de-education.29 This is a process in which the individual fails to activate or abnormally activates a given muscle because of pain, fatigue, maladaptive biomechanics, or psychological basis. Over time, the normal neuromuscular engram for the intended movement becomes more difficult to retrieve, and in time, the neuromuscular control system essentially “forgets” the normal motor control pattern for that requested movement. Most often, muscle deeducation involves the patient losing the ability to fire a muscle with the correct timing or with enough synchronous motor units for the intended movement. The patient adopts a maladaptive neuromuscular firing pattern and substitutes other muscles to perform the task. Proper motor synergy and contraction/relaxation timing is lost. Ultimately, it is the clinician’s responsibility to identify all strength deficits, determine rationale (neuromuscular or musculoskeletal etiology), decide which are clinically relevant to the patient’s symptoms, and implement an appropriate rehabilitation plan.

ENDURANCE Endurance refers to the capacity to continue to functionally exert oneself. Although patients with pain complaints may occasionally be limited by cardiovascular endurance, the more common context for assessing endurance in a pain patient is local muscular endurance. As an individual bears weight during a functional activity, the forces of 4541

his or her activity (e.g., the ground reaction force while walking) have to be borne by the different structures throughout the kinetic chain. These include bone, joints, articular cartilage, ligaments, and muscles. Ideally, muscles bear a substantial amount of these reactive forces, which reduces the forces transmitted across other structures. However, with repetitive iterations, local anaerobic energy systems are stressed and loading muscles will fatigue. Although these muscles may be able to bear reactive forces initially, with each repetition, these same muscles may lose their ability to attenuate force and, hence, allow transmission to other structures. The phenomenon of muscle fatigue has important implications both diagnostically and therapeutically. Oftentimes, patients will complain of pain presentations that are initially mild but worsen with increased activity. This is seen especially in the case of postural muscles, which must have sustained exertion against gravity and may present with pain by the end of the day or with any prolonged positioning. Strength measurements may initially appear “normal” on physical examination; however, recall that MMT inherently does not test muscle endurance. Therefore, it may be necessary during examination to exercise a patient to fatigue to simulate those circumstances when the patient is having pain. For example, if a patient complains of knee pain that worsens with walking long distances or climbing stairs, a component of the pain complaint may be poor muscular endurance in the quadriceps and hip abductors. When testing knee extension and hip abduction by MMT, the “strength” may appear normal because the patient’s limitation is muscular endurance rather than peak torque production (as tested via MMT). Therefore, the patient may be better assessed by performing repetitive single-leg squats. This can fatigue the quadriceps and hip abductors relatively quickly within the time frame of the examination and allow the clinician to assess whether poor muscular endurance is contributing to the patient’s pain complaint. If the clinician assesses that poor muscular endurance is contributing to a patient’s pain complaint, improving muscular endurance should be a focus in the patient’s physical therapy protocol.

Biomechanical Considerations in Common 4542

Musculoskeletal Pain Syndromes The first part of this chapter highlights key concepts underlying the biomechanical evaluation of pain. Following are selected common axial musculoskeletal pain syndromes that are often ameliorated by the patient engaging in a focused, active rehabilitation program. This list is not exhaustive but serves as a basis for the application of the concepts discussed earlier. The goal of this section is to enlighten the reader on the clinical utility of a biomechanical evaluation of patients presenting with musculoskeletal pain. It will be noted that these anatomic regions overlap in their presentation and redundancy is a product of the very nature of the interrelatedness of biomechanical evaluation.

CERVICALGIA Patients presenting with chronic atraumatic neck pain often have a history of constant posterior neck, suboccipital, and/or upper trapezius area pain with qualities of pressure, tightness, and spasm. Often, the symptoms are present upon waking and decrease somewhat with movement and a warm shower but worsen as the day progresses. This may be exacerbated by various sedentary positions such as driving, sitting in class or meetings, computer work, reading, or knitting. The pain is usually temporarily improved with lying down or reclining with the head supported as in a lounge chair but may return or worsen with prolonged inactivity, prompting the subject to get up and move about to reduce the pain. In addition, they may have had a prior diagnosis of cervicogenic headaches. To further evaluate, one must understand the functional role of the neck and common pitfalls in daily living. The obvious functional role of the neck is to hold the head. On second pass, however, that role becomes more nuanced, as the head’s role is to house a large and heavy brain, position eyes for binocular vision, position ears for hearing in stereo, and place the nose and mouth for their respective roles. In addition, it positions the head to maximize facial expression due to social human nature. As seen earlier, positioning of the lower spine affects head posture; postural muscles that are suboptimally positioned will have to work harder but maintain the same endurance than those kept in more agreeable alignment with gravity. Slouched sitting will cause 4543

excessive thoracic flexion; in this posture, the arms and scapulae slide off the body and the shoulders round forward. This positions the head more forward than intended. Compensatory strategies for this forward head posture include excessive proximal neck extension to raise eye gaze off the floor and facilitation of the upper trapezius and levator scapulae. Muscle balance theory states that a strong, tight muscle group will reflexively inhibit the antagonist group.29 Thus, as the cervical and thoracic paraspinals along with the upper trapezius and levator scapulae become chronically hyperactive, hypertrophied, and facilitated, reflex inhibition of the middle and lower trapezius, rhomboids, and deep cervical flexors are seen. This pattern was coined by Dr. Vladimir Janda as “upper crossed syndrome.”30 Of note, this neuromusculoskeletal pattern can present clinically as pain in multiple regions, including cervical, thoracic, and periscapular regions, as well as in the presentation of rotator cuff impingement. There are several clinical patterns in addition to myofascial cervical and upper trapezius pain common to this posture that can be amenable to an active physical therapy and biomechanical restoration program which are highlighted in the following text. Occipital neuralgia: The greater and lesser occipital nerves can become entrapped as they pierce through suboccipitals that have become hypertrophied and shortened. Occipital nerve blocks have been used in this setting; however, providers may find that patients receive temporary relief. From a positioning standpoint, a forward head posture with hypertrophied/facilitated posterior cervical musculature will continue to produce entrapment of the nerves unless the tension is removed from the suboccipital region. Restoration of the head over the neck (as opposed to in front of it) will reduce tension in this region. Due to kinetic chain theory, optimization of this cervical posture requires improvement of the positioning of the lumbopelvic, thoracic, and periscapular region. This positional effort is largely patient-driven following adequate instruction and can help free the patient from cyclical pain relief by external forces (i.e., injections). Cervical facet pain: In the sagittal plane, the typical cervical vertebrae (C3–C7) are limited in extension by the zygapophysial (facet) joints.31 The 4544

forward head posture produces increased lower cervical flexion and upper cervical extension than a neutral to retracted head posture, and efforts at neck extension in the forward head posture lead to decreased extension at the lower cervical segments compared to the neutral head posture.32 (It is of note that segmentally, the atlantoaxial joint has paradoxical motion in flexion and extension when compared with the typical vertebral segments.)31 Increased efforts at neck extension in the forward head posture will presumably increase the segmental extension seen at all, but the lower cervical segments due to this inhibition and are more likely to affect facet loading. Restoration of the neutral head posture can alleviate some of this excessive upper cervical extension. Cervical radiculopathy: Similarly, the classic neural tension and distraction signs for cervical radiculopathy are Spurling’s test, which is described by placing the neck in extension and rotation with an axial load.33 In patients with poor cervical posture, the typical upper cervical vertebrae are already in a relatively extended position, and addition of rotation in this position essentially reproduces the Spurling’s maneuver. Cervical extension has been shown to decrease the cross sectional area of the neuroforamen in particularly C3–C4 and C4–C5.34 Additional rotation in this position can further compromise the exiting nerve, and clinically, a patient with poor neck posture may complain of radicular symptoms with daily functional tasks such as turning his or her head with driving as he or she is already in a relatively extended position.

PERISCAPULAR AND THORACIC PAIN In pain management involving the thoracic region (inclusive of the shoulder complex and upper extremity related referral), the attending clinician may have the tendency to direct intervention at a specific location or tissue of concern. Just as with other body regions (discussed within this chapter), this approach is not unwarranted. Musculoskeletal trigger points are an obvious concern, incurring a local pain response associated with the area of hypertonicity. A variety of interventions (not covered in this chapter) exist to manage these trigger points, inclusive of injection, dry needling, manual therapy, and thermomodalities. However, in discussing these abnormal musculoskeletal soft tissue states, one must explore the 4545

etiology from multiple perspectives. Although the exact mechanism of soft tissue trigger point development is not fully understood, there is general consensus that these myofascially derived trigger points (or “taut bands”) are related to localized muscle overuse syndrome, such as that following a novel, repetitive, or excessive cyclical loading task.35–37 This is not surprising, given that a general “training effect” is based on principles, outlined by Hans Selye in the “general adaptation syndrome.”38 The patient may report performing large amounts of repetitive or intense loading, such as typing, repeated lifting, pulling, or pushing, which would serve to create an “overtraining” condition and negative tissue response. However, if the stimulus activity does not appear to fully justify the patient’s current presentation, the question must be posed: “Is there some force or some movement pattern lending to an inappropriate amount of stress being placed on the problematic structure(s)?” This is where the clinician must consider biomechanics associated with the movement at hand. Periscapular pain: The attending clinician’s consideration of faulty movement pattern is paramount in assessing etiology of the patient’s current localized complaints. This is especially true with regard to the shoulder and thoracic region complex. Although the labrum serves to deepen the glenoid fossa to an extent, the humeral head is roughly 3 to 4 times as large as the admittedly shallow glenoid fossa, lending to the glenohumeral (GH) joint’s significant amount of mobility.39 The tremendous amount of movement available to the GH joint lends itself to risk of injury. If structures that are designed to stabilize this joint are not performing properly, the region is at risk. One must consider the stability of the GH joint, neuromuscular control, and scapulohumeral rhythm as well as patient posture. As an example, let us consider a patient with subacromial region pain and upper trapezius region pain. One may be concerned about impingement (primary or secondary) as well as upper trapezius trigger point presentation. First, the anterior-posterior force coupling created by the infraspinatus, teres minor, and subscapularis, when operating symmetrically, serve to compress the humeral head into the glenoid fossa during dynamic activity. This limits aberrant arthrokinematic translation 4546

that may be associated with impingement. However, research has noted that overdevelopment of the internal rotators and subscapularis musculature (especially within a throwing population) typically lend to an imbalance in this coupling.40 It would behoove the clinician to consider this proper strength and activation coupling with regard to pain. A second consideration is that of proper scapular dynamic stability. A generally accepted ratio of humeral to scapular movement is 2 to 1 (in that for every 2 degrees of humeral movement, the scapula moves 1). This needs to be maintained and appropriately timed to ensure proper GH joint position. Researchers has shown that in those with shoulder impingement, the serratus anterior has decreased levels of activity, the lower and middle trapezius have delayed activation, and there exists an overtly dominant activation of the upper trapezius.41,42 This thereby lends to faulty scapular mechanics, altered scapulohumeral rhythm, and hence a potentially excessive stress to subacromial structures. Additionally, static and postural concern warrants attention. If a patient, such as that mentioned earlier, is continuously performing an overhead reaching task in an excessively kyphotic position, he or she may be “asking” the shoulder complex to perform a significantly larger amount of relative overhead flexion than capable of (an amount potentially not available passively) regardless of proper scapula-humeral rhythm. The patient may present with a dysfunctional scapular position, such as medial border dysfunction, where in the scapula is excessively internally rotated such that the medial border is raised from the rib cage. This posture has been associated with GH instability.43 Such a posture may imply weakened, inhibited, excessively stretched supportive structures (serratus anterior musculature, middle and lower trapezius musculature, rhomboid musculature) or even restricted pectoralis minor musculature, such as that noted in the commonly termed upper crossed syndrome. Such concern would then warrant tests to rule in/out neuromuscular concerns in activation or pure musculoskeletal concerns in length, strength, or restriction. Patients may complain of thoracic region pain; however, the treatment requires correction of dysfunctions of the GH and scapulothoracic regions for long-term improvement: Simply injecting trigger points will not resolve the offending process. 4547

Furthermore, if an excessively kyphotic resting position were evident, he or she would be required to achieve correlating and likely excessive amount of cervical lordosis in order to maintain gaze forward on the horizon. Such a pathologic resting state may lend toward the muscle overuse scenario as etiology of trigger points (i.e., prolonged levator scapulae, scalene, and/or deep posterior cervical musculature activation) and may even lend to excessive cervical facet joint closure stresses (as discussed in further detail within other sections of this chapter). Thoracic pain: Interestingly, pure thoracic region spinal pain is reported much more rarely than other spinal region complaints regardless of the previously mentioned postural and dynamic concerns. One report noted that out of all spinal pain reports, only 15% of those resided within the thoracic region (vs. 44% in the neck and 56% in the low back).44 Although not common, and typically experienced unilaterally and localized,45 pain related to thoracic spine dysfunction must be mentioned, given that the contractile structures making up the scapulothoracic complex utilize both the ribs and vertebral segments as points of attachment (serratus anterior, trapezius musculature, pectoralis major, and anterior scalenes to name a few), thereby lending to relative scapular or relative rib movement. Clinicians should be versed in, aware of, and able to assess concern for abnormal rib positions and consider postural abnormalities and muscle activation patterns within the kinetic chain when ruling out thoracic positional concerns. Proper shoulder and thoracic biomechanics must be considered in lieu of localized management of irritable structures. However, this is not to say that local tissue management is to be overlooked or minimized. In fact, literature has shown a correlation between local musculature trigger points and correlating muscle inhibition as well-altered motor activation patterns.35 The cause-and-effect relationship becomes muddied to some extent as one considers this correlation. Local injection is not by any means contraindicated as it is a valuable intervention for pain management with a soft tissue, myofascial component. Rather, it is recognized as valuable only within a comprehensive approach, acknowledging that there may be a complex interplay among causality and perpetuation of complaints involving mechanics of movement. 4548

LUMBAR PAIN Low back pain is the leading cause of disability in the world and is the sixth leading contributor to global disease burden.46,47 The cause of chronic low back pain can be frustratingly difficult to elucidate. Although various studies have documented the primacy of the intervertebral disk,48,49 followed by the zygapophysial48,50,51 and SI48,52 joints, these diagnoses can require invasive techniques, such as provocation discography or image-guided diagnostic injections. Axial low back can occur with or without leg pain. When leg symptoms are present, they may signify radiculopathy, radicular pain, or somatically referred pain. These entities have been defined by the International Association for the Study of Pain53 and have been more recently articulated by Bogduk.54 Briefly, radiculopathy implies a conduction block along a spinal nerve or its roots and may or may not be painful.53 Radicular pain is evoked by ectopic discharges from a dorsal root or its ganglion and does not suggest the presence of an objective neurologic deficit.53 Somatically referred pain is not dermatomal and signifies the convergence of nociceptive afferents on second-order neurons in the spinal cord.53 The variability of these clinical presentations may lead treating providers to obtain cross-sectional imaging to help localize the source of pain. Yet, the situation is hardly helped by magnetic resonance imaging (MRI), which can commonly show abnormalities, even in asymptomatic individuals.55 The confluence of these factors illustrates a common clinical reality: Identifying the pathoanatomic source of low back pain is often difficult, resourceintensive, and may be impossible. In these scenarios, the treating provider may wish to use a biomechanical and active rehabilitation approach for both diagnostic and therapeutic purposes. Core stability: Perhaps, no single intervention for chronic, axial low back pain has received as much as attention as core stability. The “core” has been defined as a box with the abdominals in the front, paraspinals and gluteals in the back, diaphragm as the roof, and the pelvic floor/hip girdle as the floor.56 Clinical instability is defined as a significant decrease in the capacity of the stabilizing system of the spine to maintain the intervertebral neutral zones within the physiologic limits.57 Objective changes of core musculature have been demonstrated in patients with 4549

chronic low back pain. The lumbar multifidus muscles are important extensors of the lumbar spine. The lumbar multifidi have been noted to atrophy and become replaced with fatty tissue in patients with chronic low back pain.58–60 When noted, a stabilizing program directed at activating the lumbar multifidi is an important part of the rehabilitation of a patient with chronic low back pain. In addition to muscular dysfunction, impaired neural feedback control may also lead to instability. A basic framework may be conceptualized as follows. The central nervous system, upon sensing a lack of intervertebral stiffness, may compensate by increasing trunk muscle activation to maintain stability, and static contractions prolonged over a period of time may lead to pain.61 The goal of core stabilization is to achieve muscular contraction to achieve stability.62 Although a variety of core stabilizing programs are possible, many seem to incorporate elements from the Saal and Saal’s protocol on conservative treatment of patients with lumbar disk herniations.62,63 Per their description, stabilization exercises may be divided into basic and advanced levels. Basic levels of core stabilization involve supine and prone positioning. Patients may be advanced through transitional, kneeling, and standing positions. The goal of this program was to develop isolate and cocontraction muscle patterns to stabilize the lumbar spine in neutral position. Although core stabilization exercise has strong construct validity, further research will be needed to determine its efficacy.64 Mechanical diagnosis and therapy: A patient may present with leg pain, which may be radicular or somatically referred. The history and examination, which may include an evaluation for ANT, can assist with this distinction. The mechanical diagnosis and therapy (MDT) is a paradigm that was developed by Robin McKenzie in the 1950s.65 The MDT provides a means for treating the patient’s symptoms without necessarily establishing a pathoanatomic source. A key portion of establishing a mechanical diagnosis hinges on patients performing repeated end-range lumbar movements to establish whether leg pain may “centralize.” McKenzie66 himself has defined centralization as the phenomenon “whereby the intensity of pain reduces or disappears distally but remains or moves (and in some cases increases) proximally.” The “directional preference” is that direction of testing that elicits a 4550

centralization response. Once the directional preference that achieves centralization is identified, the patients are then empowered to self-manage their problem through the use of directional exercises that match their directional preference.67 The value of this approach is that it allows the patients to transition to self-care and affords them the ability to control their symptoms. The prevalence of centralization and directional preference has been reported to be 70% to 87% for acute low back pain and 32% to 52% for chronic or radicular low back pain.67 If a directional preference exists, patients will benefit the most from exercise that matches their directional preference. One protocol had matched patients to exercise that was opposite of their directional preference.68 One-third of this group had to withdraw from the study within 2 weeks due to nonimproving or worsening symptoms. Additionally, the presence of centralization and directional preference is a predictor of outcome. In a study of 243 subjects, those who centralized had significantly greater pain reductions and returnto-work rates than those who did not centralize.69 In addition to being therapeutic, the presence of centralization and directional preference may be diagnostic as well. The only conclusive test for discogenic pain remains provocation discography which is invasive and of debatable clinical value. However, one study has found the presence of centralization to correlate with positive discography. In this study of 63 patients, 47 expressed a directional preference and 16 did not.70 Of the 16 who did not show a directional preference, only 2 had positive discography. Of the 47 who did show a directional preference, 34 showed had positive discography. This study demonstrates the strong correlation between the presence of a directional preference and discogenic pain. In summary, the cause or treatment of chronic low back pain is often not illuminated through history, exam, or advanced imaging. However, the need to establish a pathoanatomic diagnosis may be eliminated through active biomechanical techniques, which may serve both a diagnostic and therapeutic value.

SACROILIAC AND HIP GIRDLE PAIN If there is one theme that has emerged through this discussion of pain and biomechanics, it is that one cannot completely isolate a specific joint or 4551

region with regard to etiology of musculoskeletal pain when repetitive movement is involved. The human body, as a functional closed chain system of joints, works synergistically, with the proper amount of joint excursion, proper amount of muscle activation, and in the correct temporal sequence in order to successfully carry out the task at hand. These functional tasks could be as simple as everyday ambulation or as unique as repeated single-leg squatting in an attic, hopping down a step or rapidly sidestepping to in sport. One could argue that during daily activity, the loading of the lower extremity and lumbopelvic complex is more relevant to pain management than any other region. Although it is beyond the scope of this chapter to fully delve into the biomechanics of the lower extremity and lumbopelvic complex, the correlation between faulty loading mechanics, dysfunctional muscle activation, and pain must be acknowledged and discussed. There is a body of literature drawing kinetic/kinematic connections between the foot, ankle, knee, femoroacetabular joint, and pelvic complex. As cited previously in this chapter, the pronated STJ is associated with a position of medial tibial rotation, knee valgus, femoral medial rotation, and a hip adduction.6 Loading of the foot is associated with a pronation moment, serving to increase the impulse time and reduce the amount of force placed through the lower extremity during loading. Accordingly, the body is required to oppose all associated moments (at the knee, hip, and pelvis) throughout the loading chain. This entails producing subtalar supination, ankle plantarflexion, lateral tibial rotation, lateral femoral rotation, femoral abduction, and femoral extension (for our purposes, innominate and SI movement are not discussed here). More recent bodies of literature have confirmed these multijoint correlations, noting that lateral tibial rotation assists in raising the medial longitudinal arch of the foot71 and that proximal (hip) musculature is highly involved in controlling both femoral and tibial rotation.72 The musculature within the lower extremity must work synergistically and with proper synchronicity to maintain alignment. Just as in the shoulder complex, if one region is restricted, weakened, or activated with an improper timing sequence, the other regions are required to overcompensate or suffer faulty mechanics, either of which may lend to stress of musculoskeletal structures and 4552

potential pain. Patellofemoral joint pain is a prime example. In the setting of patellofemoral joint pain, literature emphasizes deficiency in quad activation/strength73 and poor hip stability (with emphasis on gluteus maximus deficiency)74 as well as poor foot control and excessive pronation75 as contributing factors to continued complaints. It would behoove the clinician managing such a patient to attend to these biomechanical concerns. If, in fact, the hip cannot compensate for a weakened gluteus musculature, one may note development of Trendelenburg gait, potential bursal irritation, and/or glut medius overuse pathology. Scenarios such as this must be pursued and considered for proper long-term remediation. However, select populations of patients may have faulty mechanics, poor musculature activation, and/or altered motor control/timing in the lower extremity but without painful presentation in the lower extremity. One must be concerned about manifestation more proximally (i.e., lumbopelvic region). There is a biomechanical correlation between the lower extremity and the lumbopelvic region. As an example, deficits at the hip may manifest proximally rather than distally depending on that patient’s abilities to compensate, and this must be acknowledged, thereby drawing attention to the pelvic ring. As discussed in earlier sections, the lumbosacral region is a common site of pain management. However, one cannot discount the importance of loading forces placed on the entire pelvic complex during weight bearing. The relationship between the lumbar spine, SI joints, and femoroacetabular joints are inseparable when it comes to movement and determination of pain etiology. Current thinking acknowledges the pelvic girdle as a loadtransfer system76 and, as such, able to both attenuate and generate forces. The proper function of this system depends on the stability of both hip joints and SI joints. The hip joints have a multitude of muscular support and an obvious congruency associated with the ball and socket–type joint. However, the SI joints, being planar, rely heavily on a system of dense ligamentous structure as well as less direct muscular elements connected via fascia tensioning. These elements are in a delicate balance, serving to tension across the SI joints and create stability. Literature has reported a multitude of structures highly involved in SI 4553

joint and general pelvic ring stability. It is beyond the scope of this chapter to discuss these in full detail. However, emphasis has been placed on myofascial attachments of the latissimus dorsi and the multifidus as well as the “guy wire system” of dynamic stabilization created by the deep erector spinae, the psoas major, and the quadratus lumborum.77 Given a general understanding of anatomy, one can understand how integrated the lumbar and pelvic region become given such information. To complicate matters further, the gluteus maximize has been recognized as a dynamic link between the thoracolumbar fascia and the tensor fascia lata, thereby emphasizing the connection to the lower extremity loading during tensioning of the pelvic girdle.78 As noted earlier, the SI joint’s planar shape dictates that adequate pelvic girdle function relies very heavily on the concept of dynamic stability. Adequate muscle force generation is required each loading bout, local muscular endurance is needed for repetitive activation, and effective neuromuscular control is required and must ensure proper timing of each muscle activation. If any one attribute is in deficit (i.e., a relevant structure is inflexible, overly flexible, weak, or activated improperly), the system begins to fail, and the patient may become symptomatic due to overstress of any single structure. Although it is not the purpose of this chapter to explore in detail true medical diagnoses, pain at the SI region cannot be assumed to stem from the SI joint. Referral patterns as mentioned previously (with regard to the lumbar spine) must be considered. Furthermore, pain at the SI joint is not synonymous with true sacroiliitis (as potentially ruled in/out with intraarticular injection). Both the dorsal SI and interosseous ligament have been implicated as an overlooked source of pain in the setting of lumbopelvic dysfunction.79 Ultimately, poor dynamic stability, passive restrictions, or altered neuromuscular control within the entire lower closed chain system have the potential to affect the pelvic ring structures and vice versa. It may be thought of as “uncommon” for overpronation to lend to pelvic stress and resultant dysfunction or for weakened gluts to lend to SI region pain. However, such biomechanical-based concerns should be entertained and ruled out. With regard to pain, mechanics, and effective long-term 4554

management, the mindful clinician must acknowledge, assess, and implement intervention to address these concerns.

Conclusion Thorough evaluation of neuromusculoskeletal pain requires the use of biomechanical evaluation and principles to guide pain treatment and patient expectations. The principles of kinetic chain theory, ANT, and neuromuscular control form the groundwork whereupon pain syndromes can be addressed. The clinician should have raised suspicion for kinetic chain dysfunction in patients with neuromusculoskeletal pain whose symptoms are recalcitrant to focal treatment modalities, that are only temporarily improved with passive treatments, or that are poorly defined by anatomic structures. Treatment begins with educating the patient on the global nature of the body dysfunction and includes the patient actively engaging in improving found deficits. Improvement is sustained through the patient continuing with active management techniques over time, often with a physical or occupational therapist–prescribed home exercise program, and adherence begins with the patient recognizing the clinician’s understanding of the biomechanical interface of the body with its environment. References 1. Khalaj N, Abu Osman NA, Mokhtar AH. Effect of exercise and gait retraining on knee adduction moment in people with knee osteoarthritis. Proc Inst Mech Eng H 2014;228(2):190–199. 2. Reuleaux F. The Kinematics of Machinery. New York: Macmillan and Company; 1876. 3. Ellenbecker TS, Davies GJ. Closed Kinetic Chain Exercise: A Comprehensive Guide to Multiple Joint Exercise. Champaign, IL: Human Kinetics; 2001. 4. Steindler A, ed. Kinesiology of the Human Body Under Normal and Pathological Condition. 3rd ed. Springfield, IL: Charles C Thomas Books; 1955. 5. Buckwalter J. Arthur Steindler: founder of Iowa Orthopedics. Iowa Orthop J 1981;1:5–12. 6. Tibero D. Pathomechanics of structural foot deformities. Phys Ther 1988;68:1840–1849. 7. Shacklock M. Neurodynamics. Physiotherapy 1995;81:9–16. 8. Butler D, Gifford L. The concept of adverse mechanical tension in the nervous system part 1: testing for “dural tension.” Physiotherapy 1989;71(11):622–629. 9. Cavafy J. A case of sciatic nerve-stretching in locomotor ataxy: with remarks on the operation. Br Med J 1881;2(1094):973–974. 10. Marshall J. Bradshaw lecture on nerve-stretching for the relief or cure of pain. Br Med J 1883;2(1198):1173–1179. 11. Ellis R, Hing W. Neural mobilization: a systematic review of randomized controlled trials

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patellofemoral pain. J Orthop Sports Phys Ther 2003;33:671–676. Snijders C, Vleeming A, Stoeckart R. Transfer of lumbosacral load to iliac bones and legs. Part 1: biomechanics of self-bracing of the sacroiliac joints and its significance for treatment and exercise. Clin Biomech 1993;8(6):285–294. Jackson R, Porter K. The pelvis and sacroiliac joint: physical therapy patient management utilizing current evidence. In: Hughes C, ed. Current Concepts of Orthopaedic Physical Therapy. 3rd ed. Alexandria, VA: American Physical Therapy Association; 2011:12–14. DeRosa C, Porterfield J. Anatomical linkages and muscle slings of the lumbopelvic region. In: Vleeming A, Mooney V, Stoeckart R, eds. Movement, Stability, and Lumbopelvic Pain: Integration of Research and Therapy. 2nd ed. New York: Churchill Livingstone; 2007:47–62. Borowsky C, Fagen G. Sources of sacroiliac pain: insights gained from a study comparing standard intra-articular injection with a technique combining intra- and peri-articular injection. Arch Phys Med Rehabil 2008;89(11):2048–2056.

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CHAPTER 90 Pain Rehabilitation STEVEN P. STANOS and WILSON J. CHANG “Rehabilitation is a continuous process.”1 Rehabilitation may be described as a “return to ability . . . the return to the fullest physical, mental, social, vocational, and economic usefulness that is possible for the individual.”2 The focus is placed more on one’s abilities rather than their disabilities.2

Historical Overview: Pain Rehabilitation and Functional Restoration In 2016, in response to the Institute of Medicine’s (IOM)3,4 recommendations to improve the scope and breath of pain management, the National Pain Strategy (NPS), a call to develop a comprehensive population health level strategy to address pain prevention, care, education, and research, was released. Included in the plan is a need to focus on biopsychosocial-based self-management and more formal multidisciplinary team-based models of care. NPS defined “high-impact pain” as pain associated with “substantial restriction of participation in work, social, and self-care activities.” This chapter is a foundation to apply a “rehabilitation model” to address the critical needs facing those patients suffering with the debilitating effects of chronic pain, including highimpact chronic pain. In this approach, “function” and “restoration” of previous activity remains the focus of providers in the rehabilitation team.

HISTORY OF PAIN REHABILITATION Early evidence of a rehabilitation approach to the injured person or worker dates back to the Egyptians under Ramses II in 1500 BC where organized treatments of injured workers, fees for treatment, and compensation for 4560

injury were established.5 The development of more expertise and a more rational treatment and management approach of pain was delayed until the birth of the field of anesthesia in the 1840s and the isolation and synthesis of morphine by Serturner in 1806 and salicylates from willow bark in the late 1800s.6 The modern development of a rehabilitation model evolved only after World War I and World War II with the birth of the fields of physical and occupational therapy as a means to “rehabilitate” injured returning soldiers.7 Pain rehabilitation developed in the context of evolution of the medical specialties of physical medicine and rehabilitation, anesthesia, psychiatry, and occupational medicine during the 20th century. John Bonica championed a more comprehensive “multidisciplinary” approach in the United States in 1947 and later at the University of Washington in 1960.8 Wilbert Fordyce, a psychologist and collaborator of Bonica, incorporated operant conditioning and other behavioral approaches with more specialized 8-week inpatient programs in the late 1960s. In 1982, John Loeser formalized a more “structured program” at the University of Washington, a 3-week daily program, which has become a model for “interdisciplinary” treatment. A more biopsychosocial approach to pain rehabilitation has also been facilitated by the merging of behavioral and cognitive fields and the subsequent cognitive-behavioral approach to the assessment and treatment of pain in the 1980s and 1990s.9–11 A proliferation of pain treatment facilities was seen between 1980 and 1995 and included the advancement of interventional procedures.12 A more recent conceptualization of pain focuses on behaviors within the pain system, a biopsychomotor model of pain, which incorporates three interdependent behavioral subsystems: (1) communicative, (2) protective, and (3) social response behaviors.13 This model assumes that a pain system can only be adaptive if the sensory component of the pain system is accompanied by behaviors designed to act on the source or cause of injury or illness. This may help to explain the wide variability observed in pain behaviors seen across different patients despite relatively similar levels of reported pain intensity and objective tissue pathology. The biopsychomotor model of pain can be extended to include behavioral factors such as communicative behavior (grimacing), protective behaviors (i.e., withdrawing a limb from the fire), and behaviors 4561

designed to elicit social responses (i.e., empathy and solicitous behavior from others). This model, like the biopsychosocial one, emphasizes that dysfunction may develop in behavioral systems separate from pain sensation, and subsequent treatments targeting pain behavior would more likely lead to greater clinical outcomes and provide a more pragmatic and inclusive model for the spectrum of pain rehabilitation (Fig. 90.1).

FIGURE 90.1 Biopsychomotor response to pain. (Redrawn from Sullivan MJ. Toward a biopsychomotor conceptualization of pain. Clin J Pain 2008;24[4]:281–290, with permission.)

HISTORY OF FUNCTIONAL RESTORATION AND WORK REHABILITATION Functional restoration (FR) programs, based on a return-to-work model, evolved along with advancements in occupational medicine beginning in the 1970s. Prior to this, programs of “habit training” focused on restoring workers affected by disease or injury in the 1920s and later by the incorporation of vocational rehabilitation mandated at the federal level in 1923 and the Vocational Rehabilitation Act. In the 1950s, more objective measures were used to track progress and measure outcomes and served as the starting point for more formal work conditioning and work hardening programs championed by Lillian Wegg and Florence Cromwell.14,15 In the 1970s, work hardening emerged as a formal industrial management service16 and adopted a similar multidisciplinary approach used in the management of chronic pain and disability. Standardized work stimulation equipment, assessment, and treatment protocols were incorporated into 4562

standard practice in the 1980s and led to formal accreditation by the Commission on Accreditation of Rehabilitation Facilities (CARF) in the late 1980s and early 1990s.17–19 Gatchel et al.20 described eight classic critical elements of an FR approach which serves as the foundation for most multi- and interdisciplinary rehabilitation-based programs. Elements include quantification of physical deficits on an ongoing basis, psychosocial and socioeconomic assessment used to individualize and monitor progress, and an emphasis on reconditioning of the injured area or body part. The teamcentered FR approach also includes generic simulation of work or activity, disability management with cognitive-behavioral approaches, psychopharmacologic management focusing on improving analgesia, sleep, and affective distress, many times detoxifying patients from medications (i.e., opioids or benzodiazepines).20

WHAT IS PAIN REHABILITATION? A pain rehabilitation model can be applied to the entire spectrum of pain conditions, from acute musculoskeletal injuries, to subacute and recurrent injuries aggravated by poor ergonomics and/or physical impairments, to more complex chronic pain conditions where interplay of biologic, psychologic, and social influences is more apparent. Pain rehabilitation is based on a structured, individualized approach. The formal assessment identifies specific problems and needs most relevant to the patient and relates the problem to impairments and psychosocial factors, selecting appropriate measures to monitor progress and treatment. The rehabilitation program includes planning and coordinating various interventions with a focus on treating the specific impairments by restoring function and identifying compensatory strategies. Additionally, addressing activity limitations by addressing environmental and personal factors may help in restoring patients to previous levels of functioning and preventing or limiting disability.1 A traditional definition of rehabilitation, based on a biomedical model, places the concept of rehabilitation as a secondary intervention, used to restore patients to their previous level of (residual) physical, psychologic, and social functioning, and, if possible, return them to (modified) work.21 4563

Waddell and Burton22 question this assumption in that the biomedical definition assumes that disability is a “matter of permanent impairment,” that sickness and disability imply an incapacity to work, that rehabilitation focuses on “irremediable permanent impairment,” and that rehabilitation is a second-stage process following acute medical management and only is carried out after treatment ceases. Waddell and Burton22 have implied this may be inappropriate in that in many chronic pain conditions (i.e., low back pain), objective factors (pathology and impairment) accounts for a small part of the incapacity. These chronic conditions are characterized more by “symptoms and distress” than tissue abnormality.22 A number of biopsychosocial risk factors (i.e., lower level of education, higher preoperative pain, low work satisfaction, longer duration of sick leave, somatic complaints, and passive avoidance coping) have been identified as predictors of poor outcomes after surgical interventions contributing to loss of function, increased disability, and persistent elevated levels of subjective reports of pain.23,24 These biopsychosocial risk factors may serve as important potential targets for pain rehabilitation.

STAKEHOLDERS IN REHABILITATION Pain rehabilitation also involves the coordination of a number of important stakeholders involved in the care of the individual patient or worker. Stakeholders may include various health care providers, managed care organizations and insurers, the workers’ compensation carrier, society, the individual patient, and family members. This complex health care process and related list of stakeholders involved may sometimes add, as described by Shultz et al.25 and Gatchel et al.,20 a political dimension to the individual patient’s assessment and treatment process. Success in treatment may vary depending on stakeholder and may indirectly lead to antagonistic, confrontational, and misinterpreted feelings by the patient suffering with pain. Criteria of success may vary significantly depending on whether it is assessed by the patient or by society in general (Fig. 90.2). Many times, contrary to what is seen in other areas of clinical medicine, the pain rehabilitation clinician may find himself or herself in a potentially conflicting role in the treatment of patients with chronic pain (Table 90.1). The focus of care should remain on providing appropriate clinical services, 4564

serving as a patient advocate or adjudicator, without crossing ethical boundaries resulting in harm to the client.26

FIGURE 90.2 Criteria for success in comprehensive pain programs. (Redrawn from Gatchel RJ, Okifuji A. Evidence-based scientific data documenting the treatment and cost-effectiveness of comprehensive pain programs for chronic nonmalignant pain. J Pain 2006;7[11]:779–793. Copyright © 2006 American Pain Society. With permission.)

TABLE 90.1 Conflicting Roles of Rehabilitation Specialist 1. Clinical service provider working to reduce the client’s suffering 2. Client’s advocate working to protect the client in conflicts with an insurer 3. An adjudicator working to help the insurer detect evidence of client’s fraudulent behavior From Sullivan MJL, Main C. Service, advocacy and adjudication: balancing the ethical challenges of multiple stakeholder agendas in the rehabilitation of chronic pain. Disabil Rehabil 2007;29(20–21):1596–1603. Reprinted by permission of Taylor & Francis Ltd. http://www.tandfonline.com.

This chapter focuses on an overview of assessment and treatment strategies included in a pain rehabilitation–based approach to acute and chronic pain conditions. As part of the clinical continuum, the more comprehensive and integrated treatment approaches commonly referred to as multidisciplinary, interdisciplinary, and/or FR27 will be examined. Important psychological factors related to chronic pain and disability, the continuum of treatment models from more acute to integrative approaches, specific responsibilities of members of a pain rehabilitation team (i.e., physical and occupational therapist, psychologist, relaxation therapist, and vocational specialist), and an overview of more specific work rehabilitation approaches including work conditioning, work hardening, and functional capacity testing will be reviewed. 4565

Models of Rehabilitation Conceptual models of pain rehabilitation are based on historical advances that initially described pain as a purely sensory phenomenon evolving to include a more mind–body approach to understanding disability and function (Table 90.2). Hippocrates and Galen (c. 150 AD) described an imbalance of bodily “humors” as a means of developing chronic pain and distress as a model for understanding suffering.28 In the 1600s, a dualistic mechanistic model emerged. René Descartes (1596–1650) theorized damage to the body would stimulate specific neural pathways, giving rise to the sensation of pain.28 Through the mid-19th century, medicine focused on the individual’s unique manifestations of the disease process. In the mid-1800s, the expanding understanding of pathologic anatomy shifted the focus to a more biomedical model. In 1965, Melzack and Wall29 proposed the gate control theory of pain which proposed that pain experience was determined by physical, motivational, cognitive, and emotional factors, and transmission of nerve impulses could be modulated by spinal gating mechanisms at the level of the dorsal horn. Melzack30 elaborated on this more dynamic role of pain networks further with the “neuromatrix” model, arguing that the brain and central nervous system play a dominant role in the pain experience. TABLE 90.2 Historical Overview: Models of Pain Hippocrates and Galen28 Descartes28

Bodily humors

Melzack and Wall29 Engel30

Gate control theory

Melzack and Wall30 Turk and Gatchel9

Neuromatrix model

Sullivan13

Biopsychomotor approach

Dualistic theory

Biopsychosocial approach in medicine

Biopsychosocial approach

BIOPSYCHOSOCIAL APPROACH VERSUS BIOMEDICAL MODEL FOR PAIN MANAGEMENT The biomedical model assumes a causal relationship between a specific physical pathology and the presence or intensity of pain symptoms. It 4566

emphasizes the importance of eliminating pain by restoring normal function in the organ or body part from which pain is thought to emanate. Although the more disease-based biomedical model enabled the medical sciences to flourish and improved our ability to treat infection and other disease processes, its fundamentally limited scope led to less profound success and relative treatment resistance in the treatment of many chronic pain states. A biomedical model may be more advantageous in treating more acute pain states, where interventional procedures, pharmacotherapy, and surgical interventions may lead to recovery of pain or hasten time to recovery. But the biomedical model poorly addresses related mental health issues and frequently relies on dualistic decision pattern, whereby if the patient does not respond to an intervention, then the pain may be not be “real” or just “in their heads.”31 Many more complex pain conditions remain resistant to a purely biomedical approach (i.e., chronic low back pain, neuropathic pain, and fibromyalgia).32 George Engel33 helped to shift the thinking from a purely biomedical model of disease management to a more comprehensive biopsychosocial model of illness. Recently, the World Health Organization34 has embraced a biopsychosocial model of disability (Fig. 90.3), which incorporates a dynamic interaction between the individual health condition and contextual factors.

FIGURE 90.3 Domains of the biopsychosocial approach to pain rehabilitation. (Redrawn from Waddell G, Burton AK. Concepts of rehabilitation for the management of low back pain. Best Pract Res Clin Rheum 2005;19[4]:655–670. Copyright © 2005 Elsevier. With permission.)

The pain rehabilitation approach is based on a fundamental understanding of the individual’s unique condition as it relates to (1) impairment, (2) disability, and (3) functional limitation. Impairment is the loss of normality psychologically, physically, or functionally at the level of 4567

the organs and body systems.35 Examples of physiologic impairments include muscle weakness, loss of range of motion, and pain. Disability is a restriction or lack of ability to perform activities due to related impairments such as inability to function in a specific vocation, as a spouse, student, or parent. Functioning has been described as an umbrella term for body functions, body structures, activities, and participation, denoting a positive interaction between the individual or patient and contextual factors (i.e., background of the individual’s life and current situation). Functional limitation is a deviation from the normal behavior of performing activities of daily living (ADLs) and may include problems with transfers, standing, ambulation, running, and stair climbing.35 A formal model proposed by the International Classification of Functioning, Disability and Health integrates the individual components into a biopsychosocial-based model where a “health condition” is substituted by “chronic pain” (Fig. 90.4). Chronic pain is affected by body function, activities, and participation as well as influences from the environment and personal factors.

FIGURE 90.4 A formal model demonstrating the relationship among individual components that affect an individual’s function was proposed by the International Classification of Functioning, Disability and Health. This model was proposed for any “health condition,” and here, we have substituted “chronic pain” for the more generic term. (Redrawn from Weigl M, Cieza A, Cantista P, et al. Physical disability due to musculoskeletal conditions. Best Pract Res Clin Rheum 2007;21[1]:167–190. Copyright © 2006 Elsevier. With permission.)

A patient-centered approach is necessary if one is to effectively address these important individual concepts. A team-centered approach focuses on helping patients to achieve individual goals, which enable them to improve physical and psychosocial function, decrease pain, and improve quality of life. By working together, the rehabilitation team is able to help patients achieve better outcomes than could be achieved by an individual 4568

practitioner or intervention (i.e., surgical procedure, injection, pharmacotherapy). Basic treatment goals of both acute and chronic pain rehabilitation programs focus on functional improvement; improved abilities to perform ADLs, return to leisure, sport, or vocational activities; and improved pharmacologic management of pain and related affective distress (Table 90.3). TABLE 90.3 Pain Rehabilitation Goals 1. 2. 3. 4. 5.

Functional improvement Improvement in activities of daily living Relevant psychosocial improvement Rational pharmacologic management (analgesia, mood, and sleep) Return to leisure, sport, work, or other productive activity

TREATMENT APPROACHES: PAIN REHABILITATION A pain rehabilitation approach encompasses a wide range of treatment options including more directed therapies for acute pain conditions to more comprehensive and collaborative multi- and interdisciplinary approaches (Table 90.4). TABLE 90.4 Pain Rehabilitation Levels of Care Unimodal (acute) Collaborative Coordinated Multidisciplinary Work conditioning Work hardening Interdisciplinary Integrative

Acute Rehabilitation An approach to managing acute pain conditions relies on a more focused understanding of causative and aggravating factors, changes to affected tissues and related overload stresses, and includes three important phases: (1) acute, (2) recovery, and (3) functional. Within each phase, specific treatment focuses are applied by the therapist or clinician, and tools or skills are taught by the treating therapist with a goal of ongoing selfmanagement and practice. Acute management may involve relative rest, 4569

passive modalities (ice, heat, ultrasound), interventional procedures (i.e., trigger point injections, epidural, and facet injections), and oral and topical analgesics. Recovery phases focus on more advanced stretching and strengthening, increasing endurance, and assessing and treating postural changes that may be contributing to chronic pain.36

More Comprehensive Team Models: A Pain Continuum Rehabilitation treatment models include a continuum of care based on patient severity and needs with increasing complexity of treatment philosophies, a need for greater communication, and decreasing individual team member autonomy.37 Each of these models occupies a position along a continuum of care based on increasing levels of coordination, diversity of philosophies, and decreased hierarchical structure and practitioner autonomy. The left side of the treatment continuum (Fig. 90.5) shows the least collaborative model, parallel practice, where health care providers function quite independently. As one moves to the right, services become more coordinated with decreasing level of autonomy and increasing diversity of philosophies. From a structure standpoint, moving left to right increases the complexity of care, whereas reliance on hierarchy and clearly defined roles decreases. Complexity and diversity of outcomes increases while, from a process perspective, communication, participants, synergy, and importance of consensus building increases. Multi- and interdisciplinary treatment is even more structured, usually involving a number of specialties with less evidence of practitioner autonomy.

FIGURE 90.5 Continuum of team models. The most common practice model is parallel practice in which each practitioner oversees only the problems within their isolated discipline with little or no interaction with other practitioners caring for the same patient. The most effective models for caring for those with chronic pain involve programs designed to allow for frequent, direct, and repeated interactions among the providers caring for each patient in the form of multidisciplinary and interdisciplinary treatment programs. (Redrawn from Boon H, Verhoef M, O’Hara D, et al. From parallel practice to integrative health care: a conceptual framework. BMC Health Serv Res

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2004;4[1]:15. © Boon et al; licensee BioMed Central Ltd. 2004. https://doi.org/10.1186/1472-69634-15.)

With parallel practice, independent health care practitioners are working within their defined scope of practice such as in an emergency room setting or an acute cardiac unit (i.e., nurse, phlebotomist, physician, radiology technician) where the goal is rapid assessment and treatment in the most efficient manner. Consultation may include a pain physician referring a patient to an addiction specialist or surgeon for recommendations and shared treatment responsibilities. Collaborative practice may include the use of a case manager to help coordinate treatment between the patient and physical therapist. In a collaborative approach, information is shared on an ad hoc basis; practitioners normally practice independently sharing information regarding a particular patient. In coordinated treatment, patient records are shared among clinicians providing treatment for a specific therapy where the case coordinator or case manager is responsible for ensuring information is transferred to all team members. Differentiating between multi- and interdisciplinary treatment will be reviewed in greater detail in the following text. Although commonly used interchangeably, the terms interdisciplinary and multidisciplinary have important distinguishing features.

Multidisciplinary Treatment Focused treatment programs for acute conditions may involve individual physical therapy directed by the pain physician, followed by a coordinated program including ongoing communication with the patient’s case manager and therapist. With chronic pain conditions, more diverse assessment and treatment teams include multi- and interdisciplinary programs. In the multidisciplinary model, patient care is planned and managed by a team leader, usually a pain specialist (anesthesiologist, physiatrist, neurologist, psychiatrist, or primary care provider) or a psychologist and is often hierarchical with one or two individuals directing the services of a range of team members, many with individual goals. Treatment may be delivered at different facilities or centers where individual patient progress is not regularly shared between distinct disciplines. The growth of multidisciplinary pain treatment centers in the 4571

1980s led to the need for development of standards and formal accreditation processes. A committee on standards for Pain Treatment Facilities was established by the American Pain Society in the early 1980s, and a process was subsequently developed to accredit multidisciplinary pain centers (MPCs) by the CARF. Non–CARF-accredited programs also exist. Furthermore, the International Association for the Study of Pain delineated four levels of pain programs38: MPCs, multidisciplinary pain clinics, pain clinics, and modality-oriented clinics. Multidisciplinary pain clinics and centers, many of which include an even more integrated comprehensive interdisciplinary approach, include similar basic treatment disciplines; however, the MPCs are usually associated with major health science institutions with an additional focus on pain-related research and outcomes.

Interdisciplinary Treatment Even more collaborative, the interdisciplinary model involves team members working together toward a common goal. Team members are able to communicate and consult with other team members on an ongoing basis, facilitated by regular face-to-face meetings. Incorporation of the cognitive and behavioral psychological approaches along with the development and emergence of the field of health psychology led to the development of more interdisciplinary models under the more general “multidisciplinary” umbrella. Interdisciplinary pain programs may also be referred to as FN programs, which provide outcome-focused, coordinated, goal-oriented services. FR as an approach implies an emphasis on quantification and graded increases in function versus pain reduction, cognitive-behavioral therapy (CBT), occupational therapy, and work conditioning. FR programs were developed in the mid-1980s by Mayer et al.27 in the United States and have been incorporated with the basic program structure of interdisciplinary programs. The basic treatment model is based on Fordyce’s classic contingency management techniques and graded activity related to operant learning processes. FR aims at decreasing or eliminating learned pain behaviors.39 The interdisciplinary model provides practical strategies for assessing and treating pain-related deconditioning, psychosocial distress, and 4572

socioeconomic factors related to disability. An interdisciplinary team model is characterized by team members working together for a common goal, making collective therapeutic decisions, and having face-to-face meetings and patient team conferences to facilitate communication and consultation. Importantly, in this model, team members possess a combination of skills that no single individual demonstrates alone. Interdisciplinary teams may be led by a physician (medical director), psychologist, or nurse and include comprehensive assessment including pain medicine, pain psychology, and vocational rehabilitation. In some institutions, physical and occupational therapy assessments are also included in the formal assessment. Interdisciplinary programs are usually housed in one facility with periodic interdisciplinary team meetings to assess and adjust treatment progress, program coordination, and discharge planning. Programs primarily focus on restoring joint mobility, muscle strength, endurance, and conditioning and cardiovascular fitness. Coordinated vocational and therapeutic recreation services are also important aspects of care and focus on aiding patients in returning to work, improving behavioral factors (i.e., coping, catastrophizing, and problem solving) in the workplace, clarifying return-to-work level of functioning, and many times, individual occupational therapy. In general, formal interdisciplinary programs vary in intensity and may include 3 to 8 weeks of 4- to 8-hours-per-day programs with tailored group and individual therapies usually provided in an outpatient or, less often, in an inpatient hospital setting. Long-term follow-up studies of interdisciplinary treatment programs have demonstrated improved returnto-work rates, pain reduction, and quality of life.40,41 The reader is referred to the chapter on interdisciplinary pain treatment (see Chapter 106).

Outcomes of Multi- and Interdisciplinary Treatment Programs An early prospective trial documented high rates of returnto-work versus control subjects with improved physical capacities, self-reported disability, depression, and pain scores.42 Maintained posttreatment improvements in pain, perceived health, and psychological and physical function have been demonstrated in long-term studies (6 months and 5 years).43,44 The 4573

interdisciplinary treatment approach is supported by evidence suggesting these programs are more cost-effective and provide at least equal or greater efficacy than other pain treatments (i.e., spinal cord stimulation and implantable devices, conservative care, and surgery).45 Additional evidence-based studies have demonstrated outcomes and treatment costeffectiveness data supporting FR treatment which included multidisciplinary and interdisciplinary treatment programs.46–48 A recent analysis examined the cost utility of interdisciplinary treatment of chronic spinal pain.49 Cost utility involved the calculation of cost of the specific treatment relative to desired treatment goal (increased functioning and decreased pain) relative to pharmacologic treatment with or without anesthetic interventions. Interdisciplinary treatment was associated with better cost utility supporting interdisciplinary treatment as both less costly and more effective.49 Patients undergoing complex lumbar spine surgeries have also demonstrated improvements in pain and function.50 Although early intervention and referral for pain rehabilitation treatment should intuitively favor greater outcomes as compared to referrals late in the treatment process, studies have demonstrated that patients with long-term disability, many of whom have a greater incidence of pretreatment surgery, may still benefit from comprehensive treatment with similar improved return-to-work rates and decreased lost time rates.51 Rehabilitation-based multidisciplinary treatment has demonstrated high cost-benefit with regard to decreasing treatment costs and increasing workplace return to work.52,53 Sustained improvement in pain, mood, function, and opioid reduction or discontinuation was demonstrated in a large cohort of patients enrolled in a structured FR program. Patients entering treatment on opioids retained similar benefits regardless of opioid dose (i.e., high or low daily morphine equivalent doses).54

Team Building and Stakeholder Coordination CASE MANAGEMENT Case management involvement is an important resource in the management of work-related injuries. Case management has been conceptualized as a system-based approach based on Bronfenbrenner’s55 4574

systems theory, which incorporates an interaction of microsystems (worker factors), mesosystems (workplace, health care utilization, insurance system factors), and macrosystems (economic, social, and legislative factors). Case managers are primarily assigned to injured workers’ cases to help facilitate communication between stakeholders and medical providers and coordinate and clarify issues related to return to work and job description, respectively. A practical problem-based approach in rehabilitation management process is the rehabilitation cycle and includes four important interdependent steps: assessment, assignment, intervention, and evaluation (Fig. 90.6).56 Case management assessment includes identification of patient problems and modification and adjustment of goals. The assignment step involves the assignment to specific health care professionals who understand intervention principles and goals. Intervention more specifically refers to treatment disciplines and interventions with specific goals and milestones. Finally, evaluation refers to the evaluation of goals and level of achievement.57

FIGURE 90.6 The rehabilitation cycle. (Redrawn from Stucki G. International Classification of Functioning, Disability, and Health (ICF): a promising framework and classification for rehabilitation medicine. Am J Phys Med Rehab 2005;84[10]:733–740, with permission.)

Tate et al.58 suggested success of any collaborative workplace rehabilitation relationship is contingent on (1) company policy endorsing a commitment to rehabilitation, (2) educational opportunities offered or available for the injured worker by the employer, and (3) identification of key decision-making points involved in the ongoing relationship. Training the nurse case managers in basic fundamentals led to improved work placement as compared to untrained case managers who were more likely to place the injured worker in a sedentary or light duty job position. Applying a continuum of care model, many times facilitated by strong 4575

case management presence, includes a coordination of disciplines, services, providers, and care levels. A continuum of care model developed in Canada for the treatment of musculoskeletal conditions included medical management, active physical therapy, chiropractic management, and multidisciplinary assessment and rehabilitation. Implementation of the program resulted in more rapid and sustained recovery, greater patient satisfaction, and dramatic cost savings as compared to usual care.59

APPLYING TEAM VALUES Decision making in pain rehabilitation has been found to incorporate common decision values shared by the team members, worker, and stakeholders. Shared “general values,” as described by Loisel et al.,60 are those that stress work is therapeutic, pain is multidimensional, and interventions should be graded. These values should in turn be shared by the team members, the worker, and stakeholders facilitated by reassurance and the delivering of a single message as a way of more successfully returning a patient to work or previous level of function.60 These same values can be applied to the many barriers presented to the individual patient and stakeholder (Table 90.5). TABLE 90.5 Strategies Applied by the Rehabilitation to Overcome Barriers to Collaboration Stakeholders

Strategies Applied

Worker

Pain management Relaxation Education Confrontation Rational polypharmacy: analgesia, sleep, mood Education Asking for employer’s opinion on the TRW setting Sensitizing the employer to its support role in relation to the worker Asking the insurer to use its authority to exert influence on the employer Education Sensitize to the issues involved in the intervention Clarification of the roles and objectives Meeting with the insurer’s case worker before meeting the worker or the employer to ensure consistency in information delivered Acting without interfering Choosing convincing information Asking for the case worker’s support for the intervention

Employer

Insurer

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Physician

Inform the physician about the rehabilitation process Convincing him or her to take action to facilitate return to work Recommendation that worker find another physician if too great a hindrance to the TRW process

TRW, therapeutic return to work. Adapted by permission from Springer: Loisel P, Durand M, Baril J, et al. Interorganizational collaboration in occupational rehabilitation: perceptions of an interdisciplinary rehabilitation team. J Occup Rehab 2005;15(4):581–590. Copyright © 2005 Springer Science + Business Media, Inc.

Assessment, Goal Setting, and Progression through Treatment PAIN REHABILITATION PRINCIPLES Assessment of patients prior to entering a rehabilitation program is based on a comprehensive examination of physical, psychological, and social or relevant vocational factors. Also, the evaluating clinician must work to develop trust and rapport with the patient in order to understand barriers to recovery (i.e., contentious relationships involving family, employer, case manager, and/or the legal system) that may potentially lead to a delay or reduction of clinical improvement. Many times, the success of developing that relationship starts at the initial evaluation. Understandably, patients undergoing a rehabilitation program are often asked to make significant changes in the ways they cope with pain and function. Readiness to make such important changes has been found to be associated with treatment success,61,62 and readiness to self-manage pain increases from pre- to postMPC treatment.63 Based on the transtheoretical model of behavior change, individuals are seen to progress through a number of stages involving decisions about change and include precontemplation, contemplation, action, maintenance, and acceptance phases.64 These basic concepts are important for the physician to explore during the evaluation and often become a focus of discussion between other potential treatment disciplines (i.e., pain psychologist, physician, and vocational counselor) when deciding whether the patient is an appropriate candidate for treatment. The pain rehabilitation clinician must be consistent and clear in promoting exercise and activity as essential, safe, and effective for the correction of functional impairments. The clinician must also be aware of various fears, 4577

negative attitudes, financial, and vocational stressors many chronic pain working and nonworking patients are sometimes struggling with and be able to confront the patients on these issues in an open and understanding manner (Table 90.6).65 TABLE 90.6 Patient Perceptions Pathways to Becoming Injured

Seeking Treatment

Work, workplace, and degree of unsafe practices lead to injury

Desperate for a diagnosis; difficulty accessing appropriate and timely treatment

Fear of unemployment; continued hazardous job

Negative attitudes by doctors and other health practitioners toward the injured worker Medical uncertainty led to different diagnoses from different specialists; uncertainty led to more doctor shopping and inconsistent message regarding level of activity and restrictions.

Lack of knowledge about reporting injuries

Seeking Return to Adequate Work

Living as an Injured Worker

Returned to modified work yet disillusioned to find accommodations short-lived or nonexistent Lack of choice and control over vocational issues

Financial hardships; loss of marriages; change in family structure

Workers believed employer-based actions on the need of company rather than the workers

Legal action with compensation system drained of financial resources, adding to distress Psychological deterioration; limitation in selfcare activities led to feelings of dependency and social isolation

Reprinted with permission from Beardwood BA, Kirsh B, Clark NJ. Victims twice over: perceptions and experiences of injured workers. Qual Health Res 2005;15(1):30–48. Copyright © 2005 SAGE Publications.

Rehabilitation Specialists: Activities and Conceptual Models A pain rehabilitation team may include a pain physician (i.e., anesthesiologist, physiatrist, psychiatrist, neurologist, and/or primary care physician), physical and/or occupational therapist, a pain psychologist, relaxation (biofeedback) therapist, vocational and therapeutic recreational 4578

therapists, social workers, and nurses. Ongoing communication between treating disciplines, including monitoring of progress and adjustment of patient goals, is coordinated by the pain physician. A rehabilitation model is based on a clear, concise, and consistent therapeutic message, which focuses on the patient assuming a more active role in self-management, flare-up management, and exercise progression. Goals of treatment remain somewhat consistent across all disciplines and focus on improving function and decreasing pain. More specialized roles of individual therapists (i.e., physical and occupational therapy, pain psychology, and vocational rehabilitation) and treatment goals are reviewed in the following text based on an FR approach.

THE THERAPIST’S ROLE: BUILDING AN EFFECTIVE THERAPEUTIC RELATIONSHIP Besides obvious clinical skills and application of therapies by specific disciplines, the relationship between treating therapist (i.e., physical therapist, occupational therapist, psychologist, etc.) and patient is based on an ability to establish a mutually effective relationship based on ongoing respect, collaboration, and exchange of ideas. A successfully established working alliance will only help to improve outcomes. A process model for patient–practitioner collaboration includes a four-component model based on initially developing a therapeutic relationship, followed by mutual inquiry, problem solving, and negotiation.66 The therapist must also be cognizant of the patient’s beliefs, skills, emotional state, and expectations in effectively developing and adjusting a specific treatment plan and subsequent interventions.67 A therapeutic relationship involves the establishment of clear and attainable short- and long-term goals, the therapy intervention and training, and discharge planning (i.e., home exercise program). Therapists involved in pain rehabilitation treatment must be adept in their ability to assess initial levels of functional ability and then monitor and progressively increase the individual patient’s level and complexity of therapeutic exercises. Therapists assess secondary impairments in addition to their primary pain-related diagnoses (i.e., general inflexibility, deconditioning, regional myofascial pain and dysfunction, and other related postural abnormalities), which expands the 4579

area of treatment. Physical and occupational therapists apply a more functional cognitive and behaviorally mediated therapeutic approach and help the patient slowly integrate other aspects of the program into his or her home program. The basic principles of CBT are also introduced and facilitated by the physical and occupational therapy team members and may include goal setting, education, monitoring and documenting exercise and conditioning progress, and ongoing challenging and redirecting of maladaptive thoughts and behaviors.68–70 The integration of these approaches may help foster patient optimism, may decrease the fear of reinjury, and may maximize patient compliance. Common cognitive-behavioral objectives may be applied across disciplines as well as by pain psychology professionals in helping the pain rehabilitation patient change maladaptive thoughts and behaviors and include helping patients to combat demoralization, view pain as more manageable, alter or unlearn maladaptive thoughts or behaviors, bolster confidence, and improve problem solving (Table 90.7). TABLE 90.7 Pain Team Shared Primary Objectives of a CognitiveBehavioral Approach for Pain Patients 1. To combat demoralization by assisting patients to change their view of their pain from overwhelming to manageable 2. To teach patients the coping strategies and techniques to help them to adapt and respond to pain and the resultant problems 3. To assist patients to reconceptualize themselves as active, resourceful, and competent 4. To learn the associations between thoughts, feelings, and behavior and subsequently to identify and alter automatic, maladaptive patterns 5. To utilize more adaptive ways of thinking, feeling, and behaving 6. To bolster self-confidence and patients’ attribution of successful outcomes to their own efforts 7. To help patients anticipate problems proactively and generate solutions, thereby facilitating maintenance and generalization Adapted from Main CJ, Sullivan JM, Watson PJ. Pain Management: Practical Application of the Biopsychosocial Perspective in Clinical and Occupational Settings. 2nd ed. Edinburgh: Churchill Livingstone; 2007 and Turk DC, Okifuji A. A cognitive-behavioral approach to pain management. In: Melzack R, Wall PD, eds. Handbook of Pain Management: A Clinical Companion to Wall and Melzack’s Textbook of Pain. Edinburgh: Churchill Livingstone; 2003:533–541.

INCORPORATING BEHAVIORAL APPROACHES IN PAIN REHABILITATION 4580

Pain rehabilitation approaches rely heavily on incorporating behavioral principles and approaches (i.e., operant, cognitive, and respondent) into active therapies. The cornerstone of operant therapy is graded activity. The basic premise of a graded activity program is based on Fordyce’s combined use of graded activity progression and contingency management techniques. This treatment targets helping patients to increase healthy behaviors with positive reinforcement while, at the same time, decreasing maladaptive pain behaviors and beliefs and increasing tolerance for activity.39,71 Often, graded activity programs are also incorporated with exercise therapy and problem-solving training.72

PHYSICAL THERAPY Physical therapists specialize in gait training, locomotion, core strengthening and stability, joint deficiencies, and proper biomechanics. Active treatments include instruction in strengthening, postural reeducation, and related therapeutic exercise (see Chapter 93). Passive treatment modalities (i.e., local application of heat, cold modalities) may be more efficacious for acute injuries; they are used more judiciously with chronic pain conditions. The use of modalities with chronic pain rehabilitation should shift to an emphasis on facilitating increased activity before or after formal treatment sessions or exercise and as a means of managing pain flare-ups more independently. Manual therapy, the manipulation of soft tissues, continues to occupy a large part of the modern physical therapist’s scope of practice. Not necessarily new to medicine, manual techniques were described by Hippocrates (460 BC) with traction and immobilization as a means of reducing fractures.73 Galen later recommended techniques to treat “outwardly dislocated” vertebrae.74 Modern physical therapy’s use of manual techniques is based on principles of osteopathic medicine introduced by Andrew T. Still in 1871 and chiropractic treatment pioneered by Daniel Palmer in the late 1800s. Today, many therapists receive special training and certification from a number of “schools” of manual therapy including Maitland, Paris, Kaltenborn, and McKenzie (Table 90.8).75–77

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TABLE 90.8 Manual Therapy Manual Therapy Theories

Basic Principles

Key Terminology

Maitland (Australian)

Graded oscillatory movements to evaluate and treat joint stiffness and restore lost mobility

Paris, Stanley B. (New Zealand)

Focus on examination of spine, facet joint primary source for dysfunction in spine Arthrokinematics principles (e.g., concave-convex, closed-loosely packed positions), treat hypomobility even if asymptomatic Directional preference “Centralization” vs. “peripheralization” of symptoms Overpressure Identify “lesion” Heat and friction massage for contractile structures and forceful manipulation with manual distraction to treat intraarticular displacement

“S.I.N.S.” algorithm Severity, Irritability, Nature of the complaint, Stage of the pathology Incorporates Maitland and Kaltenborn principles

Kaltenborn (Norwegian)

McKenzie, R (Australia)

Cyriax, James (United Kingdom)

Cortical reorganization is coming in to focus for chronic pain management through physical therapy. Evidence of neuroplasticity in amputees with restructured primary sensory cortex receptive fields has been well established.78 Techniques include graded motor imagery and mirror therapy. These efforts target a rehabilitation program designed for synaptic exercises through the use of tactile and visual stimuli (i.e., computer, flashcards, mirror) and behavioral relevance (i.e., imagined movements, education) controlling for attention.79

THERAPEUTIC EXERCISE Therapeutic exercises targets muscle and joint deficiencies (i.e., weakness, decreased conditioning, and contracture) and serves as the basis for rehabilitation of patients with acute or chronic musculoskeletal, postoperative, and posttraumatic rehabilitation protocols (Table 90.9). The pain clinician must be cognizant of basic principles of physiology and guiding a patient through an individualized active strengthening program. 4582

This section reviews important definitions and concepts related to therapeutic exercise. With rehabilitation of any injury, strength and endurance are important targets for assessment and treatment. Muscular strength is the ability of a muscle to generate force against resistance. Maintenance of strength of one’s muscle, or, more importantly, muscle groups, will help to improve function and prevent new or reinjury. Strength training also incorporates balance and coordination of movement. Muscular endurance is the ability to perform repetitive muscular contractions against some resistance over time. Endurance will tend to increase with strength. Improvements in muscular endurance may be more advantageous with regard to improving daily function. TABLE 90.9 Common Therapeutic Exercises Exercise Type Closed kinetic chain Concentric Core stability Eccentric Isometric

Isotonic Open kinetic chain

Description

Therapeutic Uses

Proximal segment of the extremity moves on a fixed distal segment (e.g., leg press, squats, elliptical walker) Muscle contracts as it shortens (e.g., flexion phase of a biceps or hamstring curl) Targets low back, trunk, and abdominal muscles (e.g., sit up, back extension, abdominal crunch, Pilates) Muscle contracts as it lengthens (e.g., extension phase of biceps or hamstring curl) Muscle contracts, but its length stays the same (e.g., holding a weight in a stationary position for a few seconds)

Shoulder and knee rehabilitation, dynamic stability Increase muscle mass and strength Relief of low back pain or pregnancy-related pelvic pain Sport-specific strengthening to prevent injury Muscle toning and strengthening when joint mobility is not advised; quadriceps exercises to treat patellofemoral pain syndrome General muscle conditioning

Constant resistance applied to a muscle through a joint range of motion (e.g., free-weight lifting) Distal segment of the extremity moves about the proximal segments (e.g., long arc quadriceps extension, most weight-lifting exercises using the arms)

Functional improvement in activities of daily living

From Rand SE, Goerlich C, Marchand K, et al. The physical therapy prescription. Am Fam Physician 2007;76(11):1661–1666. Copyright © 2007 American Academy of Family Physicians. All rights reserved.

In general, skeletal muscular contraction can be divided into three types 4583

of contractions: isometric, concentric, and eccentric.80 Isometric contraction occurs when the muscle contracts without changing length. Isometric or static strength is necessary for performing many ADLs and in functional tasks or sports activities where a stable base of support is necessary for effective and efficient movement of joints. In pain rehabilitation, isometrics may be useful when joint motion is painful, a joint or joints are immobilized, or muscle or muscle groups are weak. In concentric contraction, the muscle shortens in length while tension increases to overcome or move some resistance. With eccentric contraction, resistance is greater than the muscular force being produced, lengthening the muscle while producing tension. This type of muscle activation may be associated with a higher incidence of delayed-onset muscle soreness after exercise.81 Thus, concentric exercises may be the focus of the program prior to progressing to more eccentric, unloaded ones. Strength and muscular endurance are dependent on size of muscle or muscle groups, number of muscle fibers, neuromuscular function and efficiency, and biomechanical factors. Neuromuscular training (NT) is a growing area of practice with most work in rehabilitation of musculoskeletal injuries including anterior cruciate ligament reconstruction. NT can include balance exercises, plyometrics, agility training, and joint mobility exercises. Plyometric exercise, initially used to enhance sports performance, may also be used in later stages of an active therapy program as a means of returning the patient to previous levels of sport or work. Plyometric exercise causes a lengthening of the muscletendon unit followed immediately by shortening, hence called the stretchshortening cycle. Plyometrics are used with various demands placed on the musculoskeletal system, usually initiated at lower intensity and progressed to more difficult and physically challenging higher intensity levels. The higher intensity levels may serve to resolve postinjury neuromuscular impairment and prepare the body to respond more effectively and safely to rapid changes in position and movement as well as greater levels of force seen in higher intensity exercise and physically demanding work tasks.82

EXERCISE PRESCRIPTION 4584

The goal of an exercise prescription is to maximize the benefit for the patient with pain. Four basic goals include36,83: 1. Changing sedentary behaviors to more active ones 2. Modifying risk factors for disability (e.g., obesity, hypertension, deconditioning) 3. Maintaining or improving exercise capacity as it relates to strength, aerobic capacity, balance, and flexibility 4. Enhance psychosocial function Exercise prescription and focus may vary depending on the patient’s age, medical comorbidities, and individual pain-related impairments (i.e., muscle strength, joint pain, joint contracture). Clinicians should be able to optimize therapeutic treatment by balancing the focus of therapy while being mindful of potentially harmful activities. Stretching has been known to increase range of motion of joints, enhance muscle coordination, reduce muscle tension, and increase circulation/energy levels.84 Strengthening enhances the integrity of muscle, tendons, and other connective tissues, which in turn, improve motor performance and decrease injury risk. Endurance exercise may help to reverse the cycle of deconditioning and weakness commonly seen with chronic pain patients and is an important part of the pain rehabilitation program. Circuit exercise programs, popular with the elderly population, have been shown to provide significant improvements in cardiorespiratory fitness, muscular strength, body composition, and serum cholesterol levels.85 Aquatic-based therapies offer a partial reduction of stress throughout weight-bearing joints by lowering gravitational burden.86 This can be considered for patients who have limited range of motion, generalized weakness, poor motor coordination, and/or at a fall risk due to impaired postural deficits (i.e., balance issues, spatial/proprioceptive deficits, sensory disorders). Temperature-controlled facilities can be recommended for additional physiologic effects of exercise have been shown to have analgesic effects, enhance mood, and improve self-efficacy.

OCCUPATIONAL THERAPY Activities of Daily Living Occupational therapy focuses primarily on functional mobility and ADLs 4585

as well as activity tolerance and ergonomic retraining. Occupational therapists typically concentrate on educating patients regarding proper posture and ergonomics related to upper limb functional activities such as lifting and computer usage as well as proper standing, sitting, carrying, and lifting postures (Table 90.10). TABLE 90.10 Desktop Ergonomics Environment Set up Keyboard

Chair

Monitor

Mouse

Phone

Lighting

Reasoning

Position keyboard align to forearms to be parallel to thighs at 90- to 110-degree elbow angle Elbows held close to trunk Wrists should be neutral. Keyboard “legs” collapsed Sitting as far back in the chair as possible keeping in contact with backrest at all times Knees at 90-degree angle with feet flat on floor Backrest at 10- to 15-degree recline Hips at 100- to 105-degree angle Use of footrest if chair is elevated. Avoid leaning forward.

Centered directly in front, not to the side Eyes should align with a point 1–2 in below the top of screen. Arm length distance with middle finger just touching the screen Bifocals: place monitor slightly lower without bending neck or tilting the chin to view screen Invest in full-lens computer glasses. Place mouse on dominant side or more comfortable side. Elbows tucked and wrist in neutral Maneuver with full arm/shoulder motion; not isolated wrist motion Placed in arm’s length while in chair. Avoid cradling headset between neck and shoulder. Consider hands-free headset. Avoid glare by placing screen parallel to light source such as windows. Tilt 5–15 degrees downward to avoid glare from overhead lights.

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Decreases shoulder/neck tension and strain Prevents nerve compression (i.e., carpal tunnel) and tendonitis of wrists and fingers Decreases stress on mid/low back muscles Hip and knee angles keep the low back posture in neutral position Aligns head and neck over spine Reduces forward head posture/neck tension and headaches Avoids forward head posture/neck tension and shoulder impingement Spine in neutral posture without rotational forces

Decreases shoulder/neck tension and strain Prevents nerve compression and tendonitis at the wrist Decreases shoulder/neck tension and strain Avoids cervical nerve impingement Reduces eye strain and fatigue Reduces migraine/headache

Writing surface

Turn off backlighting behind the computer screen. Separate writing surface from computer station Keep chest upright and arms resting comfortably with elbow at 90- to 100-degree angle. Avoid forward posture of head or neck.

triggers Decreases shoulder/neck tension and strain Reduces forward head posture and back strain

In general, occupational therapists address upper extremity–related ADLs including feeding, hygiene, grooming, bathing, and dressing. Occupational therapists spend considerable time with the patient, educating them on the potential for increases in pain with reinitiation of movement early in the treatment process. Focus may later change to lifting training and tolerance building. Coaching on proper body mechanics could include a basic assessment of maladaptive movement patterns, restriction in joint and soft tissue structures, as well as abnormal postures and bending or lifting techniques, which may exacerbate and/or be the cause of ongoing pain and dysfunction. Occupational therapists are also responsible for managing and directing more individualized work conditioning and work hardening programs as well as administering functional capacity evaluations (FCEs), often in coordination with the vocational rehabilitation team and employer.

Pacing Another important concept occupational therapists are primarily responsible for is directing and instructing patients on activity, work, and leisure pacing. Pacing may be either an appropriate or a maladaptive behavior. Good pacing may include activity scheduling, taking breaks to complete a pain-inducing activity as compared to overdoing activities, and the “crashing and burning” approach with prolonged periods of rest and “down time” in order to recover from activity related flare-ups (Table 90.11). TABLE 90.11 Pacing: Useful versus Maladaptive Responses Useful 1. Gradual increase in activity 2. Increase on a quota system 3. Varies mixed activities and rest

Maladaptive Overdo activities Increase activity until “intolerable” pain “Crash and burn”: take extended periods of rest or

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4. Realistic and manageable

prolonged down time after an activity or pain flare-up Too busy to incorporate

Adapted from Harding VR, Williams AC. Extending physiotherapy skills using a psychological approach: cognitive-behavioral management of chronic pain. Physiotherapy 1995;81(11):681– 688. Copyright © 1995 Chartered Society of Physiotherapy. With permission.

The therapist is then able to work with the patients in improving their daily routines, incorporating pacing, taking appropriate breaks, and prioritizing activities while incorporating self-management skills learned in other disciplines such as relaxation techniques and stretching into the patient’s daily routine at work, at home, and in leisure activities. Occupational therapists may also provide job site interventions, which include assessing ergonomics and monitoring for job site safety issues. Services may also include job site training where a trained occupational or physical therapist accompanies the injured worker.

PAIN PSYCHOLOGY Psychological interventions as part of a pain rehabilitation program have been shown to enhance recovery, decrease disability, and enhance psychosocial functioning.87–90 Psychological interventions focus on addressing maladaptive cognitions, passive avoidance, depression, anger, and pain-related anxiety. Initial focus of psychological treatment includes challenging patients to change maladaptive thoughts and behaviors. As stated earlier, an individual’s readiness to make important changes has been hypothesized to be an important factor in treatment success and serves as an important initial clinical question posed by the treating psychologist.61,63,91 Over time, patients are also challenged to consider taking a more active role in management and incorporating nonpharmacologic and pharmacologic therapies into their individualized program. Problem-solving training may help to teach patients to choose more effective responses to pain and improve function.72 Incorporating group pain psychology interventions with an active physical therapy program has been shown to enhance posttreatment outcomes as compared to physical therapy alone on measures of functional impairment, employment of active coping strategies, medication use, and self-efficacy beliefs.92 4588

One of the more critical elements of pain psychology involves CBT. As regarded as first-line psychosocial treatment for individuals with chronic pain,93 CBT techniques include relaxation training, setting and working toward behavioral goals/activation, problem solving, and cognitive restructuring.94,95 Symptom associations of pain-related beliefs and appraisals regarding pain intensity, depression, physical disability, and activities/social role limitations are indicated for CBT.96 In particular, catastrophizing—magnification and rumination about the source of pain and perceived inability to cope with pain—has consistently been found to be associated with physical and psychosocial dysfunction.97 Combining group CBT and relaxation therapy with an individually based multidisciplinary treatment (CBT, physical and occupational therapy, and social work) program demonstrated an additive effect with greater improvement on measures of pain, sleep, activity levels, and medication use.98,99 Chronic pain frequently accompanied by underlying psychiatric/psychological disorders often benefit from mindfulness meditation.100 It is characterized by paying attention to the present moment with openness, curiosity, and acceptance.101 The premise behind mindfulness meditation to target the high prevalence and refractory nature of chronic pain in conjunction with negative consequences of maladaptive behavior, which improved self-referential processing, leads to increased interest in treatment plan including adjunct to therapy and alternative interventions.100,102 The goal is to refocus the mind on the present, thereby increasing awareness of one’s external surroundings and inner sensations, allowing the individual to step back and reframe experiences. Clinical applications of mindfulness meditation include substance use, stress reduction, tobacco, fixation, and chronic pain.

RELAXATION TRAINING Furthermore, incorporating relaxation techniques (i.e., deep breathing, progressive muscle relaxation) with therapeutic stretching can help the patient progress in the exercise program and improve activity tolerance. Biofeedback is a treatment that has been shown to be quite effective in the management of pain.103 The treatment serves to help a patient become 4589

more aware of their physiologic responses to pain or other stressors. In general, relaxation training focuses on helping the patient to acquire selfmanagement tools for reducing tension and decreasing pain. Initial treatment involves basic education explaining how biofeedback-assisted therapies work and helping the patient to understand they are able to control or modulate physiologic functioning of their own bodies by “seeing” or “hearing” their own physiologic function (i.e., breathing, limb temperature, and sweat). Respiration assessment should always precede heart rate variability (HRV)-related biofeedback due to potential for dysfunctional breathing. Stimulation of the parasympathetic system through biofeedback produces autonomic relaxation, which in turn, directly counteracts stress effects.104 Clinical application of breathing assessment includes postural or biomechanical deficits such as clavicular or reverse breathing, thoracic versus inappropriate abdominal usage, hyperventilation, or transient apnea.

Representation of reverse breathing. X-axis is time. Y-axis is blood volume pulse heart rate. Notice the discordant inhalation/exhalation and respiratory rate (blue line) patterns in relation to heart rate. (Source: Adapted from Chapter 16 Respiration Assessment. Shaffer F. HRV Biofeedback Tutor 2018. biosourcesoftware.com.)

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Representation of transient apnea. X-axis is time. Y-axis is blood volume pulse heart rate. Notice two successive periods of transient apnea indicated by yellow arrows. (Source: Adapted from Chapter 16 Respiration Assessment. Shaffer F. HRV Biofeedback Tutor 2018. biosourcesoftware.com.)

Skills training include training with basic biofeedback technologies such as respiratory biofeedback, surface electromyography, and/or thermal biofeedback. Techniques include diaphragmatic breathing, progressive muscle relaxation, and autogenic techniques. Patients are encouraged to log their practice sessions in their relaxation practice log. Relaxation training is provided in one-on-one and in group settings usually provided by a health psychologist, biofeedback specialist, or physical or occupational therapist. At the conclusion of formal treatment, patients should be independent with relaxation self-management techniques and be able to incorporate practice and technique integration with normal daily activities and during times of symptom flare-up or elevated levels of distress.

Work Rehabilitation: Work Conditioning and Work Hardening Work conditioning and work hardening are an important core component of work therapy in the field of industrial and pain rehabilitation. This field of modern occupational therapy developed after World War II with a focus of FR in wounded veterans as a means of securing employment in the civilian world after returning from duty. Work therapy also includes acute treatment, job analysis and placement, and FCE. Multidisciplinary 4591

principles were applied to occupational therapy–based work rehabilitation in the 1950s with the development of improved assessment tools and systems and the addition of vocational counseling, medical management, and industrial engineering. In the 1970s, work hardening and conditioning programs were combined with behavioral medicine approaches that focused on reducing abnormal illness behaviors in a more comprehensive treatment of injured workers primarily with low back pain. Eventually, standards were established and subsequently updated by CARF in the late 1989s and early 1990s, respectively. Work rehabilitation usually begins once a patient has reached a treatment plateau in active physical therapy and is unable to return to work due to pain-related impairments (Table 90.12). TABLE 90.12 Work Rehabilitation Musculoskeletal exercise

Aerobic training

Education

Work activity

Stability–mobility Strength–endurance Balance–coordination Equipment based Aerobic classes Functional activities Principles Technique training Problem solving Simulated activity Actual equipment Actual work

From Isernhagen SJ. Work hardening. In: Demeter SL, Andersson GB, eds. Disability Evaluation. 2nd ed. St. Louis: Mosby; 2003:769–780. Reprinted with permission of Dr. Gunnar Andersson.

Work conditioning is usually concentrated on the physical components of flexibility, strength, coordination, and endurance and involves one discipline of treatment (i.e., physical or occupational therapy). A more multidisciplinary approach is seen with work hardening, which incorporates behavioral and vocational components with a formal focus on return to job-specific tasks or positions. Work conditioning is routinely coordinated with acute medical management as compared to work hardening, which is usually provided later in therapy within the rehabilitation phase of treatment. Work hardening programs were initially described by Matheson19 at 4592

Rancho Los Amigos Hospital as a work-oriented program focused on improvement in the client’s productivity versus symptom reduction or increased physical capacity. A “client” can be described as an injured worker with impairments that do not match their job position, a worker with disease-based impairments with diminishing physical capacity, a job applicant who may not have the physical abilities to perform the intended job, or a currently employed worker in transition to a job requiring higher physical function.105 Work hardening is an individualized, work-specific, multi- and interdisciplinary program centered primarily on returning patients (i.e., the injured worker) to their previous level of work or work demands. Work hardening uses real or simulated work tasks and progressively increasing conditioning, flexibility, neuromuscular control, and tolerances (Tables 90.13 and 90.14). Goals of work hardening include (1) attaining optimal physical tolerances and abilities, (2) maximizing cognitive and psychosocial functioning, (3) developing appropriate worker behaviors, (4) reducing fear and increasing confidence for the resumption of productive work, and (5) identifying problems that may necessitate placement in an alternative job.106,107 TTABLE 90.13 Components in a Typical Work Hardening Program Step I Job Analysis Understand worker’s specific job requirements Critical job tasks Physical job demands Psychosocial demands High-risk job factors If job analysis available: review and validate primary job functions If job analysis not available: on-site job task analysis

Step II Establishing Work Tolerance Baseline Medical history Worker interview Job description with critical job demands Pain assessment Physical assessment Work posture and mobility Strength, sensation, coordination, lifting, reaching, carrying, pushing and pulling, stooping, bending, kneeling, sitting and standing, work task stimulation

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Step III Individual Work Hardening Plan/Goals 1. Increase duration of daily participation 2. Increase physical tolerances to the level of critical job demands 3. Improve body mechanics and postures 4. Develop pain management strategies 5. Develop problem-solving skills for self-management at the work site 6. Facilitate appropriate worker behaviors

TABLE 90.14 Work Hardening Program Standards 1. Improve strength and endurance in relation to return to work goal 2. Simulation of critical work demands, tasks, and environment of the job worker will return to 3. Education: body mechanics, pacing, safety, and injury prevention, promoting worker responsibility and self-management 4. Assess for need for job modifications (i.e., equipment changes or additions, ergonomic modification); availability for on-site job modification assessments 5. Individualized written plan which includes observable and measurable goals 6. Safe work or therapy environment that is appropriate for reaching vocational goals 7. Quality assurance system; outcomes based on program and worker goals 8. Documentation or reporting system that includes initial plan, regularly scheduled team conference notes with monitoring of progress, record of attendance, and compliance 9. Evaluation and modification of work behaviors (i.e., timeliness, attendance, interpersonal relationships) 10. Criteria for admission includes physical recovery sufficient to allow for progressive reactivation and participation for a minimum of 4 h/d for 3 to 5 d/wk along with a defined work goal 11. Criteria for discharge clearly stated (i.e., patient met goal stated in plan, patient did not participate according to program plan, goals not feasible to attain) Adapted from State of Washington Department of Labor and Industries. Work hardening program standards. Available at: http://www.lni.wa.gov/ClaimsIns/Files/ReturnToWork/WhStds.pdf. Accessed October 12, 2008.

An individualized work hardening program incorporates a three-step process which includes an initial formal job analysis to determine specific duties, completion of a baseline work tolerance evaluation, and establishment of the individual work hardening plan. Work hardening standards have been established by a number of groups and may vary depending on the state or the federal governing body.108 Occupational therapy manages most work conditioning and work hardening treatments as part of the pain rehabilitation program. Assessment of the injured worker is more comprehensive than the assessment done during standard occupational therapist evaluations. Patients are placed in programs of a set number of days, usually 4 to 5 days per week over a 4- to 8-week period. Both programs are highly based on objective measures obtained during the program evaluation which includes tolerances and capacities for lifting, pulling, standing, sitting, reaching, climbing, kneeling, and/or crawling. The treatment program is based on the individual patient’s own job demands and work level (sedentary, light, medium, heavy) and developing improved conditioning 4594

and tolerances for activities (Table 90.15). Although formal psychological counseling is not a core discipline, these programs are based on helping patients work through and unlearn fear-avoidance beliefs and movement patterns, pain-related fear, catastrophizing, and pain-related anxiety. TABLE 90.15 Physical Demand and Level of Job Duty Physical Demand

Occasionally

Frequently

Constantly

Sedentary duty

Lift or carry up to 10 lb Sit 6–8 h Stand or walk 0–2 h Lift or carry up to 20 lb Stand 4–8 h Walk 0–4 h Lift or carry up to 50 lb Stand or walk 8 h Lift or carry up to 100 lb Stand or walk 8 h Lift or carry over 100 lb

Negligible — —

Negligible — —

Up to 10 lb — —

Negligible — —

Up to 20 lb —

Up to 10 lb —

Up to 50 lb —

Up to 20 lb —

Over 50 lb —

Over 20 lb —

Light duty

Medium duty

Heavy duty

Very heavy duty

From U.S. Department of Labor. Dictionary of Occupational Titles. Washington, DC: U.S. Government Printing Office; 1986.

OUTCOMES OF WORK CONDITIONING AND WORK HARDENING PROGRAMS Reviews of work conditioning and work hardening programs have found evidence of improved return-to-work rates and fewer work days off in treated patients versus controls.109–111

Measuring Physical Capacity Functional capacity testing provides a means of measuring function by obtaining objective and subjective data with performance-based testing. Testing can be divided into two groups of tests including examining isolated parts of the body or “functional units” (i.e., lumbar spine, shoulder) and the ability of the functional unit to interact with other bodily functional units or activities such as lifting capacity. Lifting capacity many 4595

times involves the interplay of the biomechanical chain of a number of systems. A common example of the biomechanical chain includes transferring forces from a simple lifting task from the ground. Here, forces of the biomechanical chain include transferring forces from the hands through the elbow and shoulder (upper extremity functional unit) to the lumbar spine and hips (lower extremity functional unit) to placing the object and transmitting forces to the floor.

FUNCTIONAL CAPACITY TESTING FCE is a process where the individual’s ability to perform a specific task or physical demands of a job is assessed, bridging the gap between observed physical impairment and work capacity. Matheson112 describes the FCE as “a systematic method of measuring an individual’s ability to perform meaningful tasks in a safe and dependable basis.” FCEs have three specific purposes: (1) to improve the likelihood that the patient will be safe in a job task, (2) to assist in improving role performance through assessing and identifying functional decrements as a means of providing appropriate treatment or therapy, and (3) to determine presence of disability for bureaucratic or legal entities that may assign a quantifiable level of impairment or apportionment or deny monetary or medical disability benefits.113 The FCE is a valuable tool for the physician, vocational counselor, therapist, or employer to establish a specific attainable work goal based on objective data. In theory, by comparing performance demonstrated on the FCE to the required physical job demands of the individual worker, meeting or exceeding all job requirements simulated during testing will help to determine if the patient is safe to return to work.114 Better performance on an FCE, many times defined by lower number of failed tasks during testing, may be associated with lower risk of recurrence after return to work.115,116 Various types of FCEs can be performed as a means of obtaining specific vocational goals including establishing functional goal setting, disability rating, job and occupation matching, and work capacity evaluation.117 In general, the FCE can be done before treatment and usually once a patient has reached a treatment plateau or has completed a 4596

formal acute or subacute therapy program. As a means of determining impairment of disability, an FCE may compare measured functional capacity either to the patient’s preinjury baseline abilities or population norms. Accurate measurements of a worker’s preinjury capacities rarely exist, and health care providers are many times inaccurate in estimating the worker’s preinjury functional level or physical capabilities.118 The FCE is used to establish a final level of functioning and includes a statement regarding validity, effort, and pain behaviors. A number of validated FCE tests and programs are available from a number of vendors and are individually designed for specific disorders such as low back pain or upper extremity conditions. These tests can be incorporated into a larger battery of tests used in the formal FCE. Strength testing may include assessing lifting, carrying, pushing and pulling, work stimulation, and circuit testing (Table 90.16). TABLE 90.16 Functional Capacity Evaluation Lifting Protocols Test

Test of

Specific tests

Progression

Isoinertial lifting evaluation

Occasional lifting tolerance

4 lifts: floor to knuckle, 12 in to knuckle, waist to shoulder, shoulder to overhead carry 1. Carrying 2. Pushing (sled) 3. Pulling (sled) Lumbar PILE: (floor to 30in-high shelf) Cervical PILE: (30-in shelf to 54-in shelf)

Weight increased in 10-lb increments, if too much pain, decrease by 5 lb

Dynamic carrying, pushing and pulling tests Progressive isoinertial lifting evaluation (PILE)

Frequent lifting capacity

Resistance increased in 10-lb increments Starting weight 13 lb (male), 8 lb (female)

End Point/Outcome

End points: 85% of max predicted age adjusted heart rate, 55% to 60% body weight

Common assessment and job simulation devices include the Purdue Pegboard Test, the Crawford Small Parts Dexterity Test, and the Jebsen Hand Dexterity Test. Testing usually lasts between 2 and 6 hours and may 4597

also be performed over a number of days to observe for fluctuations in performance depending on change in pain or to make sure the patient meets the demands of more continuous work-related physical activity. Performance reliability is used to determine performance credibility based on the assumption an individual will produce similar outcomes in a series of trials.119 Additional objective measures may also be assessed including increase in heart rate during and immediately following performance of a strenuous task. Performance credibility can be subjectively determined by assessing for consistency and incongruity between specific tasks and tests. Reports of pain and pain behavior should be specific to the body part and correlate with the level or area of injury.120 Performances that do not follow normal or expected patterns may also be indicative of less than sincere effort. Subjective credibility measures may include the individual’s perceived physical strain or effort and may be rated on a number of Ratings of Perceived Exertion scales. In one example, scores range from 6 to 19 (e.g., 6 [“no exertion”], 7 [“very, very light”], 15 [“hard”], to 19 [“very, very hard”]) and increase linearly with exercise intensity. Values of the scale correlate to heart rate (0.8 to 0.9), ranging from 60 to 200 beats per minute.121 Grip strength assessment in the FCE serves two important purposes: to assess handgrip strength and to document performance of maximum voluntary efforts. A common test used in many clinics and mentioned in FCE reports is the Jamar hand dynamometer (Sammons Preston Rolyan, Bolingbrook, IL), a calibrated hydraulic hand dynamometer, which measures static grip strength at five grip spans. The therapist is able to produce a graphical representation of the forces produced at five grip positions, revealing a classic “biomechanical curve,” with the lowest force values occurring in positions 1 and 5 and the highest at positions 2, 3, or 4. Inability to produce this bell-shaped curve could cast doubt on the individual’s sincerity of full maximal effort. Force variability of multiple trials can be applied to normative data and can also be used to indicate noncredible performance.122

FUNCTIONAL CAPACITY TESTING UTILITY 4598

An important and controversial area of FCE results lies in its ability to demonstrate validity, reliability, and accuracy.123,124 Lemstra et al.125 examined the tester’s ability to judge maximal effort in a standard lifting protocol. They found high specificity but low sensitivity (62%), with only a small number of commonly used maximal lifting tests (5 of 17) able to differentiate between maximal and submaximal effort.125 Results of a functional capacity test can be used in conjunction with a more detailed understanding of the individual’s job description as a means of establishing return-to-work restrictions and formal levels of work (see Table 90.15).125,126

What Does an “Invalid” Test Mean? In clinical practice, “invalid” test results may be related to the patient demonstrating less than full effort in performance. Although not always consistent with malingering, a number of other causes (i.e., physical ability, disability, pain intensity, and fear of reinjury) have been identified and should be considered when interpreting and making clinical decisions based on an invalid test or test with evidence of less than “full” or “maximal effort” (Table 90.17).127–131 TABLE 90.17 Causes of Invalid Functional Capacity Evaluation Tests/Less Than Full Effort 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.

Malingering syndrome Factitious disorder Learned illness behavior Conversion disorder, pain disorder, or other somatoform disorders Depressive disorders Test anxiety Fear of symptom exacerbation or injury Fatigue Medication and psychoactive substance effects Lowered self-efficacy expectations Need to gain recognition of symptoms

Reprinted with permission from Gaudino E, Mael F, Matheson L. Synthesis of Research and Development of Prototypes for a New Disability Determination Methodology: Measurement Concepts and Issues Relevant to the Social Security Administration’s Disability Determination Process. Washington, DC: American Institutes for Research; 1999. Table 90.17: Causes of Invalid Functional Capacity Evaluation Tests/LessThan Full Effort.

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The result of an FCE can have far-reaching consequences including injured workers having compensation terminated or losing their job or seeing a reduced medicolegal settlement in patients believed to be exhibiting submaximal effort.132 In order to establish one’s functional capacity, the injured worker must perform at his or her maximal ability or effort. A number of tests have been used as a means of validating effort. Methods used to assess sincerity of effort include Waddell nonorganic signs, pain behavior description, symptom magnification, coefficients of variation, correlations between physical evaluation and function, grip measurements, and temporal relationship between heart rate and increased levels of pain with activity.132

Role of Opioid Management in Pain Rehabilitation The role of chronic opioid management in pain rehabilitation remains a controversial topic. Pain rehabilitation programs as early as the 1960s focused primarily in reducing and/or eliminating opioids secondary to fears of tolerance and development of iatrogenic addiction. This approach still characterizes many interdisciplinary programs today. However, the shift to more liberal use of opioids for chronic noncancer pain in the 1990s and the assumption that risk for addiction was minimal led to increased use of opioids in the treatment of chronic pain.133–136 The more recent reappraisal of the benefits and potential harms of chronic opioid use has also led to more questions regarding the accuracy of predicting aberrant behavior, and quantifying rates of addiction137–140 use has been complicated by an appreciation for not only the potential risk for developing aberrant behaviors, misuse, abuse, and opioid use disorders, including overdose-related deaths. Common adverse effects include cognitive impairment, endocrine dysfunction (sexual dysfunction and opioid induced hypogonadism), mood disorders,141–145 and hyperalgesia. In 2016, the Centers for Disease Control and Prevention (CDC) published guideline for opioid management in primary care and recommending nonpharmacologic therapy, including biopsychosocial-based rehabilitation approaches, as preferred first-line treatment to opioid therapy, and if opioid therapy is necessary, their use should be in conjunction with 4600

nonpharmacologic interventions.146 Unfortunately, patients referred for pain rehabilitation treatment include many opioid treatment “failures” and/or patients additionally managed with other controlled substances (i.e., benzodiazepines and hypnotics). A number of reasons for “failing” should be considered during the evaluation and subsequent treatment planning and include ruling out improper or maladaptive opioid or controlled substance use, poorly designed opioid and/or pharmacologic regimen, poor or limited analgesic response with adverse effects, opioid-induced pain sensitivity, or a combination of these factors (Table 90.18). TABLE 90.18 Potential Scope and Spectrum of Use of Opioids in Pain Rehabilitation 1. Rule out improper or maladaptive use of opioids for their nonanalgesic reasons (i.e., depression, psychological tolerance, anxiety) 2. Adjust regimen, limit short-acting, limit total daily dose while patient learns additional nonpharmacologic skills to manage pain and pain-related disability 3. Detoxification secondary to failed analgesia, poor functional outcomes related to use 4. Slow taper down in total daily dose while monitoring for changes in mood and cognition 5. Detoxification secondary to development of possible opioid-induced hyperalgesia 6. Detoxification secondary to pain condition not fully or partially responsive to opioid analgesics

A pain rehabilitation approach may also offer a patient self-management treatment tools with potentially similar or even greater clinical outcomes than those achieved by his or her opioids. Concurrent pharmacologic management may include a structured taper off the currently used opioid, conversion to methadone, or conversion to buprenorphine products. Use of U.S. Food and Drug Administration-approved buprenorphine products for opioid dependence (i.e., buprenorphine and buprenorphine and naloxone) requires specialized licensure by clinicians. Treatment of withdrawal signs and symptoms primarily includes the use of oral or transdermal clonidine, an α2-adrenergic agonist,147 and adjuvants for withdrawal-related myalgias, insomnia, anxiety, and gastrointestinal distress.148 The advantage of a structured and relatively controlled environment of most multi- and interdisciplinary treatment programs is that it offers an opportunity for patients with limited or maximized improvement on chronic opioids to reduce or eliminate opioids while at the same time 4601

learning to apply new nonpharmacologic approaches to management of their pain. This structured environment is ideal for more successfully integrating a more rational polypharmacy approach. Behavioral medicine treatments can be effectively incorporated into a structured multi- or interdisciplinary rehabilitation-based program. Treatment of the chemically dependent patient can include two types of therapies: (1) psychotherapeutic strategies and (2) mind–body therapies.149 Psychotherapeutic strategies include supportive-expressive psychotherapy, drug counseling, family therapy, and motivational enhancement therapy. Mind–body therapies, in general, include CBT, group support and education therapy, and relaxation therapy (i.e., deep breathing, imagery, hypnosis, and biofeedback) (Table 90.19). TABLE 90.19 Behavioral Treatment Techniques for the Chemically Dependent Patient Psychotherapeutic strategies Supportive-expressive psychotherapy Multidimensional family therapy Motivational enhancement therapy Mind–body therapies Cognitive-behavioral therapy Relaxation techniques Meditation, guided, or self-guided imagery, progressive muscle relaxation, deep breathing Adapted from Wooten J. Behavioral medicine treatment in the management of the chemically dependent patient. In: Smith HS, Passik SD, eds. Pain and Chemical Dependency. New York: Oxford University Press; 2008:253–258.

Patients can be successfully weaned or have their opioid dose decreased during an FR rehabilitation-based approach. Active opioid withdrawal did not adversely impact short-term outcomes following a 3-week outpatient pain program,150 and physical and emotional functioning were favorable in a fibromyalgia cohort that completed an interdisciplinary pain rehabilitation program which included withdrawal of opioids, nonsteroidal anti-inflammatory drugs, benzodiazepines, and muscle relaxants.151

Conclusion Rehabilitation is a continuous process, relying on a comprehensive, 4602

pragmatic approach that focuses on an individual’s physical impairments and function-related disability. The field of modern pain rehabilitation developed along with the growth of a number of medical specialties (i.e., anesthesia, rehabilitation medicine, psychiatry, neurology, and occupational medicine), physical and occupational therapy, and health psychology. Pain rehabilitation assessment and treatment is based on a biopsychosocial model. A narrower dualistic biomedical model may fail to adequately assess and help patients to manage the complexities of ongoing pain, affective distress, and environmental and social issues. Treatment goals in pain rehabilitation programs include improving psychosocial functioning; decreasing pain; improving aerobic conditioning; and facilitating safe and successful return-to-work status, return to leisure pursuits, and activities at home and in the community. A pain rehabilitation approach includes planning and coordinating various medical interventions (i.e., pharmacologic and nonpharmacologic), educational activities, and coordinating a patient’s participation with specific rehabilitation-based disciplines (i.e., physical and occupational therapy, pain psychology, relaxation, and other mind–body therapies). Vocational rehabilitation can serve as an additional treatment option and may be coordinated in patient-specific work-based therapies such as work conditioning and work hardening programs. Work conditioning and work hardening may be more specific levels of treatment for the injured worker as a bridge to progress patients after completing acute rehabilitation and more closely simulating work activities, respectively, prior to returning to previous levels of sport, function, or work. Functional capacity testing may be used as a more objective means of establishing a baseline level of function, establish treatment and work goals, or finalize return-to-work level of functioning. Validity measures may also help to identify physical and psychosocial factors that are contributing to the injured worker’s level of functioning and clarify discrepancies in tolerances and effort. The pain rehabilitation clinician must work with the patient in conjunction with various stakeholders (i.e., case managers, insurance providers and adjustors, legal personnel, and family members). The clinician’s role may include additional responsibilities beyond not only working to help patients decrease pain and increase function but also as an 4603

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behavioral approach. Phys Ther 1002;72:279–290. State of Washington Department of Labor and Industries. Work hardening program standards. Available at: http://www.lni.wa.gov/ClaimsIns/Files/ReturnToWork/WhStds.pdf. Accessed October 12, 2008. Bendix AF, Bendix T, Baegter K, et al. Comparison of three intensive programs for chronic low back pain patients: a prospective, randomized, observer-blinded study with one year follow-up. Scand J Rehab Med 1997;29:81–89. Schonstein E, Kenny D, Keating J, et al. Physical conditioning programs for workers with back and neck pain: a Cochrane systematic review. Spine 2003;28:E391–E395. Schonstein E, Kenny DT, Keating J, et al. Work conditioning, work hardening and functional restoration for workers with back and neck pain. Cochrane Database Syst Rev 2003; (1):CD001822. Matheson L. Functional capacity evaluation. In: Andersson G, Demeter S, Smith G, eds. Disability Evaluation. Chicago: Mosby Yearbook; 1996:168–177. Matheson LN, Mooney V, Grant JE, et al. Standardized evaluation of work capacity. J Back Musculoskelet Rehabil 1996;6:249–264. Innes E, Straker L. A clinician’s guide to work-related assessments: 1—purposes and problems. Work 1998;11:183–189. Isernhagen SJ. The Comprehensive Guide to Work Injury Management. Gaithersburg, MD: Aspen Publishers; 1995:821. Gross DP, Battié MC. The prognostic value of functional capacity evaluation in patients with chronic low back pain: part 2. Spine 2004;29:920–924. Matheson LN. The functional capacity evaluation. In: Demeter SL, Andersson GB, eds. Disability Evaluation. 2nd ed. St. Louis, MO: Mosby; 2003:311–325. Fishbain D, Khalil T, Abdel-Moty E, et al. Physician limitations when assessing work capacity: a review. J Back Musculoskelet Rehabil 1995;5:107–113. Matheson LN. How do you know that he tried his best? The reliability crisis in industrial rehabilitation. Industrial Rehab Quart 1988;1:10–12. Owens KA, Buchholz RL. Functional capacity assessment, worker evaluation strategies, and the disability management process. In: Shrey DE, Lacerte M, eds. Principles and Practices of Disability Management in Industry. Boca Raton, FL: CRC Press; 1995:269–299. Borg GA. Psychophysical bases of perceived exertion. Med Sci Sports Exerc 1982;14:377– 381. Matheson L, Carlton R, Niemeyer L. Grip strength in the disabled sample: reliability and normative standards. Industrial Rehab Quart 1988;1(3):9. Vasudevan SV. Role of functional capacity assessment in disability evaluation. J Back Musculoskelet Rehabil 1996;6:265–276. Vlozo CA. Work evaluations: critique of the state of the art of functional assessment of work. Am J Occup Ther 1993;47:203–209. Lemstra M, Olszynski WP, Enright W. The sensitivity and specificity of functional capacity evaluations in determining maximum effort. Spine 2004;29:953–959. U.S. Department of Labor. Dictionary of Occupational Titles. Washington, DC: U.S. Government Printing Office; 1986. Gross DP, Battié MC. Factors influencing results of functional capacity evaluations in workers’ compensation claimants with low back pain. Phys Ther 2005;85:315–322. Gross DP, Battié MC. The construct validity of a functional capacity evaluation administered within a workers’ compensation environment. J Occup Rehab 2003;13:287–295. Cutler RB, Fishbain DA, Steele-Rosomoff R, et al. Relationships between functional capacity measures and baseline psychological measures in chronic pain patients. J Occup Rehab

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2003;13:249–258. Lackner JM, Carosella AM. The relative influence of perceived pain control, anxiety, and functional self efficacy on spinal function among patients with chronic low back pain. Spine 1999;24:2254–2260. Geisser ME, Robinson ME, Miller QL, et al. Psychosocial factors and functional capacity evaluation among persons with chronic pain. J Occup Rehab 2003;13:259–276. Lechner DE, Bradbury SF, Bradley LA. Detecting sincerity of effort: a summary of methods and approaches. Phys Ther 1998;78:867–888. Moulin DE, Iezzi A, Amireh R, et al. Randomised trial of oral morphine for chronic noncancer pain. Lancet 1996;347:143–147. Tennant FS, Uelmen GF. Narcotic maintenance for chronic pain. Medical and legal guidelines. Postgrad Med 1983;73:81–94. Portenoy RK. Chronic opioid therapy in nonmalignant pain. J Pain Symptom Manage 1990;5:46–62. Porter J, Jick HN. Addiction rare in patients treated with narcotics. N Engl J Med 1980;302:123. Kalso E, Edwards JE, Moore RA, et al. Opioids in chronic non-cancer pain: systematic review of efficacy and safety. Pain 2004;112:372–380. Eisenberg E, McNicol ED, Carr DB. Efficacy and safety of opioid agonists in the treatment of neuropathic pain of nonmalignant origin: systematic review and meta-analysis of randomized controlled trials. JAMA 2005;293:3043–3052. Fishbain DA, Bole B, Lewis J, et al. What percentage of chronic nonmalignant pain patients exposed to chronic opioid analgesic therapy develop abuse/addiction and/or aberrant drugrelated behavior? A structured evidence-based review. Pain Med 2008;9:444–459. Furlan A, Sandoval J, Mailis-Gagnon A, et al. Opioids for chronic noncancer pain: a metaanalysis of effectiveness and side effects. CMAJ 2006;174:1589–1594. Ballantyne JC, Mao J. Opioid therapy for chronic pain. N Engl J Med 2003;349:1943–1953. Mao J. Opioid-induced abnormal pain sensitivity: implications in clinical opioid therapy. Pain 2002;100:213–217. Angst MS, Clark JD. Opioid-induced hyperalgesia: a qualitative systematic review. Anesthesiology 2006;104(3):570–587. Daniell HW. Hypogonadism in men consuming sustained-action oral opioids. J Pain 2002;3:377–384. Michna E, Ross EL, Hynes WL, et al. Predicting aberrant drug behavior in patients treated for chronic pain: importance of abuse history. J Pain Symptom Manage 2004;28:250–258. Dowell D, Hagerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain— United States, 2016. MMWR Recomm Rep 2016;65(RR-1):1–49. Charney DS, Heninger GR, Kleber HD. The combined use of clonidine and naltrexone as a rapid, safe, and effective treatment of abrupt withdrawal from methadone. Am J Psychiatry 1986;143:831–837. Collins ED. Pharmacologic approaches to opioid dependence and withdrawal. In: Smith HS, Passik SD, eds. Pain and Chemical Dependency. New York: Oxford University Press; 2008:247–251. Wooten J. Behavioral medicine treatment in the management of the chemically dependent patient. In: Smith HS, Passik SD, eds. Pain and Chemical Dependency. New York: Oxford University Press; 2008:253–258. Rome JD, Townsend CO, Bruce BK, et al. Chronic noncancer pain rehabilitation with opioid withdrawal: comparison of treatment outcomes based on opioid use status at admission. Mayo Clin Proc 2004;79:759–768.

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151. Hooten WM, Townsend CO, Sletten CD, et al. Treatment outcomes after multidisciplinary pain rehabilitation with analgesic medication withdrawal for patients with fibromyalgia. Pain Med 2007;8:8–16.

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CHAPTER 91 Assessment and Treatment of Substance Use Disorders ANDREW J. SAXON, JAMES P. ROBINSON, and MARK D. SULLIVAN This chapter on assessment and treatment of substance use disorders provides guidance, particularly for practitioners interested in pain medicine, on how various forms of substance use disorders are diagnosed and managed clinically. Because detection and management of opioid use disorder poses a major concern for physicians using opioids to treat patients, and because diagnosis of opioid use disorder in this context is often confounded by pain issues, the chapter focuses special attention on this complex clinical conundrum. More specifically, the chapter focuses on patients with chronic nonmalignant pain (CNMP) because issues related to opioid use disorder are more vexing in these patients than in patients with cancer or other life-threatening illnesses. Various surveys indicate that individuals with chronic pain disorders are more likely to have substance use disorders than are individuals in the general population,1,2 and individuals with substance use disorders also have high rates of pain disorders.3 Therefore, practitioners treating pain disorders are likely to encounter patients with substance use disorders and will need to know how to screen for and recognize these disorders, diagnose these disorders, make appropriate referrals for and/or treat these disorders, monitor for these disorders during ongoing pain treatment, and manage therapy for chronic pain in the context of these disorders. The first section of the chapter presents the assessment and treatment of all major forms of substance use disorders from the perspective of addiction medicine. The second section focuses on assessment and treatment of opioid use disorder from the perspective of the pain specialist.

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Assessment and Treatment of Substance Use Disorders—Addiction Medicine Perspective The panoply of substance-related disorders includes intoxication, withdrawal, substance use disorder (otherwise known as addiction), and substance induced psychiatric disorders (e.g., psychosis, mood disturbance, or anxiety caused directly by the use of the substance). Substance use disorders occur with a variety of commonly used substances such as alcohol, cannabis, cocaine, opioids, sedative/hypnotics, stimulants like amphetamines and methylphenidate, inhalants, psychedelic agents, and tobacco. A standardized set of criteria characterizing these disorders is provided in the Diagnostic and Statistical Manual of Mental Disorders (5th ed., DSM-5).4 Intoxication and withdrawal obviously differ by substance and can generally be diagnosed through history and physical examination. The criteria for substance use disorder which will be covered in greater detail in the following text are identical across substances. What is currently termed a substance use disorder in DSM-5 was known as either substance abuse or dependence in prior versions of the DSM, with abuse being considered a milder form of the disorder. The use of the term dependence generated some confusion and controversy. In contrast to a commonly held conception of “dependence” as notating purely physiologic changes that occur in response to repeated exposure to a substance, in prior versions of the DSM, “dependence” referred to a syndrome of physiologic signs and symptoms combined with an array of behavioral disturbances. Prior to the advent of DSM-5, some suggested that the phrase “substance dependence” referring to the Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev., DSM-IV-TR) syndrome be replaced with the term addiction to avoid confusion between purely physiologic dependence and the syndrome of substance dependence.5 Others felt that the term addiction has negative connotations leading to stigmatization. A compromise was settled on with DSM-5 using the term substance use disorder. It is commonly understood that the terms addiction and substance use disorder are essentially synonymous and interchangeable.

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SCREENING AND RECOGNITION Clearly, some initial evidence must arise through screening to suggest that a patient has a substance use disorder to trigger a thorough diagnostic assessment. In many cases, screening and diagnostic evaluation may overlap. The idea of “universal precautions” in pain medicine has been advanced as one way to detect potential substance use problems in all pain patients, so there may be some value in routine use of some or all of these screening procedures.6 However, it is often too time-consuming and cumbersome to perform them in primary care, and there is no strong evidence that universal precautions or routine screening leads to better outcomes.

History Generally, a thorough history of substance use obtained through a matterof-fact, nonjudgmental interviewing style will provide a great deal of information or even a formal diagnosis. Most patients are not aware of guidelines for safe quantities of alcohol consumption and will readily divulge the amount of their drinking. Many patients are more reluctant to discuss use of illicit substances, but some will freely admit to such use if they do not fear sanctions or punishment. Oftentimes, this openness is more likely to occur during initial intake. Patients may be less forthright during the course of treatment if they believe they have something to lose by admitting to use. If time allows, it is worth asking explicitly about frequency and quantity of use for each class of substance along with route of administration. It is also quite important to ask about any history of current and past problematic substance use, as such problematic use is known to increase the risk of recurrence in the context of pain management. It is useful to know what types of substance use disorders treatment, if any, have been helpful for the patient in the past. Recommended safe quantities of alcohol use consist of no more than four standard drinks per day (or more than 14 total per week) for men and three standard drinks (or more than 7 total per week) for women.7 The recommended quantities are less for women because women tend to have less total body water and thus a lower volume of distribution for alcohol.8 Quantities of different forms of alcohol that define a standard drink are 4614

listed in Table 91.1. If patients acknowledge regularly consuming more than the recommended amounts or describe heavy drinking such as five or more drinks on one occasion for men or four or more for women, a more thorough diagnostic evaluation for alcohol use disorder should be pursued. TABLE 91.1 Quantities of Alcohol that Define a Standard Drink (14 g Pure Alcohol) Beverage Beer Malt liquor Table wine Fortified wine Liqueur Brandy Spirits (gin, vodka, whiskey)

Percent Alcohol

Quantity in Standard Drink (in Fluid Ounces)

5% 7% 12% 17% 24% 40% 40%

12 8.5 5 3.5 2.5 1.5 1.5

For illicit substances, any suggestion of more than occasional recreational use of marijuana should prompt a more thorough diagnostic evaluation. It is also important to look for tobacco use disorder, as this disorder has been associated with increased risk of opioid misuse in a number of studies.1,9

Physical Examination Signs of possible substance use problems evident on physical exam include hypertension (common with excessive alcohol use), track marks indicative of recent or past injection drug use, pupillary constriction or dilation, inflamed nasal turbinates from intranasal substance insufflation, wheezes or rhonchi on lung exam from substance smoking, enlarged, tender liver from excessive alcohol use, other substance toxicity or hepatitis, or any stigmata of excessive alcohol use such as flushed facies, spider angiomas, palmar erythema, etc. Any of these findings should trigger further screening and possible thorough diagnostic evaluation.

Laboratory Routine blood work can provide an indication of excessive alcohol use. Suggestive findings include elevations in liver transaminases or 4615

macrocytic, hyperchromic red blood cells related to alcohol’s interference with folate absorption, and subsequent folate deficiency. Positive serologies for past or current hepatitis B or C infection or HIV infection would raise concerns about a substance use–related mode of transmission. In addition, specific laboratory testing to detect presence of substances in body fluids offers a convenient component of screening. Typically, urine is tested,10 although tests can also be readily performed in oral fluid or blood.11,12 Substances that have been used are likely to remain present in urine for a longer period than they will in other body fluids (Table 91.2). For urine testing, a screening test is typically performed via immunoassay. When needed, confirmatory tests using high-performance liquid chromatography/mass spectrometry or gas chromatography/mass spectrometry can be ordered. It is important to note that the routine urine assay for opioids does not detect oxycodone, methadone, buprenorphine, or fentanyl which each requires a specific screening test. Heroin can only be detected shortly after use if its intermediate metabolite, 6monoacetylmorphine, is present. Subsequently, 6-monoacetylmorphine is rapidly metabolized to morphine. If morphine appears in a urine toxicology specimen, it could represent either pharmaceutical morphine use or heroin use. It is difficult to detect alcohol in urine, blood, oral fluid, or breath unless the use has been quite recent. However, the alcohol metabolites, ethyl glucuronide or ethyl sulfate, indicating recent alcohol use can be detected in urine, blood, or hair.13 TABLE 91.2 Drug Detection Times in Urine and Drug Plasma Half-lives Drug Amphetamine Cocaine metabolite (Benzoylecgonine) Opioids Morphine glucuronide Codeine glucuronide Heroin metabolite (6monoacetylmorphine) Methadone

Detection Time in Urine (Based on Standard Cutoff Values)

Plasma Half-life

2–3 d 2–3 d

12 h 7.5 h

2d 3d 2–4 h

7.5 h 12 h 20 min

3 d single use 7–9 d maintenance dosing

24 h

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Oxycodone Hydromorphone Hydrocodone Barbiturates Short acting Intermediate acting Long acting Benzodiazepines Short acting Intermediate acting Long acting Cannabis single use Cannabis chronic use

2d 1–2 d 1–2 d

5h 2.5 h 4h

1d 2–3 d ≥16 d

25 h 38 h 100 h

1d 2–4 d ≥7 d 3d ≥30 d

1.5 h 10 h 48 h 20 h 20 h

Self-report Questionnaires A number of self-report questionnaires have been designed to help in screening for substance use disorders, and these can be utilized prior to, concurrent with, or subsequent to the history, physical, and laboratory evaluation to help determine whether a patient warrants more thorough diagnostic evaluation. Although the instruments described in the following text have definite utility in primary care and general populations as well as selected samples such as psychiatric patients, they have not been tested in pain patients. In screening for alcohol use disorders, the currently most frequently used instruments are the Alcohol Use Disorders Identification Test (AUDIT)14 and the Michigan Alcoholism Screening Test (MAST).15 The AUDIT has 10 items related to quantity and frequency of alcohol consumption and to maladaptive behaviors associated with alcohol use and can be completed in about 5 minutes. Each item is scored 0 to 4. A score of 8 or more for men under age 60 years or 4 or more for women or men over age 60 years are considered positive screens indicative of need for further assessment. A shorter version of the AUDIT, the AUDIT-C, which asks only 3 questions related to consumption has also been validated as a screening instrument in primary care settings.16 The MAST contains 25 questions and focuses more on problem behaviors associated with alcohol use. Each item counts for 1 point, and a score of 6 or more indicates a positive screen with need for further assessment. There are shorter versions of the MAST which also appear to function as adequate screening 4617

instruments. In the context of managing pain patients where urine toxicology should be readily available, self-report instruments to screen for drug use problems are probably less useful than a positive urine toxicology. However, if use of a self-report screening instrument is desired, a commonly used instrument is the Drug Abuse Screening Test (DAST).17 The DAST is based on the MAST and has 28 items concerning both intensity and frequency of drug use and problematic behaviors associated with drug use. As with the MAST, each item counts for 1 point, and a score of 6 or more points to the needs for further assessment. Shorter versions of the DAST also exist. A much briefer option to screen for a possible drug use disorder is the single item question, “How many times in the past year have you used an illegal drug or used a prescription medication for nonmedical reasons?” This single item performed as well as the DAST-10 at detecting a substance use disorder.18 One recently validated instrument that screens for all major substances is the Tobacco, Alcohol, Prescription Medication, and Other Substance Use (TAPS) tool, which is reasonably brief and can be self-administered.19

PRESCRIPTION DRUG MONITORING PROGRAM Most states in the United States provide prescription drug monitoring programs (PDMPs). How they function and what the requirements are to access them vary widely from state to state. They do provide information on most controlled substance prescriptions that individual patients have obtained. Checking the PDMP can be very helpful in verifying the prescription medications that the patient is reporting via history.20

DIAGNOSTIC ASSESSMENT As noted earlier, criteria provided in DSM-5 represent the most standard way to make a diagnosis of a substance use disorder. At times, it proves fruitful to interview family members if the patient is not forthcoming. Table 91.3 contains DSM-5 criteria for opioid use disorder as an example. The criteria for a substance use disorder are identical across all substances. To determine the presence or absence of the diagnosis, the 4618

interviewer should focus one by one in turn on each substance of potential relevance and systematically go over each of the criteria with the patient for each substance. TABLE 91.3 Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, Diagnostic Criteria for Opioid Use Disorder A problematic pattern of opioid use leading to clinically significant impairment or distress, as manifested by at least two of the following occurring within a 12-mo period: 1. Opioids are often taken in larger amounts or over a longer period than was intended. 2. There is a persistent desire or unsuccessful efforts to cut down or control opioid use. 3. A great deal of time is spent in activities necessary to obtain the opioid, use the opioid, or recover from its effects. 4. Craving, or a strong desire or urge to use opioids 5. Recurrent opioid use resulting in a failure to fulfill major role obligations at work, school, or home 6. Continued opioid use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of opioids 7. Important social, occupational, or recreational activities are given up or reduced because of opioid use. 8. Recurrent use of opioids in situations in which it is physically hazardous 9. Continued opioid use despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance 10. Tolerance,a as defined by either of the following: a. A need for markedly increased amounts of opioids to achieve intoxication or desired effect b. A markedly diminished effect with continued use of the same amount of opioid 11. Withdrawala as manifested by either of the following: a. The characteristic opioid withdrawal syndrome b. Opioids (or a closely related substance) are taken to relieve or avoid withdrawal symptoms. aThis

criterion is not considered to be met for those taking the substance solely under appropriate medical supervision. Mild = 2–3 symptoms. Moderate = 4–5 symptoms. Severe = 6 or more symptoms.

There are 2 physiologic criteria, tolerance and withdrawal, and 9 behavioral criteria. Two or more of the 11 criteria must be present at any one time over a 12-month period to make the diagnosis. If 2 to 3 criteria are present, the disorder is classified as mild; if 4 to 5 are present, as moderate; and if 6 or more, as severe. The physiologic criteria are not 4619

considered to be met for individuals taking the substance under medical supervision. For example, a pain patient treated chronically with opioids who is taking them precisely as prescribed might display tolerance to the effects of opioids and withdrawal signs and symptoms if the medication is stopped, but in this situation, these two criteria would not be applied to the diagnosis of opioid use disorder. Similarly, this scenario could occur with an attention-deficit/hyperactivity disorder patient treated chronically with stimulants, or with an anxiety disorder patient treated chronically with benzodiazepines. Conversely, an individual might not have either tolerance or withdrawal but could have the DSM-5 defined substance use if he or she meets at least two of the behavioral criteria, although this scenario occurs rarely in clinical practice. Inspection of the criteria reveals that questions about each criterion are unlikely to be interpreted by patients as critical or threatening and unlikely to engender resistance or deception, particularly if posed in a matter-of-fact, nonjudgmental fashion. Although this procedure sounds time-consuming, it frequently can be accomplished in a matter of minutes for each substance of concern. As mentioned at the outset, the diagnosis of opioid use disorder in a patient with CNMP being treated with opioids may not be as straightforward as simple application of the DSM-5 criteria and is discussed in detail in the following text. Diagnosis of a substance use disorder certainly should not preclude appropriate interventions for a pain problem and in rare instances, with appropriate monitoring and safeguards, may not categorically preclude opioid treatment of chronic pain.

Co-occurring Psychiatric Disorders Mental health disorders frequently co-occur with substance use disorders.21,22 It is likely that chronic pain patients who have substance use disorders will have another non–substance-related co-occurring mental health disorder.23 Oftentimes, co-occurring mental health and substance use disorders interact with negative synergy so that exacerbation of one disorder in turn exacerbates the other.24 Thus, if a pain patient does have a substance use disorder, it is imperative to evaluate that patient for other cooccurring mental health disorders and provide appropriate clinical intervention (including pharmacotherapy and/or psychotherapy) for any 4620

that are diagnosed.

MONITORING DURING ONGOING PAIN TREATMENT Even if a patient does not manifest a substance use disorder at the onset of chronic pain treatment, a disorder can certainly arise during the course of treatment. Maintaining vigilance for the development of a disorder involves both observation of the patient for behavioral evidence and routine monitoring techniques.6 Behaviors that may increase the index of suspicion include missing appointments, having medication shortages, failure to pay bills, or a markedly changed affect during appointments. Depending on the setting and resources available, it may prove worthwhile to establish routine, monitoring procedures for all pain patients even in the absence of concern. This approach normalizes these procedures, allows patients to expect them, and creates structure that may actually help the patient to feel supported while removing any sense of stigma or accusation that may supervene if the procedures are applied only for cause. The procedures that will be utilized should be specified at the outset of treatment in a written treatment agreement. One obvious routine monitoring procedure to consider is urine toxicology testing as described earlier.25 Another potential procedure is unscheduled medication call backs. For this procedure, patients are telephoned and asked to return to the office within 24 hours with all their outstanding medication. When the patients come in, pill counts are performed to ensure that all expected outstanding medication is accounted for. It is also possible to obtain a urine toxicology specimen at that time.

TREATMENT AND/OR REFERRAL Some general comments about treatment and referral will be made, and then specific interventions for use disorders involving each particular class of substances will be outlined. Most physicians get virtually no training or experience in treatment of substance use disorders and, therefore, often feel helpless or hopeless in the face of these disorders. Although many patients with these disorders who do get treatment get it in specialized settings that operate in parallel to and oftentimes outside of mainstream 4621

medicine, many patients will refuse a referral to such settings, and a growing body of literature supports the efficacy of physician intervention as a reasonable first attempt at treating these disorders.

Brief Interventions Brief office interventions conducted by physicians have demonstrated efficacy in reducing alcohol consumption for patients with problematic alcohol use that does not rise to the level of an alcohol use disorder but very limited if any benefit for alcohol use disorder.26,27 Motivational interventions (see following text) which can be incorporated into brief office interventions have demonstrated modest efficacy in nonalcohol substance use disorders.28 Brief interventions should be delivered in a manner that is matter-offact, nonjudgmental, supportive, and empathic and definitely not in a manner that is confrontational. The first step consists of stating concern about the patient’s level of alcohol use (or any level of illicit drug use). It is helpful to give the patient direct examples from his or her medical record including bothersome symptoms, physical findings, specific diseases, or lab abnormalities. The next step involves giving direct advice to cut down (or quit) the substance use along with an offer to help. If the patient is not receptive to this advice, and the situation is not emergent, the physician can encourage him or her to consider it carefully and reflect on why he or she considers ongoing use to be a reasonable course of action. A follow-up can be arranged for further discussion. If the patient appears receptive to advice to cut down or quit, the physician helps the patient to establish a specific goal to cut down or abstain (for a use disorder). Also, the physician provides explicit behavioral suggestions such as avoiding acquaintances who use, avoiding places where use has previously occurred, or seeking social support for quitting, including attending mutual-help groups such as Alcoholics Anonymous or Narcotics Anonymous. A follow-up appointment should be scheduled to monitor progress. If the patient has alcohol use disorder and is willing to try for abstinence, the brief intervention could be combined with prescription of an appropriate alcohol treatment medication as described in the following 4622

text. If the patient has developed opioid use disorder, the brief intervention could be combined with a recommendation to try buprenorphine also described in the following text. If the pain physician treating the patient has a federal waiver to prescribe buprenorphine, arrangements could be made to stop any opioid analgesic the patient may currently be taking and make a switch to buprenorphine.

Specialty Substance Use Disorders Treatment If a referral to a specialized substance use disorders treatment provider is needed, the referral could be made to an individual practitioner, another physician, psychologist, social worker, or chemical dependency counselor who specializes in substance use disorders treatment and could work with the patient in a private office setting using one or more of the psychotherapeutic or behavioral interventions detailed in the following text. Frequently, the referral will be made to an addiction treatment or substance use disorders program or agency. The American Society of Addiction Medicine publishes Patient Placement Criteria that can aid in determining what level of addiction treatment is appropriate for a given patient. These criteria have not, however, been fully scientifically validated and are based largely on expert opinion.29,30

Medically Supervised Withdrawal Some patients, who manifest withdrawal when stopping their substance use, may need medically supervised withdrawal (also known as detoxification) to stop the substance safely and engage in treatment. The most common substances which require supervised withdrawal are alcohol, sedative-hypnotics, and opioids, although patients may have very unpleasant withdrawal symptoms from marijuana, cocaine, or amphetamines and need some support and monitoring. Medically supervised withdrawal can be accomplished on an outpatient or inpatient basis depending on the severity of the withdrawal. Clearly, alcohol or sedative-hypnotic withdrawal can be life-threatening. Usually, benzodiazepines are prescribed over several days in tapering doses.31 Supervised opioid withdrawal for physiologic dependence on opioids can be accomplished using methadone in a licensed treatment program32 (see 4623

the following text) or with buprenorphine33 by appropriately qualified physicians. Alternatively, the α2-adrenergic agonist, clonidine, can be prescribed to attenuate opioid withdrawal signs and symptoms and tapered over several days.34 Some paradigms, known as ultrarapid opioid withdrawal, have been developed whereby opioid withdrawal is precipitated with an opioid antagonist such as naloxone or naltrexone under sedation or general anesthesia to complete the withdrawal in a brief period of time. These rapid procedures have no better outcomes than more gradual withdrawal but do have more adverse events such as pulmonary problems and psychiatric instability so they are not recommended.35 It is very important to understand that medically supervised withdrawal (detoxification) alone does not constitute treatment. If medically supervised withdrawal is not immediately followed by more definitive substance use disorders treatment, relapse is almost universal.

Opioid Maintenance Treatment Many patients with primary opioid use disorder do not want to undergo withdrawal or have tried it previously with subsequent relapse. These patients might be referred to a federally licensed opioid treatment program.36 These programs provide opioid maintenance therapy with either methadone or buprenorphine. Because these medications have long half-lives, they can prevent the emergence of opioid withdrawal when taken on a once a day basis. (More detail on the clinical use of these medications for the treatment of opioid use disorder is provided in the following text.) The structure of the program is largely dictated by federal and state regulations. Patients must have a minimum of a 1-year history of opioid use disorder. In the early stages of treatment, patients must come to the clinic daily for observed doses of medication with take home doses of medication for weekend days when the clinic is closed. The maximum allowed first dose of methadone is 30 mg with subsequent gradual dose escalation to an optimally therapeutic dosage. A physical examination and basic laboratory tests are required as is periodic urine toxicology testing. Regular counseling visits are delivered as needed. As patients stabilize in treatment, as evidenced by regular attendance at dosing visits and other appointments, remaining on a stable dose of medication, and ceasing illicit 4624

substance use as demonstrated by drug-free toxicology specimens, take home doses of medication become available so that patients do not have to attend clinic every day. After 2 years of continuous treatment, stable patients on methadone may receive up to a maximum of 1 month’s take home doses. Patients treated with buprenorphine in these settings can gain access to take home doses whenever they meet criteria for stability without regard to time in treatment. Opioid maintenance treatment has exceptionally good outcomes not only in terms of reducing illicit opioid use but also in terms of reducing other substance use, reducing mortality and morbidity, reducing criminal justice involvement, and improving employment.37,38 It is considered to be as cost-effective as other potential life saving treatments such as coronary bypass surgery or renal dialysis.39 All physicians are permitted to prescribe methadone for pain management, but only specially licensed facilities can order and dispense methadone specifically for opioid use disorder. Prescription of methadone for pain in patients with signs of opioid use disorder has obvious inherent risks and should be undertaken with careful monitoring precautions in place.

Intensive Outpatient Treatment For patients who do not have opioid use disorder or who have opioid use disorder but decline maintenance therapy and have completed withdrawal, intensive outpatient treatment is often employed. This type of treatment is generally abstinence-based in that it emphasizes the goal of total abstinence from alcohol and all illicit substances. Some programs would accept pain patients on prescribed opioid therapy if the patient has a goal of abstinence from other substance use. Intensive outpatient treatment involves behavioral interventions usually via a group format with several meetings per week over a 4- to 12-week period so that patients receive up to 72 or more hours of total treatment.40 Frequent urine toxicology testing is also typically performed. The therapeutic content of the group sessions varies but often includes one or more of the types of behavioral interventions described in the following text. Attendance at mutual help groups such as Alcoholics Anonymous is strongly encouraged. Not surprisingly, patients who complete these programs have better outcomes than those who drop out. Depending on the setting and patient 4625

characteristics, the dropout rate can be substantial.

Inpatient Treatment For patients who fail outpatient treatment and who can obtain funding for it, inpatient treatment is an option. Inpatient treatment could be as brief as a few days41 but frequently lasts 28 days and can be extended for many months in a model known as a therapeutic community42 for patients who have severe, intractable substance use disorders that do not respond to any other interventions. Ongoing outpatient treatment subsequent to completion of inpatient treatment is recommended. Inpatient treatment, like intensive outpatient treatment, is almost always abstinence-based. Many short-term inpatient programs would accept pain patients on opioid therapy if the patients committed to abstinence from other substances. Most therapeutic communities would not accept patients receiving opioid therapy even for pain. The content of the care in inpatient treatment does not differ substantially from the content delivered in intensive outpatient treatment, but the inpatient setting provides a controlled environment that minimizes the risk of relapse and can compress more hours of actual treatment into a shorter overall time frame.43 In the aggregate, it appears that the quantity or “dose” of behavioral treatment received rather than the setting in which it occurs serves as the key mediator of outcome.

Specific Behavioral Treatments Numerous types of behavioral interventions are used to treat substance use disorders, and many have been empirically validated. Mastery of specific techniques often requires considerable training and practice. Most studies comparing various behavioral intervention techniques find, as with setting, that the specific technique is less important than the total amount of behavioral intervention received. Many practitioners do not deliver the specific interventions in their pure form. In addition to the amount of intervention received, other important mediators of success are the skill of the specific therapist and the therapeutic alliance achieved between the therapist and patient regardless of what technique is used.44 To impart at least passing knowledge of the names and basic philosophies of the more common techniques, brief descriptions are provided. 4626

Motivational Interviewing Motivational interviewing is a directive, patient-centered counseling style for eliciting behavior change by helping patients explore and resolve ambivalence. Compared with nondirective counseling, it is more focused and goal-directed. The examination and resolution of ambivalence is its central purpose, and the counselor is intentionally directive in pursuing this goal using the following techniques.45 • Seeking to understand the person’s frame of reference, particularly via reflective listening • Expressing acceptance and affirmation • Eliciting and selectively reinforcing the client’s own self motivational statements expressions of problem recognition, concern, desire and intention to change, and ability to change • Monitoring the client’s degree of readiness to change and ensuring that resistance is not generated by jumping ahead of the client • Affirming the client’s freedom of choice and self-direction Relapse Prevention Therapy Relapse prevention is a cognitive-behavioral intervention based on the notion that learning processes play an important role in the development of maladaptive behavior patterns. As applied to substance use disorders, relapse prevention explores the positive and negative consequences of continued substance use, encourages self-monitoring to recognize substance cravings early on, identifies high-risk situations for use, and develops strategies for coping with and avoiding high-risk situations and the desire to use.46 A central element of this treatment is anticipating the problems that patients are likely to meet and helping them develop effective coping strategies. The skills that patients learn through relapse prevention therapy remain after the completion of treatment, and many maintain the gains they made in treatment throughout the year following treatment. Drug Counseling Drug counseling focuses directly on reducing or stopping the patient’s substance use. It also addresses related areas of impaired functioning such as employment status, illegal activity, and family/social relationships as 4627

well as the content and structure of the patient’s recovery program. Through its emphasis on short-term behavioral goals, drug counseling helps the patient develop coping strategies and tools for abstaining from substance use and then maintaining abstinence. The addiction counselor encourages 12-step participation and makes referrals for needed supplemental medical, psychiatric, employment, and other services. Individuals are encouraged to attend sessions one or two times per week.47 12-Step Facilitation Therapy Twelve-step facilitation consists of a structured and manual-driven approach to facilitating early recovery from substance use disorders. It is intended to be implemented on an individual basis in 12 to 15 sessions and is based in behavioral, spiritual, and cognitive principles that form the core of 12-step fellowships such as Alcoholics Anonymous and Narcotics Anonymous. Twelve-step facilitation seeks to achieve two general goals in patients with substance use disorders: acceptance of the need for abstinence from substances and surrender, or the willingness to participate actively in 12-step fellowships as a means of sustaining sobriety. These goals are in turn broken down into a series of cognitive, emotional, relationship, behavioral, social, and spiritual objectives.48 Twelve-step facilitation has shown excellent results for patients with alcohol use disorder but shows less promise for patients with drug use disorders.49 Contingency Management Contingency management treatments are based on operant conditioning principles as elucidated by B.F. Skinner: If a behavior is reinforced or rewarded, it is more likely to occur in the future.50 In many contingency management treatments, patients leave urine specimens multiple times each week and receive explicit rewards for each specimen that tests negative for drugs. These rewards often consist of vouchers that have a monetary value and can be exchanged for retail goods. However, contingencies that lack monetary value can also be used. For example, in opioid treatment programs or office-based buprenorphine treatment, the frequency of attendance can be contingent on drug-free urine specimens. Patients who provide drug-negative urine specimens get more take home medication or larger prescriptions, and those who provide drug-positive 4628

specimens have their take home privileges reduced or have to pick up a prescription more frequently. Contingency management has been demonstrated to reduce substance use significantly in numerous studies, but its implementation in clinical practice has lagged,51 although it has now been implemented widely and successfully throughout the Veterans Affairs health care system.

Pharmacotherapies Currently, there are three U.S. Food and Drug Administration (FDA)approved medications for the treatment of alcohol use disorder (disulfiram, acamprosate, and naltrexone) and three available FDA-approved medications for the treatment of opioid use disorder (methadone, buprenorphine, and naltrexone). All of the alcohol treatment medications can be used by all physicians, including pain specialists if desired, within the scope of their own practice. Although methadone can be ordered and dispensed for the treatment of opioid use disorder only within licensed clinics, buprenorphine can be prescribed by appropriately qualified physicians (as described in the following text) outside of licensed clinics. Naltrexone for either alcohol or opioid use disorders is not likely to have much utility in pain patients because of its antagonism of µ-opioid receptors and its tendency either to precipitate opioid withdrawal in patients on opioids or to block the effects of opioid analgesics. Nevertheless, it may rarely have potential benefit in selected pain patients not currently on opioids. There are currently no FDA-approved pharmacotherapies for use disorders involving other substances such as cocaine, methamphetamine, sedative-hypnotics, or cannabis, so these disorders must be treated with behavioral interventions alone. Disulfiram By inhibiting aldehyde dehydrogenase, a key enzyme in the major metabolic pathway for ethanol, disulfiram causes accumulation of acetaldehyde after alcohol ingestion. The buildup of acetaldehyde usually causes an “alcohol–disulfiram reaction” that typically ensues within minutes of alcohol ingestion.52 Different individuals exhibit varying degrees of the reaction which may last for several hours. Signs and

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symptoms of the alcohol–disulfiram reaction include diaphoresis, flushing, tachycardia, hypotension, nausea, vomiting, and headache. The concept behind the idea of disulfiram is that patients taking disulfiram will fear getting an uncomfortable reaction and thus will be deterred from drinking alcohol. To some extent, change occurs during the informed consent discussion between physician and patient at the time the patient agrees to take disulfiram. During that discussion, the patient may, by agreeing to try disulfiram, be arriving at a decisive interest in achieving abstinence from alcohol. Obviously, patients must have achieved some time of abstinence before starting disulfiram to avoid provoking the alcohol–disulfiram reaction. Typically, 48 hours of abstinence proves sufficient. The usual starting dose of disulfiram is 250 mg per day. Genetic variability may determine sensitivity to the medication, and patients with high levels of aldehyde dehydrogenase may be less sensitive to the effects of disulfiram and require higher doses of medication, up to 500 mg per day. Some patients may not tolerate 250 mg per day and should have the dose reduced to 125 mg per day. Disulfiram is associated with a number of mild side effects such headache, metallic aftertaste, erectile dysfunction, mild fatigue or sedation, and rash. Such side effects frequently dissipate spontaneously or with a dosage decrease. Much more serious adverse events such as optic neuritis, peripheral neuropathy, hepatic injury, or psychotic symptoms or delirium, although rare, necessitate immediate disulfiram discontinuation. Disulfiram-induced hepatic injury can occur idiosyncratically at an estimated rate of 1/25,000 to 1/30,000 patient treatment years.53 Disulfiram-induced hepatic injury can rapidly proceed to total liver failure. It most usually occurs within the first 6 months of treatment. Symptoms include extreme fatigue, malaise, anorexia, fever, jaundice, scleral icterus, nausea, vomiting, and bilirubinuria. Baseline liver function tests should be obtained prior to initiation of disulfiram treatment and then at 1- to 2month intervals during the first 6 months of treatment. With the decreased risk of disulfiram-induced hepatic injury after the first 6 months of treatment, liver monitoring can subsequently be done every 3 to 6 months if treatment continues. Many patients who might be considered for 4630

disulfiram therapy present with moderately elevated transaminases related to alcohol use (particularly in the context of hepatitis C). These modest transaminase elevations do not represent a total contraindication to disulfiram therapy. Very rapid rises in bilirubin and transaminases occur in disulfiram-induced hepatic injury and indicate the need to stop disulfiram at once. If the medication is discontinued promptly, the signs and symptoms of liver injury typically fully resolve. If the medication is not stopped, total hepatic failure and death can supervene unless a liver transplant is performed. Patients with preexisting cirrhosis or other serious liver disease generally are not good candidates for disulfiram. Other contraindications include pregnancy or lactation, history of prior hypersensitivity to disulfiram, or significant coronary artery disease. The latter group could experience myocardial ischemia during a severe alcohol–disulfiram reaction. Disulfiram has greater benefit with monitoring of medication administration. Although the largest study to date demonstrated that disulfiram dosed at 250 mg per day over 1-year did not lead to increased abstinence rates or longer time to first drink compared to placebo, it did lead to significantly fewer drinking days over the study year.54 Acamprosate Acamprosate, which has seen widespread use in Europe for many years, received FDA approval for the treatment of alcohol use disorder in 2004. Acamprosate is believed to modulate both the major excitatory system in the brain, the glutamate system, as well as the major inhibitory system, the γ-aminobutyric acid (GABA) system. Alcohol interacts with these systems as well, but when alcohol is stopped after chronic exposure, glutamatergic hyperactivity and GABA hypoactivity contribute substantially to the alcohol withdrawal syndrome. Acamprosate theoretically acts to counteract these imbalances and so may attenuate symptoms associated with subsyndromal, prolonged alcohol withdrawal such as insomnia, anxiety, and restlessness which could provoke alcohol cravings and relapse.55,56 Acamprosate also may diminish reinforcement derived from alcohol ingestion55 and the amount of alcohol consumed by patients in 4631

treatment who do experience relapse.57 Numerous controlled studies of acamprosate demonstrated higher total abstinence rates and longer time to relapse for acamprosate compared to placebo.58 For reasons that remain incompletely understood, acamprosate failed to show efficacy in two large clinical trials conducted in the United States.59,60 It has been proposed that subjects in the US studies may not have experienced sufficient prolonged subsyndromal withdrawal to benefit from acamprosate.61 Acamprosate has very limited oral bioavailability. It achieves steady state after 5 days and is not metabolized by the liver but excreted unchanged in the urine. The usual dose is 666 mg (two 333-mg tablets) three times daily. The labeling indicates that acamprosate should be started after a modicum of abstinence has been achieved, but there are no safety issues if acamprosate is taken concomitantly with alcohol and abstinence is not essential. In fact, acamprosate should be continued in the patient who relapses to alcohol use. It is recommended that a serum creatinine level to evaluate kidney function be obtained prior to initiation of therapy because the dose should be lowered in patients with impaired kidney function. Acamprosate is FDA category C, so women of childbearing age must use an effective method of birth control when on acamprosate. All patients should be monitored for suicidal thoughts because such thoughts occurred more frequently among acamprosate treated patients than among placebo-treated patients in clinical trials. Diarrhea is the only common side effect noted with acamprosate. It is recommended that acamprosate treatment be continued for 12 months, and follow-up studies show increased abstinence rates that persist 1 year after cessation of treatment.62 Advantages of acamprosate include its lack of drug–drug interactions and the fact that it is not contraindicated in patients with serious liver disease. Naltrexone The µ-opioid antagonist, naltrexone, originally developed to treat opioid use disorder (see the following text) was subsequently approved to treat alcohol use disorder in 1994 and is now available in an oral generic formulation. An involvement of the endogenous opioid systems in the 4632

reinforcing effects of alcohol seems likely based on the fact that opioid antagonists block the alcohol-induced release of dopamine into the nucleus accumbens.63 The ability of alcohol to promote the release of endogenous opioids64,65 or to affect opioid receptor binding66 may account for dopamine release engendered by alcohol and for the blockade of this event by opioid antagonists. Naltrexone changes the subjective experience of alcohol consumption in humans rendering it less reinforcing and more sedating.67 Naltrexone has demonstrated efficacy in delaying and preventing relapse to heavy drinking and reducing the percentage of drinking days but not in promoting total abstinence in numerous (but not all) clinical trials.68 Naltrexone is rapidly and almost fully absorbed after oral administration, achieves its peak effect after 1 hour, and has a half-life of approximately 4 hours (metabolite half-life = 12 hours). The usual dose is 50 mg per day which is sufficient to occupy the majority of µ-opioid receptors.69 Many clinicians begin naltrexone at 25 mg per day for a few days to minimize side effects and then titrate up to 50 mg per day. Although data are sparse, some clinicians will also increase naltrexone to 100 mg per day if a suboptimal response occurs at 50 mg per day, and the 100 mg per day dose demonstrated modest efficacy in the COMBINE Study.59 Common side effects of naltrexone include nausea, headache, dizziness, fatigue, sedation, and anxiety and typically resolve with continued treatment. Oral naltrexone does have a boxed warning for acute hepatitis, although most of these events occurred at doses of 300 mg per day in clinical trials for obesity, and there is little evidence of hepatotoxicity at currently recommended doses for alcohol use disorder. Nevertheless, given the boxed warning, it is judicious to obtain liver function tests prior to initiation and then at months 1, 3, 6, and 12 during therapy. Because naltrexone blocks µ-opioid receptors, opioid medications will be much less effective in the situation in which an injury or serious medical condition calls for acute pain control. If given in adequate doses (usually higher than would otherwise be required), opioids can generally overcome the blockade, but close monitoring of the patient in an inpatient setting to observe for and manage respiratory depression is advised. Also, 4633

naltrexone is quite obviously contraindicated in patients taking opioids for chronic pain. Long-Acting Injectable Naltrexone Although oral naltrexone generally appears efficacious compared to placebo in reducing relapse to heavy drinking, it has not performed well in some studies. However, when patients found to be nonadherent for oral naltrexone are factored out in several other studies, naltrexone demonstrates efficacy for treatment of alcohol use disorder compared to placebo.70,71 Consequently, long-acting intramuscular naltrexone, FDAapproved in 2006 for treatment of alcohol use disorder, may eliminate concerns about adherence and has been shown to be effective compared to placebo in reducing heavy drinking.72 Additional advantages of longacting intramuscular naltrexone include lower rates of first-pass hepatic metabolism, exposing the liver to significantly lower peak dosages than daily oral dosing. The injectable formulation does not have a boxed warning for hepatic injury. The reduced first-pass metabolism of intramuscular naltrexone leads to lower levels of the active metabolite 6βnaltrexone, which has been correlated with side effects such as nausea. Lower levels of this metabolite may lead to better tolerability of naltrexone’s intramuscular form. Long-acting injectable naltrexone is indicated for patients who have achieved some period of abstinence which could be as brief as several hours. The dosage is one 380-mg gluteal injection every 4 weeks. Patients can be started directly on the injection without a trial on oral medication. In addition to typical side effects seen with oral naltrexone, injection site reactions can occur with the injectable formulation. Naltrexone for Opioid Use Disorder For patients with opioid use disorder who have withdrawn from opioids and who do not wish to continue opioid therapy, naltrexone offers, from a theoretical standpoint, an ideal pharmacotherapy. Once a state of full withdrawal is achieved as verified by a naloxone challenge test, naltrexone can be started. With naltrexone on board, the effect of exogenously administered opioids will be blocked so that no euphoria is experienced and physiologic dependence cannot be reestablished. Unfortunately, very 4634

few patients with opioid use disorder remain on oral naltrexone for an extended period so that it performs only slightly better than placebo.73 Some populations such as individuals with legal mandates or impaired professionals may do better on oral naltrexone. Obviously, as noted in the preceding text, naltrexone represents a poor choice of pharmacotherapy for some pain patients because it prevents the use of opioid analgesics. If the oral formulation is prescribed, the typical dose is 50 mg per day. The injectable formulation was approved for opioid use disorder in 2010. A double-blind randomized, controlled trial conducted in Russia showed that active naltrexone injection compared to placebo produced significantly fewer days of using illicit opioids and better retention in treatment.74 The only sizable randomized trial conducted in the United States was open label among criminal justice involved patients with opioid use disorder and did show benefit of the injectable formulation compared to treatment as usual, which typically did not include medication.75 Methadone As noted earlier, methadone can only be ordered and dispensed for the treatment of opioid use disorder through federally licensed and regulated clinics. Thus, in most cases, patients with chronic pain who need methadone treatment must be referred to one of these clinics. Such clinics are not available in many geographic regions and at times also have waiting lists. Methadone is ordered and dispensed quite differently when used to treat opioid use disorder than when prescribed for pain. Typically, for treatment of opioid use disorder, a single daily dose is provided in liquid form. The maximum initial dose is 30 mg. The lowest effective dose of methadone for treatment of opioid use disorder is approximately 50 mg per day, with an optimum average dose for most patients of approximately 80 mg per day (±20 mg), although some patients require a dose higher than this range. The daily dose should be sufficient to prevent emergence of withdrawal symptoms at least through the 24-hour dosing period. The dose should be sufficient to greatly diminish or eliminate opioid cravings and opioid use (as determined by both self-report and urine toxicology testing). The dose should create sufficient tolerance such that illicit opioid use does 4635

not cause euphoria. The dose should not be so high that side effects such as sedation, constipation, or loss of libido occur.36 Patients who do not stabilize within a few weeks should be evaluated both at the end of the 24-hour dosing cycle just prior to the next scheduled dose to assess the presence of withdrawal signs and symptoms and at 4 hours postdose to observe the patient for any evidence of intoxication or excessive opioid effect at the time of peak plasma levels.36 If the patient does have withdrawal signs prior to the dose and no intoxication postdose, an upward adjustment in dose is probably warranted. When patients fail to stabilize after successive dose increases, consideration could be given to obtaining a trough (predose) serum methadone level. Levels below 100 ng/mL are associated with withdrawal symptoms and inadequate dosage.76 There are rare ultrarapid metabolizers of methadone who will not become stable on a single daily dose and will exhibit low trough serum levels of methadone. For this small group of patients, splitting the dose by giving them half of the dose observed and the other half as a take-home for the evening generally promotes stabilization. For patients on methadone maintenance, their daily dose of methadone will rarely be fully, if at all, efficacious in managing acute or chronic pain. These patients may often benefit from additional analgesics, either methadone tablets or another opioid of choice, given throughout the day in appropriately divided doses given in addition to the daily dose of methadone. For acute pain, these additional opioids can be discontinued when the pain subsides. For chronic pain, the additional opioids will need to be ongoing in most cases. Alternatively, or additionally, nonopioid pharmacotherapies and/or behavioral interventions for pain can be applied. Buprenorphine Although buprenorphine can be ordered and dispensed through licensed clinics, its pharmacologic characteristics make it a very attractive medication for office-based therapy. Its partial agonist action means that it has a ceiling effect for central nervous system and respiratory depressive effects, making it is far safer in overdose than methadone and other full µopioid agonists.77 This partial agonist property also makes it easier to withdraw from this medication than from methadone. Withdrawing from 4636

methadone can take months or years and be difficult for patients. In addition, buprenorphine has slow onset when administered sublingually (1.5 to 3 hours to peak plasma levels), a long half-life, and high affinity plus slow dissociation from the receptor.78,79 Thus, it prevents the emergence of withdrawal symptoms for 24 hours or longer, and by occupying the majority of receptors, it makes very few receptors available for binding of full agonists. Buprenorphine’s long half-life allows for once-daily or even thrice-weekly dosing. Buprenorphine is poorly absorbed by the oral route and undergoes extensive first-pass hepatic metabolism, so for treatment of opioid dependence, it is administered sublingually, buccally, or via a subdermal implant. Buprenorphine prescription in the office setting was made possible in the United States by the Drug Addiction Treatment Act of 2000 (DATA). DATA allows for office-based opioid maintenance therapy for opioid use disorder using Schedule III, IV, or V medications approved for this use by the FDA. In 2002, the FDA approved buprenorphine and buprenorphine/naloxone for this purpose, and they are the only medications at this time with this indication. In order to prescribe buprenorphine, physicians must obtain a waiver from the DEA, which requires specialty training in addictions or completion of approximately 8 hours of training in management of opioid use disorder, and physicians must be able to refer patients to appropriate counseling and ancillary services. The waiver allows physicians to prescribe buprenorphine to up to 100 patients at a given time with the potential to increase the patient limit to 275 as of 2016. Buprenorphine is available for sublingual or buccal administration as a single agent or as a combination buprenorphine–naloxone preparation with a ratio of 4 mg buprenorphine to 1 mg of naloxone. (There are also buccal and transdermal formulations available with a pain indication, but the doses are approximately an order of magnitude lower than the doses used to treat opioid use disorder.) The advantage of the combination buprenorphine–naloxone preparation is the prevention of misuse. Buprenorphine has adequate bioavailability sublingually, whereas naloxone is minimally bioavailable sublingually, so the naloxone has no effect on patients when administered as intended. If the combination 4637

medication is dissolved in an attempt to inject buprenorphine, however, naloxone, which also has a high affinity for the µ receptor, will exert its antagonist properties resulting in withdrawal instead of euphoria. The single agent should be reserved for use only in situations where there is no concern for potential misuse, such as in an inpatient setting or for pregnant women to avoid any potential exposure of the developing fetus to even trace amounts of naloxone. Due to the partial agonist properties of buprenorphine, patients need to be clearly educated that they should not take this medication soon after taking other opioid drugs because buprenorphine in that situation may precipitate withdrawal. An important component of the clinical skill in using buprenorphine involves the induction procedures. Patients who have been taking full agonist opioids must abstain from their full agonist opioids long enough to evidence signs of mild opioid withdrawal. If patients take the first dose of buprenorphine when not in active opioid withdrawal, there is a risk that buprenorphine as a partial agonist will precipitate more severe opioid withdrawal. Patients often require a fair amount of empathic emotional support to assure them that they can handle a period of several hours without opioids and can tolerate a brief episode of mild withdrawal prior to starting buprenorphine. Usually, it is not the mild withdrawal symptoms themselves that are troublesome, so much as the anxiety about more severe withdrawal. If patients are in mild to moderate withdrawal at the time of starting buprenorphine, the first dose usually alleviates much of the withdrawal within 30 to 60 minutes. Induction of buprenorphine should thus begin approximately 12 to 24 hours after last use of a short-acting opioid drug or 24 to 48 hours after last use of a long-acting opioid drug, and patients should be showing objective signs of withdrawal at the time of initiation of therapy. On the first day of induction, the maximum dose should usually not exceed 8 to 12 mg. Because the transition from methadone to buprenorphine is more difficult than the transition from short-acting opioids, patients who are receiving methadone for pain and wish to transition can be first switched from methadone to a short-acting opioid and then inducted onto buprenorphine. For patients receiving methadone in a licensed clinic for the treatment of opioid use, this switch to a short-acting opioid is not legally permissible, 4638

and such patients must be inducted directly from methadone to buprenorphine. If, after beginning buprenorphine, patients still have withdrawal symptoms after receiving the maximum first day dose, they should be treated symptomatically with adjunctive agents such as clonidine, antiemetics, antidiarrheals, and benzodiazepines for specific withdrawal symptoms. Over the course of the next 2 to 6 days, patients should be assessed for signs and symptoms of withdrawal with increases in buprenorphine given for persistent symptoms up to a total of 16 mg on the second day and a maximum of 32 mg per day by the end of the first week. Withdrawal symptoms beyond this time typically indicate persisting illicit opioid use. Following induction, patients will stabilize on a dose over the following weeks, and the dose should be adjusted to the lowest effective dose to prevent withdrawal symptoms, prevent craving of opioids, and suppress illicit opioid abuse. Once this dose is established, patients can be maintained on this medication indefinitely or may choose to taper off.80 Numerous studies have found buprenorphine to be effective in retaining patients in treatment and reducing illicit opioid abuse. A systematic review of studies, which compared 31 studies involving 5,430 subjects in trials of buprenorphine versus either placebo or methadone, found buprenorphine to be effective as a maintenance therapy for opioid use disorder when compared to placebo.81 Compared with methadone, however, especially at higher doses of methadone, buprenorphine may not be quite as effective at maintaining patients in treatment, although this difference is less pronounced at higher buprenorphine doses. Nevertheless, because buprenorphine is a safer medication than methadone, it often makes clinical sense to use buprenorphine as a first-line agent. If a patient fails buprenorphine treatment, the patient can be transitioned to methadone maintenance in a licensed clinic.82 Transition from methadone to buprenorphine is clinically more difficult than transition from buprenorphine to methadone. As a partial agonist, buprenorphine has analgesic properties, but its analgesic effects may not always be as powerful as those of a full agonist. However, recent evidence suggests that buprenorphine produces less 4639

hyperalgesia than full agonist opioids83 and so may have some benefit for pain control in patients not responding well to full agonists. Also, although buprenorphine has a ceiling on its respiratory depressant action, it does not appear to have a ceiling on its analgesic activity so higher doses should continue to elicit greater analgesia.84 Thus, buprenorphine has tremendous potential for management of patients who have combined chronic pain and opioid use disorder. It allows the physician treating such a patient to continue to manage the patient in his or her own office for both disorders along with referral for ancillary counseling if needed rather than terminating such a patient or sending the patient to an addiction treatment provider or facility with the risk of a failure to follow through. As noted, some clinical skill is required to support the patient in abstaining from full agonist opioids long enough to evidence signs of opioid withdrawal such that buprenorphine induction can take place. Patients being treated with buprenorphine for combined pain and opioid use disorder may get better analgesia by taking the buprenorphine in divided doses throughout the day rather than as a single daily dose. Although more data on the treatment of combined pain and opioid use disorder are needed, preliminary reports indicate a positive response for many patients.85

Conceptions of Opioid Use Disorder—The Pain Medicine Perspective The pain management perspective on opioid use disorder provides observations on the historical changes in the attitudes toward and practice of using opioids for chronic pain and on integration of perceptions from pain medicine with those from addiction medicine.

HISTORY OF OPIOID USE FOR CHRONIC PAIN AS IT RELATES TO IDENTIFYING OPIOID USE DISORDER Ambiguities related to the definition of opioid addiction in CNMP patients and the practical problems associated with identifying this disorder as of 2006 were detailed in the chapter on addiction in the fourth edition of Bonica’s Management of Pain. In the present chapter, we focus on changes that have occurred during the past decade in our understanding of 4640

addiction in these patients and in attitudes toward the use of opioids in the treatment of CNMP. There is no simple way to gauge the attitudes and beliefs of the various stakeholders with an interest in opioid therapy (e.g., physicians, regulators, law enforcement officers, patients with CNMP), but initiatives undertaken by legislative bodies and regulators can be viewed as indicators of prevailing attitudes. Because these differ from one community to another, the present discussion focuses on initiatives undertaken in the State of Washington in the United States.86 The practical reason for this is that we are familiar with these initiatives. There is also evidence that the State of Washington has been a leader in opioid policy. For example, the Centers for Disease Control and Prevention (CDC) opioid guidelines are largely based on the earlier Washington State guidelines. In the years since 2007, there has been a sea change in these attitudes, and it appears that opioid prescribing by clinicians peaked in 2011 or 2012 and is now declining.86,87 With the benefit of hindsight, we can now identify three periods regarding these attitudes. 1. Early history (prior to the 1990s): Before the mid-1990s, Washington State Department of Health regulations prohibited physicians from providing long-term opioid therapy for CNMP patients. This regulation existed in many other states as well and reflected the prevailing view that the risks of such therapy outweighed the benefits. 2. The period of enthusiasm (1990 to 2007): As discussed in Bonica’s Management of Pain, 4th edition, some pain specialists made the case during the late 1980s and early 1990s that opioids were safe and effective in the treatment of CNMP. In 1995, a committee was formed to change the Washington State Department of Health’s regulations regarding opioid therapy. The result, published in 1996, was a regulation that stated, “Under generally accepted standards of medical practice, opioids may be prescribed for the treatment of acute or chronic pain including chronic pain associated with cancer and other non-cancer pain conditions. . . . It is the position of the Department of Health that opioids may be prescribed, dispensed, or administered when there is an indicated medical need without fear of 4641

injudicious discipline.” This regulation reflected an emerging viewpoint that opioid therapy was safe and effective in the treatment of chronic pain. In 1996, the American Pain Society and the American Academy of Pain Medicine issued a joint statement endorsing the use of opioids in care of patients with CNMP. This time frame is also the when long-acting opioids were aggressively marketed by pharmaceutical companies as less prone to abuse and addiction. Marketing of OxyContin was especially conspicuous,88 but other opioids were also aggressively marketed. As a result of the mentioned influences, there was a dramatic increase in opioid prescribing, both nationally89 and in Washington State.90 3. The period of retrenchment (2007 to present): As indicated in the discussion in Bonica’s Management of Pain, 4th edition, by 2006, some pain specialists had become skeptical that the benefits of opioid therapy for CNMP outweighed the risks. The medical director of the Washington State workers’ compensation system noticed an increase in deaths among injured workers that were concentrated among those receiving high-dose, long-term opioid therapy. He convened a group of academic and community pain specialists who wrote the first Washington State opioid guideline, which was released in 2007. Since then, skepticism about the benefits of long-term opioid therapy has grown enormously. The CDC has declared that we are in the midst of an opioid epidemic that is killing Americans at a higher rate than HIV ever did. In 2014, the National Institutes of Health held a consensus conference that declared that there was no good evidence of the effectiveness of long-term opioid therapy. As the aforementioned dates suggest, the chapter section on addiction from the perspective of pain medicine in the fourth edition of Bonica’s Management of Pain was written as physicians and regulators were becoming skeptical of opioid therapy for CNMP and were moving into the period of retrenchment. Thus, the discussion reflected ambivalence about opioid therapy for CNMP but did not provide any definite conclusions about the pros and cons of the therapy. Since that chapter was written, several discoveries have occurred and initiatives have been undertaken that have changed the social environment 4642

surrounding opioid therapy for CNMP. The most significant are as follows: 1. Changes in the criteria for the diagnosis of “addiction” (formally called substance use disorder) in the DSM-54: These changes were discussed previously. They have dealt to some extent with concerns that we voiced in Bonica’s Management of Pain, 4th edition, about the DSM-IV criteria. However, they do not fully resolve the ambiguities and inconsistencies of usage among investigators for a variety of terms that describe problematic use of prescription opioids —including misuse, abuse, aberrancy, dependence, and addiction.91 Also, as discussed later in text, the DSM-5 definition does not fully resolve problems that clinicians face in the identification of opioid use disorder in patients with chronic pain. 2. Research on addiction and aberrant behaviors associated with prescription opioids: During the period of enthusiasm for opioid therapy, many pain specialists argued that addiction is uncommon when patients take opioids for their pain. A brief report on an inpatient sample by Porter and Jick92 was frequently cited to buttress this argument. Recent research has emphatically challenged this assertion. It has been demonstrated that a high proportion of CNMP patients on opioid therapy have abnormal urine drug screens,93 strongly suggesting aberrant behaviors (Table 91.4). Our best conservative estimate is now that 25% of patients on long-term opioid therapy will misuse their opioids, and 10% will develop opioid use disorder.94 Also, there is now evidence that a substantial proportion of people using heroin report that they got started on the path to heroin use via consumption of prescription opioids.95 TABLE 94.4 Examples of Aberrant Behaviors Related to Opioid Use 1. 2. 3. 4. 5. 6.

Used additional opioids than those prescribed Used additional opioids than those prescribed more than once Forged prescription Sold prescription Admitted to seeking euphoria from opioids Admitted to wanting opioids for anxiety

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7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23.

Overdose and death Injected drug Abnormal urine/blood screen Abnormal urine/blood screen positive for two or more substances Solicited opioids from other providers Unauthorized ER visits Concurrent abuse of alcohol Unauthorized dose escalation Resisted therapy changes/alternative therapy Reported lost or stolen prescriptions Canceled clinic visit Requested early refills Requested refills instead of clinic visit Abused prescribed drug Was discharged from practice (because of aberrant behavior) No-show or no follow-up Third party required to manage patient’s medications

ER, emergency room.

3. Research demonstrating adverse effects of opioids: Research has now documented a litany of adverse effects of opioid therapy that were either unknown or not fully appreciated during the period of enthusiasm. These include overdoses requiring emergency room care, myocardial infarctions, low testosterone levels, and injuries in motor vehicle accidents.96 Worst of all, there is now convincing evidence of substantial mortality from overdoses of prescription opioids.97,98 Thus, although practitioners and researchers have been aware for decades that opioids can cause harm, recent evidence has highlighted the frequency with which adverse effects occur. This emerging evidence has led the CDC and other agencies to use the term opioid epidemic to describe the current situation with respect to prescription opioids for CNMP.99 4. Questionable efficacy: Many RCTs, often sponsored by drug companies, have been performed over the past 25 years. They have generally supported the efficacy of various opioids in the treatment of chronic pain conditions.100,101 However, these studies almost uniformly examined the effects of an opioid for a limited period of time—usually 8 to 12 weeks. In fact, one recent review concluded that no well-controlled studies have been done addressing the 4644

efficacy of opioid therapy over a time interval of greater than 1 year.96 Moreover, research employing large insurance databases to assess longer term outcomes of opioid therapy has presented a bleak picture. For example, multiple investigators have examined the effects of opioid therapy on injured workers by looking at return to work rates (or termination of disability benefits) among workers with common injuries such as back injuries who are prescribed opioids versus who are not prescribed them. These studies have consistently found that workers receiving opioids are less likely to return to work than those not receiving them.102,103 5. Monitoring: Clinicians have been able to monitor patients taking opioids via urine drug screens for many years. However, it is very likely that clinicians are ordering urine drug screens more frequently now than at the time of Bonica’s Management of Pain, 4th edition, because during the past few years, several expert panels have recommended their use.98,104 In contrast, PDMPs were virtually nonexistent at the time when the fourth edition of Bonica’s Management of Pain was written. As noted earlier, PDMPs are now available in 49 states.87 Recent studies have shown that PDMPs reduce opioid use among Medicare beneficiaries105 and in the general patient population.20 Another study showed that Florida’s PDMP and pill mill laws were associated with modest decreases in opioid prescribing and use. The decreases were greatest among prescribers and patients with the highest initial opioid prescribing and use.106 6. Policy initiatives: As noted earlier, several initiatives have been undertaken in Washington State to rein in opioid prescribing for CNMP. The first of these was a guideline published by the Agency Medical Directors’ Group (AMDG). The AMDG consists of medical directors of the four Washington State–run medical insurance programs—Medicaid, the Department of Labor and Industries (the main Washington State workers’ compensation carrier), the Department of Corrections, and Uniform Medical (the health insurance plan for state employees). In 2006, the AMDG formed a committee to address opioid use for beneficiaries of the mentioned 4645

insurance programs who suffered from CNMP. The resulting guideline, published in 2007, recommended that primary care physicians obtain consultations from pain specialists regarding opioid use for CNMP and expressed the view that opioid doses for CNMP patients should rarely exceed a morphine equivalent dose (MED) of 120 mg per day.107 This guideline was the first in a series of initiatives to curb the excesses of the period of enthusiasm. Updated AMDG guidelines were published in 2010108 and again in 2015.109 These reiterated many of the recommendations given in the 2007 guideline and buttressed them with data about adverse effects of opioid therapy. Other initiatives included legislation that incorporated principles in the AMDG guideline110 and the development of a state PDMP. At a national level, the most visible policy initiative was the publication of a guideline by the CDC in 2016.104 It incorporated many of the principles articulated in the AMDG guidelines. 7. Changes in opioid prescribing practices: Data from Washington State document that in recent years, clinicians have curtailed opioid prescribing, and there has been a corresponding drop in accidental deaths attributable to opioid use.86 We are not aware of recent data on opioid prescribing in other states. We anticipate that reductions comparable to those in Washington State will occur, but there may well be a time lag because the CDC guideline was not published until 2016.

IMPLICATIONS FOR THE IDENTIFICATION OF OPIOID USE DISORDER Given the changes that have occurred during the past 11 years in our understanding of the risks and benefits of opioid therapy for CNMP, it is less likely that patients will be intentionally started on long-term opioids for treatment of CNMP in the future. However, many patients are started on opioids for acute pain and then provided refills indefinitely, which leads to de facto long-term opioid therapy.111 Also, there are millions of CNMP patients who are already taking opioids on a long-term basis. Opioid use disorder occurs frequently enough among these patients that clinicians 4646

who prescribe opioids need to be vigilant for its presence. For example, in a large Australian sample of patients prescribed opioids for CNMP, 8.9% met lifetime criteria for opioid dependence using DSM-IV criteria, 8.5% fulfilled International Statistical Classification of Diseases and Related Health Problems, 10th revision (ICD10) criteria, and 9.9% met International Statistical Classification of Diseases and Related Health Problems, 11th revision (ICD11) criteria. Using DSM-5, 8.9% met criteria for moderate or severe opioid use disorder. Another 11.8% met criteria for mild opioid use disorder.112 During the period of widespread use of long-term opioid therapy for CNMP, it is almost certain that many patients who actually had opioid use disorder were not identified. At least two factors contributed to this misidentification. First, if a patient has opioid use disorder but is getting opioids on a regular basis from a physician, drug craving, extreme efforts to get opioids, and other indicators of opioid use disorder are likely not to be present. Second, because there was widespread social support for opioid therapy during the period of enthusiasm, a patient’s demands for opioids could be construed not as an indicator of opioid use disorder but, rather, as reasonable demands for therapy that was widely available. This is the essence of the now discredited “pseudoaddiction” concept that has been popular in the pain management community.113,114 Thus, it is reasonable to anticipate that as opioid therapy is discontinued for patients who previously received opioids, it will become apparent that many of them have opioid use disorder. This expectation is supported by data suggesting that heroin usage has surged in response to the reduced availability of prescription opioids.115 But even if it is true that many patients have hidden opioid use disorder that is being unmasked as their clinicians taper and discontinue opioid therapy, this does not resolve the challenges that the clinicians face when they decide whether or not to diagnose opioid use disorder in individual patients receiving opioids for pain. Clinical experience strongly suggests that when patients who have been receiving opioids plead for continuation of the treatment, they will emphasize the tremendous burden that pain places on them and the respite that they get from continued or increased doses of their opioids. In fact, as described in Bonica’s Management of 4647

Pain, 4th edition, they are likely to say that their pain affects them so powerfully that they are “forced” to take opioids.

CLINICAL PREVENTION AND MANAGEMENT OF OPIOID USE DISORDER IN PATIENTS RECEIVING OPIOIDS FOR CHRONIC PAIN As noted earlier, medication treatment with opioid agonists like buprenorphine or methadone is the best treatment for patients with moderate to severe opioid use disorder. It is not clear how patients with mild opioid use disorder should be treated. Some patients might be tapered gradually to safer low-dose opioid use aligned with the CDC guidelines. Other patients might be tapered off opioids completely. There is evidence that when patients on long-term opioid therapy express motivation to reduce or discontinue their opioids, an opioid taper, combined with motivational interviewing, cognitive-behavioral, and psychopharmacologic support (largely consisting of initiating or adjusting antidepressant medication), can be successful and can be carried out without exacerbation of pain or increase in functional impairment.116 However, there is a caveat. Of the patients referred to the Sullivan et al.116 study, 76% were either found to be ineligible to participate or refused to do so. At this point, there is no evidence to guide clinicians as they consider opioid tapers for these patients. In managing prescription for opioid recipients having problem opioid use, clinicians must first decide if the management should take place in their clinics or the patients should be referred to addiction medicine programs such as the ones described earlier in this chapter. There are no clear-cut criteria for making this decision. Among patients whom pain clinicians continue to treat, the boundary between those who should be tapered off their opioids versus those who should be maintained on methadone or buprenorphine is also not well defined. Experienced clinicians often make an attempt at opioid taper and transition those patients who cannot complete a taper onto buprenorphine-naloxone for long-term maintenance.

Conclusions: Bridging the Gap between Addiction 4648

and Pain Medicine There remain significant barriers to overcome in addressing addiction to prescribed opioids. Since the passage of the Harrison Act in 1914, addiction treatment has been separate from the rest of medical treatment. Treatment facilities are separate, funding is different, and the role of private insurance and public payers is different. Patients with pain typically must accept the label of addiction or opioid use disorder to get treatment in addiction facilities or to get insurance coverage for buprenorphine/naloxone. Many are not willing to do this, and clinicians are often hesitant to force the label on them because of uncertainty about how to construe the patients’ requests for continued opioid therapy. Thus, although patients prescribed opioids for pain might benefit in multiple ways (safety, toxicity, emotional stabilization) from transition to buprenorphine/naloxone or methadone, they are often prevented from making the transition by financial considerations. Just as addiction facilities are reluctant to treat patients who do not accept the opioid use disorder label, pain facilities are reluctant to welcome addiction services under their roof. Health administrators, clinical staff, and patients in pain facilities are resistant to welcoming those with addiction into their clinics. This results in a great chasm between pain and addiction health services into which many patients with problem or high-risk opioid use fall. These patients are poorly served by the present diagnostic and health services system. We will not be able to reverse the opioid epidemic until this chasm between pain and addiction services has been bridged. References 1. Michna E, Ross EL, Hynes WL, et al. Predicting aberrant drug behavior in patients treated for chronic pain: importance of abuse history. J Pain Symptom Manage 2004;28(3):250–258. 2. Manchikanti L, Cash KA, Damron KS, et al. Controlled substance abuse and illicit drug use in chronic pain patients: an evaluation of multiple variables. Pain Physician 2006;9(3):215–225. 3. Rosenblum A, Joseph H, Fong C, et al. Prevalence and characteristics of chronic pain among chemically dependent patients in methadone maintenance and residential treatment facilities. JAMA 2003;289(18):2370–2378. 4. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013. 5. O’Brien CP, Volkow N, Li TK. What’s in a word? Addiction versus dependence in DSM-V. Am J Psychiatry 2006;163(5):764–765.

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107. Washington State Agency Medical Directors’ Group. Interagency Guideline on Opioid Dosing for Chronic Non-Cancer Pain. Olympia, WA: Washington State Department of Labor and Industries; 2007. Available at: www.agencymeddirectors.wa.gov. Accessed June 16, 2017. 108. Washington State Agency Medical Directors’ Group. Interagency Guideline on Opioid Dosing for Chronic Non-Cancer Pain. Olympia, WA: Washington State Department of Labor and Industries; 2010. Available at: www.agencymeddirectors.wa.gov. Accessed June 16, 2017. 109. Washington State Agency Medical Directors’ Group. Interagency Guideline on Prescribing Opioids for Pain. Olympia, WA: Washington State Department of Labor and Industries; 2015. Available at: www.agencymeddirectors.wa.gov. Accessed June 16, 2017. 110. Washington State Legislature. Engrossed Substitute House Bill 2876—an act relating to pain management. Available at: http://apps.leg.wa.gov/documents/billdocs/200910/Pdf/Bills/Session%20Laws/House/2876-S.SL.pdf. Accessed June 16, 2017. 111. Shah A, Hayes CJ, Martin BC. Characteristics of initial prescription episodes and likelihood of long-term opioid use—United States, 2006-2015. MMWR Morb Mortal Wkly Rep 2017;66(10):265–269. 112. Degenhardt L, Bruno R, Lintzeris N, et al. Agreement between definitions of pharmaceutical opioid use disorders and dependence in people taking opioids for chronic non-cancer pain (POINT): a cohort study. Lancet Psychiatry 2015;2(4):314–322. 113. Weissman DE, Haddox JD. Opioid pseudoaddiction—an iatrogenic syndrome. Pain 1989;36(3):363–366. 114. Greene MS, Chambers RA. Pseudoaddiction: fact or fiction? An investigation of the medical literature. Curr Addict Rep 2015;2(4):310–317. 115. Smith DE. Medicalizing the opioid epidemic in the U.S. in the era of health care reform. J Psychoactive Drugs 2017;49(2):95–101. 116. Sullivan MD, Turner JA, DiLodovico C, et al. Prescription opioid taper support for outpatients with chronic pain: a randomized controlled trial. J Pain 2017;18(3):308–318. 166(19):2087– 2093.

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CHAPTER 92 Biophysical Agents for Pain Management in Physical Therapy ROGER J. ALLEN The primary focus of physical therapy is functional restoration via physical reactivation.1 Therapeutic exercise, movement, and physical reactivation have been demonstrated not only to be central components in restoration of function following injury and disease but are also efficacious elements of managing both acute pain and chronic pain syndromes.1–4 In concert with the functional physical restoration activities, physical therapists may also utilize therapeutic biophysical agents (previously referred to as physical agents or modalities) to complement other treatment elements as part of a comprehensive patient care plan.5,6 Philosophies and approaches to pain management vary across practitioners and clinical facilities; yet, the use of biophysical agents is widespread.2,5 The Centers for Medicare & Medicaid Services reported in 2014 that electrical stimulation and ultrasound therapy ranked among the top 10 procedures receiving Medicare payments to rehabilitation providers.5 All physical therapists and physical therapist assistants receive clinical training in the biophysics and safe therapeutic application of biophysical agents as required for licensure and by the Commission on Accreditation in Physical Therapy Education (CAPTE).6–8 Biophysical agents traditionally involve application of some form of heat, cold, light, electromagnetic, or acoustic energy to the body tissue involved in generating pain.6,9 In the context of pain management, delivery of energy to tissue may modify the underlying pathophysiologic process generating pain or alter the transmission, central processing, or perception of the pain message.6 They may assist in causing temporary analgesia,4 resolving inflammation and facilitating tissue repair,6,9 modifying axonal conduction,6 generating a counterirritant,6 altering muscle activation, or 4656

increasing extensibility.6 Biophysical agents may also curb the development of maladaptive central neuropathic changes that could precipitate secondary chronic pain generators10–13 or provide other means of palliative relief via modified pain perception.11 Selection of specific biophysical agents for pain management should be done on a case-by-case basis predicated on clinical impressions regarding the loci and underlying pathophysiologic processes of pain generation.5,14 For a particular agent to be therapeutically useful, its effects must either address the pathophysiologic changes occurring at the tissue level or alter neural pain transmission or central processing.14 If the origin of nociceptive pain is due to damaged and/or inflamed tissue, then locally operating agents are indicated. However, if pain is being generated by peripheral neuropathic factors or a central neuroplastic remodeling component, then potentially effective agents should be chosen from those capable of influencing neural transmission or central processing.15 Although distal pathophysiology is the primary consideration in the selection of biophysical agents for acute or subacute pain, additional factors must be addressed when considering biophysical agents for use in treating patients with chronic pain. As distal subacute lesions evolve into chronic pain syndromes, the loci of pain generation may migrate.14,16–18 Restrictions in activity and mobility in response to initial pain from the inciting lesion may lead to connective tissue changes and alterations in vascular physiology that develop into secondary pain generation sites.16,18 Central pain generators may further develop from neuroplastic remodeling of the dorsal horn, thalamus, or cerebral cortex.13,17 The application of biophysical agents to the original lesion site may prove ineffective if the sources of the chronic pain are secondary generation sites or neural remodeling that are rostral to the location of perceived pain.15 The use of a passive modality as a sole treatment approach is unlikely to lead to long-term improvement in a patient’s functional status. In treatment planning for pain management, thoughtful use of biophysical agents coordinates their application with physical restoration activities. In 2014, the American Physical Therapy Association established the position that biophysical agents do not effectively represent stand-alone treatments, stating that clinicians should not “employ passive physical agents except 4657

when necessary to facilitate participation in an active treatment program,” reinforcing their earlier position that “exclusive use of physical agents in the absence of other skilled therapeutic, or educational intervention, should not be considered.”5 Thoughtful case-by-case consideration should be given to providing patients experiencing chronic pain an external source of passive palliative relief.3,5,14,19 Temporary pain relief via the use of biophysical agents may create a therapeutic window for the therapist to mobilize tissue or address movement impairments.3 For some patients, however, a maladaptive cycle of pain behavior may develop from psychologic dependence on passive external palliative agents. Ultimately, this may reduce progress toward functional restoration by hindering the motivation to actively engage in therapeutic physical activity.3,14 Passive agents may not only provide disincentives for the patient to approach pain management from an active or functional perspective but may also reinforce an external locus of control, whereby the patient attributes pain relief to procedures unrelated to his or her own actions or pacing.3 This underscores the importance of utilizing palliative agents as components of comprehensive treatment planning rather than as stand-alone interventions for short-lived pain relief. Biophysical agents currently in use by physical therapists for the management of pain include superficial heat and cold, light (such as lowlevel laser or monochromatic infrared energy [MIRE]), therapeutic ultrasound, electrical currents (such as transcutaneous electrical nerve stimulation [TENS] and interferential current [IFC]), materials used to facilitate multimodal somatosensory desensitization, and new techniques for influencing central neuroplastic remodeling of pain perception.

Superficial Thermal Agents THERMOTHERAPY Superficial heat, or “thermotherapy,” is used to facilitate soft tissue extensibility, increase circulation, enhance healing, induce relaxation, reduce muscle spasms, prepare stiff muscles and tight joints for exercise, and/or control pain.20 Heat is delivered to superficial tissues via conduction with clinical applications such as moist hot packs and paraffin 4658

wax dips, or for home therapy with electric heating pads, air-activated wearable heat wraps, microwavable gel packs, or rice-filled cloth bags. Superficial heat can also be applied via convection using agents such as dry heat fluidotherapy or warm whirlpool hydrotherapy.20 Thermotherapy is quite commonly utilized by physical therapists across the world, with studies reporting daily use of therapeutic heating agents ranging between 36.5% and 95% across diverse practice settings.20,21 As an adjunct to pain management, therapeutic benefits of superficial heat are due to its effects on metabolic, neuromuscular, and hemodynamic processes. Although the physiologic effects of superficial heat primarily influence tissue healing and acute nociceptive pain generation, thoughtfully applied thermotherapy may have utility in the comprehensive management of chronic pain.14 The oxygen–hemoglobin dissociation curve shifts to the right with mild increases in tissue temperature, making more oxygen available for tissue repair. Increases in enzymatic activity increase oxygen uptake by the cell, thus enhancing healing.6,20 Increased skeletal muscle temperature (to 42° C) has been reported to decrease firing rates of gamma and type II muscle spindle efferents while increasing Golgi tendon organ type Ib fiber firing rates.22 This may reflexively lower skeletal muscle tone and spasms. Reduced skeletal muscle activity may assist in breaking the pain–spasm–pain exacerbation cycle.6,23 Analgesic benefits of superficial heating of the skin may be centrally mediated, as evidenced by functional magnetic resonance imaging (fMRI) findings that warming of distal tissue increases activity of the thalamus and posterior insula, thus initiating a potentially beneficial psychosomatic effect.24,25 Elevations in nociceptive threshold have been reported due to superficial heat.20,26 By increasing activity of afferent thermoreceptive fibers, superficial heat may produce inhibitory modulation of dorsal horn pain gates.6 Indirectly, pain may be influenced via local vasomotor effects and increased blood flow. Dorsal horn synapses from first-order thermal receptor afferents inhibit sympathetic vasomotor efferents in the spinal intermediolateral grey area, thus decreasing vasoconstriction neurogenically.6 When sympathetic vasomotor outflow is decreased, local vasodilation and increased vascular perfusion may influence pain further by decreasing tissue ischemia,27 returning nociceptors to normal firing 4659

thresholds by helping to resolve hyperalgesia, and clearing exacerbating metabolites such as prostaglandins from the region. Blood flow increases of as much as 30 mL per 100 g of tissue have been reported.22 However, these effects influence primarily superficial blood vessels and the tissues they supply. Less evident is vasodilation in deep muscle vasculature because of the limited ability of superficial agents to increase temperature in deeper structures.6 Superficial heat, applied in forms such as hot packs, paraffin, hydrotherapy, and fluidotherapy, has been broadly evaluated for effectiveness in the treatment of both rheumatoid and osteoarthritis. Seven controlled studies have found it a beneficial adjunct,28–34 whereas two found it ineffective35,36 and possibly harmful by increasing collagenase activity which may have damaged compromised articular cartilage.36 Comparative studies report beneficial effects of superficial heat for trigger point pain in the neck and back,37 neck and shoulder pain,37 and chronic low back pain.38,39 Local tissue temperatures required to achieve therapeutic outcomes are in the range of 40° to 45° C (104° to 113° F).20,22,40 Exceeding this range places tissue at risk for damage because at local temperatures >45° C (113° F) metabolic activity required for repair cannot keep pace with protein denaturation.20 At therapeutic temperatures, applying heat is contraindicated over hemorrhagic areas; regions of acute injury, acute inflammation, peripheral vascular disease, malignancy, impaired sensation, or thrombophlebitis; the abdomens of pregnant women; tissues that have been devitalized by x-ray therapy: or with patients with existing fever, confusion, sedation, coma, or relevant cognitive impairments.6,9,41,42 Caution should be used when applying heat over areas of impaired circulation, edema, superficial metal implants, where topical counterirritants have been applied, or over open wounds.41 Also, exercise proper caution during use with children under 4 years old or older adult patients; patients manifesting poor thermal regulation, cardiac insufficiency, or acute inflammatory disorders; or with hypotensive patients, those manifesting orthostatic hypotension, or anyone prone to syncope when heating large body surface areas.6,9,14,36,42

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CRYOTHERAPY Application of cold, whether via water immersion, ice, gel, or vaporcoolant sprays, is one of the most effective and cost efficient modalities for managing pain and acute injury.43 Its therapeutic use has been traced as far back as in Egypt around 2500 BCE.44 Termed cryotherapy, the therapeutic use of cold can be used to control pain, minimize edema, reduce inflammation, enhance movement, and attenuate spasticity.6 A primary indication for cryotherapy is to minimize secondary hypoxic injury to adjacent tissue areas immediately following acute trauma.9 By lowering metabolism of damaged and surrounding cells, they become more resistant to hypoxia resulting from disrupted blood supply to the region, making this the primary reason that cold is the agent of choice for the first 24 to 48 hours after injury.45 This mechanism of minimizing the extent of tissue damage is dependent on immediate application of cold following trauma and is not a mechanism likely to contribute to the management of chronic pain states. It may also elevate pain thresholds and decrease muscle spasms and tension secondary to myofascial trigger points.43,46 Cryotherapy can be administered using conductive agents such as ice bags, superficial ice massage, bags of frozen corn or peas, cold compression units, cold whirlpool immersion, or via contrast baths, in which alternating heat and cold are used. It can also be administered with convective agents such as vapor-coolant sprays.46 Different cryotherapeutic modalities can produce a varied range of tissue cooling ability.43 Following 20-minute exposure over the gastrocnemius muscle, skin surface temperature was reportedly lowered by 19.6° C (35.0° F) using crushed ice, 17.0° C (30.6° F) following ice water immersion, 14.6° C (26.0° F) from contact with a bag of frozen peas, and 13.0° C (23.5° F) using a cold gel pack.47 Following 15-minute exposure, superficial ice massage decreased intramuscular temperature by 4.3° C (7.7° F) compared to contact with ice bag that lowered temperature by 2.3° C (4.1° F).48 Depth of intervening adipose tissue layers has a significant influence on the rate of intramuscular cooling and subsequent rewarming.43 It has been found that 10 minutes are required to produce a decrease in intramuscular temperature of 7.0° C (12.5° F) with a 1-cm layer of intervening adipose 4661

tissue, whereas given adipose thickness of 3 to 4 cm, 60 minutes are required to achieve the same temperature reduction.49 The therapeutic effects of cold result from its actions on metabolic, neuromuscular, and hemodynamic processes.6 Decreases in nociceptive input and pain perception via application of cold may occur because of influences in both local and central nervous system mechanisms.14 Vasoconstrictive response to cold decreases local release of vasodilating substances and chemical mediators, which in turn decreases nociceptor sensitization.6,23 For every 1° C drop in interstitial temperature, nerve conduction velocity of somatosensory afferent fibers drops approximately 2 m/s due to metabolic changes in the axon.50 It has been reported that at a skin surface temperature of 10° C (50° F) there is a 33% reduction in nerve conduction velocity50 and that local analgesia may be produced by lowering skin surface temperature to 13.6° C (56.5° F).51 Aδ nociceptive fibers display the most sensitivity to cold mediated velocity attenuation, whereas blocking conduction of C fibers requires considerably colder temperatures.22,43 The effects of application of a cryotherapy agent for 10 to 15 minutes may transcend immediate changes and produce pain reductions for more than an hour.6 Prolonged analgesia may be the result of Aδ conduction block and the maintenance of subnormal deep tissue temperature for 1 to 2 hours following cold exposure.6,52 Extended cold application has been shown to produce reversible neurapraxia.53 Theoretically, by interrupting the pain–spasm–pain cycle, cold application may reduce muscle spasm, thus continuing pain relief after tissue temperature has recovered to precryotherapy levels.6 Finally, by applying vapor-coolant sprays over skeletal muscle and combining it with stretch, evaporative cooling may reduce muscle spasm and allow muscle with excess neurogenic tone to be stretched for increased range of motion.6,46,54 The vapor-coolant spray has been hypothesized to be effective in this capacity by providing a counterirritation to cutaneous afferents, which in turn leads to a reflex decrease in motor neuron activity and resistance to stretch.6 Existing literature is clear in support of the efficacy of cryotherapy in acute trauma management. It may also play a role in treating some manifestations of chronic pain; however, at the current time, there is little 4662

well-controlled literature supporting its efficacy.43 Uncontrolled comparative studies and case studies have reported that in the treatment of muscle spasms and myofascial pain, cryotherapy may be a beneficial adjunct.46,55,56 Additional comparative studies have reported it to be a useful clinical tool in managing chronic headache,57 trigeminal neuralgia,58 chronic osteoarthritis,59 and low back pain.39 Cryotherapy is contraindicated for patients with Raynaud’s disease or phenomenon; cryoglobulinemia or paroxysmal cold hemoglobinuria; angina pectoris; those prone to cold urticaria, cold intolerance, or hypersensitivity; or over skin areas of impaired somatosensory discrimination, deep open wounds, areas of circulatory compromise or peripheral vascular disease, and regenerating peripheral nerves.6,9,42,43 Cryotherapy should be used with caution over the main branch of a superficial nerve, on individuals with unstable hypertension, those with significant loss of superficial sensation, poor thermoregulation, aversion or intolerance to cold, poor cognition, or in the very young or very old.6,9,42,43 Note that with applications to the lower extremity, proprioception and joint stability will be temporarily compromised following treatment, so caution should be exercised with ambulation or return to sports participation quickly after cryotherapy.41

Light Therapy LASER Laser light is in current use for a variety of medical conditions. The U.S. Food and Drug Administration (FDA) has three classifications for medical lasers: • Class 4 (IV)—surgical lasers (>500 mW) • Class 3B (IIIb)—nonsurgical lasers (5 to 500 mW) • Class 3R (IIIr)—nonsurgical lasers (70 Hz.4,12 One group, which has published extensively on DBS for pain, suggests that only demonstrable efficacy should guide the decision for implanting an electrode at the PAG, VP, or both sites,1,17 although their own practice is to target the PAG site initially, except in cases of head and facial pain.19 Importantly, some patients may have components of both neuropathic and nociceptive pain and may therefore derive benefit from DBS therapy to both PAG and VP sites.2 The ACC has also been reported as a successful DBS target for pain based on the effectiveness of cingulotomy.20–24 The ACC is thought to modulate pain processing and is involved in the affective component of pain. As a result, DBS therapy to this target likely affects emotional components to pain rather than nociceptive perception, thereby reducing the “unpleasantness” of pain rather than the pain itself.1,4,6,25 Other targets that have additionally been reported in the literature include the internal capsule,26,27 ventral striatum and internal capsule,28,29 centromedian parafascicular complex and the intra-laminar zone,30 and posterior hypothalamus.31,32

EFFICACY OF DEEP BRAIN STIMULATION Initial studies of DBS for pain in the United States were based on two multicenter trials from 1989 to 1995, which were not randomized or case controlled.1,33 Neither trial met criteria for efficacy, with the first trial defining effective therapy as ≥50% of patients with ≥50% pain relief at 1year follow-up and the second trial defining efficacy as ≥50% of patients with ≥30% pain relief and decrease in the usage of analgesia medication.33 Multiple reviews have subsequently commented on the limitations of these trials, which include patient heterogeneity, lack of blinded assessment, and lack of standardization among centers.1,17 Nevertheless, as a result of these studies, DBS for pain in the United States has been used with an off-label status.33 Subsequent studies, reviews, and meta-analyses have provided a mixed picture regarding the efficacy of DBS for pain. Many published studies have limited numbers of patients, with few centers reporting larger 4856

numbers. Ultimately, long-term efficacy has been reported in ~83% of patients,1 with one large case series by a well-published center suggesting an overall long-term efficacy of 67% at their center, with no significant differences in efficacy based on stimulation site.19 Several meta-analyses have suggested efficacy of DBS for pain. A 2010 meta-analysis examined 13 studies and estimated that 50% of patients had long-term relief with DBS, with a 61% success rate for nociceptive pain diagnoses and 42% success rate with neuropathic pain diagnoses.2 A 2005 meta-analysis of 6 older studies (from 1977 to 1997) had also demonstrated 55% to 70% pain relief at >1-year follow-up.13 This metaanalysis suggested good to excellent results with PAG stimulation, with further increases in success when combined with thalamic or internal capsule stimulation, a strategy that has been seen in other studies.34 However, there have been limitations to in-depth analysis of both individual studies and meta-analyses due to factors such as heterogeneity in patient diagnoses and selection criteria, DBS sites, stimulation parameters, and use of unblinded assessments. These limitations have been reflected in recent recommendations from the European Academy of Neurology (EAN) in 2016 and the European Federation of Neurological Societies (EFNS) in 2007.5,35 The EAN’s meta-analysis of studies from 2006 to 2014 that used DBS for a variety of pain diagnoses determined that there was very low quality of evidence.35 Overall, the EAN gave a recommendation of “inconclusive,” highlighting the further need for additional prospective, randomized, controlled trials. Nevertheless, they noted that the overall pain intensity reduction was close to 50% in their included studies.35 This was an update to the EFNS 2007 study, which had calculated an overall 46% long-term success rate of DBS for pain.5 Further investigations will be required to determine whether specific DBS targets are best suited for particular diagnoses, as there has been lack of consensus.5,35,36 Few studies have also utilized randomized or placebo-controlled experimental designs. Marchand et al.37 studied thalamic stimulation and examined the effects of placebo stimulation, ultimately demonstrating a significant placebo effect from thalamic DBS. Rasche et al.34 included placebo testing during the trial stimulation phase; ultimately, 57% of 4857

patients passed this phase with demonstrated analgesic effects and were implanted with a pulse generator. Fontaine et al.38 reported a randomized, placebo-controlled, double-blind trial to study the effects of hypothalamic DBS in cluster headache and found that although there was lack of efficacy during the randomized phase of the trial, patients derived a reduction in their attacks during the open phase. Finally, Lempka et al.28 targeted the ventral striatum/anterior limb of the internal capsule in a prospective, double-blind, randomized, placebo-controlled, crossover study and did not meet its primary endpoint of ≥50% improvement in ≥50% of patients with active DBS compared to placebo. However, there were improvements in other measures such as depression, anxiety, and quality of life. These studies have suggested legitimate effects from DBS, although its effects may not be adequately measured purely by pain intensity ratings. Overall, there have been persistent limitations to comparing published studies, which have included diverse patient selection criteria and diagnoses, heterogeneous methodology, and diversity of intracranial targets. In addition, certain effects may not have been fully studied or reported. For example, DBS for pain may result in substantial insertional effects.39 As increasingly examined by recent published studies, future investigations may also benefit from assessing patient improvements in areas other than pain, such as mood, anxiety, and quality of life, which may improve to a significant degree.40 Although a number of studies have suggested that DBS may be more effective for particular diagnoses, or identified particular targets as being more effective for specific diagnoses, there does not yet appear to be general consensus.13,17,36 Some studies have demonstrated loss of efficacy over time, with some series noting that up to a half of patients who have success during the trial stimulation period do not have sustained benefit at ≥1 year follow-up, which may be attributed to factors such as scarring around electrode targets, brain plasticity, and inconsistent patient reporting.17,25 To mitigate these effects, groups have resorted to intensive reprogramming, with authors noting that stimulation parameters may increase with time.1,41 Strategies for reprogramming include changing pulse width or frequency or allowing for cycled stimulation or “off” periods.17 4858

SURGICAL TECHNIQUE Optimal patient selection has been important in ensuring that those who undergo DBS benefit from therapy. A multidisciplinary approach is used to screen potential patients who may benefit from DBS, and neuropsychological testing is a key component, with patients who have psychological etiologies excluded. Patients are also typically medication refractory ≥2 years, but there are no restrictions on whether patients have undergone other surgical procedures.1,17 Some groups examine patients’ responses to analgesics prior to DBS.18 Quantitative and qualitative assessment of pain is required, as well as quality of life assessments, which may allow clinicians and patients to best see changes that occur after DBS. Contraindications include medical conditions that would make surgery unsafe or anatomic factors such as ventriculomegaly that would prevent placement of an electrode into the surgical target. DBS electrodes are implanted stereotactically, using either a frame or frameless approach (Fig. 97.1).2 As a result, high-resolution magnetic resonance imaging (MRI) is required to allow for accurate targeting. Surgery is performed with sedation and local anesthesia; however, some targets, such as the ACC, can be performed under general anesthesia. Targets in the thalamus and midbrain are contralateral to the symptomatic side, whereas the ACC target requires bilateral electrode implantation.1

FIGURE 97.1 A: T1-weighted magnetic resonance imaging (MRI) showing planned trajectory ad target for placement of a periaqueductal or periventricular gray matter (PAG/PVG) in the axial, frontal, and sagittal planes. B: Postoperative MRI showing ventral posterior lateral (VPL) electrode (lateral) and the wire to the PVG electrode (medial and inferior). (Reprinted with permission from Owen SL, Green AL, Stein JF, et al. Deep brain stimulation for the alleviation of post-stroke neuropathic pain. Pain 2006;120[1–2]:202–206.)

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For targeting coordinates, the PAG is typically found 2 to 3 mm lateral to the third ventricle at the level of the posterior commissure and 10 mm posterior to the midcommissural point and 0 mm vertical; the VP target is typically found 10 to 13 mm posterior to the midcommissural point, 14 to 18 mm lateral, and from 5 mm below to 2 mm above the midcommissural line (Fig. 97.2).1,4 To isolate a particular limb, studies have suggested that the arm representation of the VPL is 2 to 3 mm medial to the internal capsule, whereas the leg representation is 1 to 2 mm medial to the internal capsule.4 The ACC target is typically 20 to 25 mm posterior to the anterior horns of the lateral ventricles, with the electrode tip near the corpus callosum and the electrode in the cingulum bundle.4,25

FIGURE 97.2 T1 coronal image with implanted periventricular gray matter electrode. (Reprinted with permission from Owen SL, Green AL, Stein JF, et al. Deep brain stimulation for the alleviation of post-stroke neuropathic pain. Pain 2006;120[1–2]:202–206.)

Intraoperative physiologic stimulation is used to refine the final target, with microelectrode recording, microstimulation, and macrostimulation. This step is considered critical in order to obtain adequate coverage of the symptomatic region. For instance, patients undergoing VP stimulation should experience paresthesias in previously painful areas, whereas those undergoing PAG stimulation should note a sensation of warmth or analgesia.4,13 Once targets are identified, the electrodes are introduced, and the leads are externalized for trial stimulation. Patients undergo postoperative imaging, typically via computed tomography (CT), to look for possible complications. 4860

A trial assessment period typically lasts from 5 to 9 days, during which physicians may test different combinations of stimulation parameters to optimize patient effects.2 Different approaches have been taken for assessing effectiveness, with some authors using an “N-of-1 trial” approach, in which a patient undergoes randomized pairs of treatments to elucidate the effects of DBS and placebo.17 Overall, a large percentage of patients typically pass the trial stimulation period.36,39,42 Some authors have noted that DBS to the ACC may take an extended period to demonstrate effectiveness.4 Stimulation parameters have varied across the literature, with some groups reporting bipolar stimulation parameters in the range of 5 to 50 Hz with pulse widths from 100 to 450 µs and amplitudes from 0.1 to 3 V, although ACC stimulation may require higher settings.1,17 Afterward, the most effective electrodes are internalized and connected to either an infraclavicular or abdominal pulse generator. Overall, DBS is considered to be a generally safe procedure, with adverse events occurring in 8% to 9% of cases.35 One of the more serious complications is hemorrhage, which has been reported in 1.9% to 4.1% of cases.2,43 Device malfunction may also occur. There is a risk of infection, which has been reported in 1.9% to 13.3% of cases.14,43 Other minor risks include diplopia and visual gaze effects, headache, and nausea.14,17 The risk of permanent neurologic deficit has ranged from 2% to 3.4%, and mortality is rare, ranging from 0% to 1.6%.2

Motor Cortex Stimulation BASIC CONSIDERATIONS The use of MCS was initiated after a study by Tsubokawa et al.44 in 1991, with the demonstration that chronic stimulation of the motor cortex with epidural electrodes inhibited thalamic hyperactivity and ultimately led to symptom control. Following this study, neuromodulation of the motor cortex was examined as an option for the treatment of medically intractable central and peripheral neuropathic pain.45,46 Based on these initial studies, MCS has been subsequently made an option for patients who have failed pharmacologic therapy or other stimulation techniques like spinal cord stimulation.47 4861

Interestingly, MCS is able to achieve pain reduction at voltages below the threshold for muscle contraction, and, at these voltages, it can induce paresthesias.47 Numerous studies have sought to determine the mechanism of action of MCS, with several proposed explanations. Its effects have been attributed to modulation of connections among somatosensory cortex, thalamus, spinothalamic tract, and motor cortex.48–51 MCS results in both direct and indirect waves, with anodal stimulation resulting in direct stimulation and cathodal stimulation resulting in depolarization of horizontal interneurons that trigger indirect waves of stimulation.45,48,52 Ultimately, the indirect waves are thought to result in analgesia via top– down inhibition.52,53 Thalamic hypersensitivity is reduced by antidromic modulation, endogenous opioids in the periaqueductal gray and cingulate are released,54 and regions that modulate pain, such as the orbitofrontal cortex, are activated.48,55–58 A common inclusion criterion for MCS includes a diagnosis of neuropathic pain with the identification of a lesion within the central nervous system.48 A consensus meeting suggested that central and peripheral causes are both treatable and can be of a variety of etiologies including trauma or injury from procedures as well as vascular, inflammatory, degenerative, and oncologic causes.48 Notably, candidates for MCS should have psychological or psychiatric diagnoses and morbidities evaluated, and patients generally have a pain Visual Analog Scale (VAS) of at least 5.48 Specifically, centers have used MCS for indications including poststroke pain (including facial, upper and lower extremity, and dystonias),47,59–63 plexus avulsion pain, atypical facial pain, postirradiation pain for treatment of arteriovenous malformations, phantom limb pain,47,60,61,64 lumbar plexus pain, chronic regional pain syndrome,64 root lesions of the upper extremity,47,64 multiple sclerosis,47 syringomyelia,47,63 postherpetic pain,64,65 trigeminal neuropathic pain and anesthesia dolorosa,46,47,60,61,66 sciatic pain, and spinal cord injury,62,63 as reviewed in a recent study.48 Atypical facial pain is felt to be heterogeneous and therefore may have limited treatment success.48 Despite heterogeneity, most published studies have demonstrated positive responses to MCS, although this may be due to publication bias.61 4862

In addition, centers have also varied in terms of their definition of a “good” result, which may or may not depend on the VAS and therefore make comparisons across studies challenging.48 Predictive factors have been inconsistently identified. One study found that the only predictive factor was the patient’s response in the first month after the procedure.67 Other studies have suggested that motor weakness in the region of pain may be tied to reduction in efficacy,47,48,68 although this did not play a significant role in other studies.67,69,70 There is increasing evidence that rTMS may be used as a tool to determine which patients may benefit from MCS, although consensus groups have felt that it was less useful for excluding patients from MCS.48,55,71 rTMS provides high positive predictive value for response to MCS but has a high rate of false negatives and lower negative predictive value,72 although the predictive value of rTMS may be better at examining long-term effects.73

EFFICACY OF MOTOR CORTEX STIMULATION Success rates of MCS for pain have been analyzed through case reviews and meta-analyses. Examination of case series that used MCS for chronic neuropathic pain published from 1991 to 2006 demonstrated that ≥40% improvement in pain relief from MCS was seen in 56.7% of patients, with long-term benefit in 45% of patients at ≥1 year.74 Another meta-analysis of 22 studies from 1960 to 2007 found that 64% of patients undergoing MCS responded to therapy.51 Finally, a review that specifically examined MCS for facial chronic neuropathic pain indications found that 84% of patients who had implantation of the system had good pain control at the end of the study with long-term follow-up of 30.7 months.56 The effects of MCS have also been examined in specific diagnoses, in case it may be applied more effectively for specific indications, although the results have been inconsistent.47,60,62 For instance, some authors believe that MCS for poststroke pain leads to good relief in approximately two-thirds of patients, whereas therapy for trigeminal neuropathic pain leads to good relief in >75% of patients.2,75 Some studies have suggested that the use of MCS for diagnoses related to spinal cord injury or brachial plexus pain may be more challenging.47,62 4863

Study of long-term outcomes has been necessary, as many investigations have shown that MCS can lose efficacy at extended time points as patients develop “tolerance.”47,48,51,74 Reasons for this gradual loss of efficacy have included brain remodeling and plasticity or scar build up at the surgical site.76 Further intensive stimulator reprogramming may lead to return of analgesic effects.48,76 However, even with longer followup periods, one study found that on the order of 1 to 6 years of follow-up, >50% of patients still had benefit from MCS, with patients with thalamic central pain felt to have the best result.47 Several trials have been conducted with MCS, although there have been inconsistent results. One crossover trial that examined MCS for refractory peripheral pain in 16 patients demonstrated a mean rate of pain relief, as assessed by VAS scores, of 48%, with 60% having a satisfactory or good result with MCS therapy (>40% VAS score reduction) after prolonged stimulation after a crossover phase.70 However, during the crossover period which allowed comparison between “on” versus “off” conditions, there were no significant differences, which were attributed to carry-over effects.70 A second crossover trial that tested “on” versus “off” stimulation in patients found that patients had significant benefit from MCS only in the “on” setting, with 60% of patients ultimately experiencing >40% pain reduction at follow-up.77 A third crossover trial that also studied “on” versus “off” stimulation settings found that patients had pain reduction only in the “on” setting, with return of pain in the “off” setting.78 Improvement at 1 year was >40% for all tested patients.78 However, in contrast to these studies, a recent randomized study that examined conditions of low stimulation (subtherapeutic levels) versus high stimulation (therapeutic levels) was stopped due to lack of efficacy.64 No differences were seen between the two groups, and a possible nocebo effect was also discovered; however, the diagnoses of the patients involved in the study were limited.64 Some authors have noted the importance of a double-blind testing phase during MCS trial stimulation. For example, one study of MCS for trigeminal neuropathic pain in 36 patients included a double-blind testing phase.79 Seventeen percent of patients were found to be false-positive responders and did not have permanent implantation of the device, and ultimately, 57.6% of patients had >30% pain reduction.79 4864

Reasons for poor response to MCS have included the need for more intensive programming or the need for an extended testing period prior to permanent implantation.47,61 One study that did not use a trial period in all patients noted that this may be required in order to increase the rate of successful therapy in patients with permanent implantations61; one author noted that typically only about 50% of patients who undergo trial stimulation go on to have the device permanently implanted.75 In addition, many authors have noted that MCS can have significant placebo effects, with up to 35% of patients experiencing a placebo effect. Nevertheless, one study queried patients as to whether they would proceed with surgery again, and 70% stated that they would.67

SURGICAL TECHNIQUE Preoperative evaluation includes assessment of pain intensity as well as psychological evaluation in order to assess for risk factors that may affect surgical outcome.47,60 TMS, as discussed previously, is used at some centers to help predict which patients may have better response to MCS.48,72,73 Preoperative studies aim to improve target selection and include highresolution MRI for identification of anatomic landmarks and functional MRI to ensure optimal placement of electrodes over motor cortex.48,55,60,65,80 For instance, cases of phantom limb pain and thalamic pain may result in plasticity-related changes that may complicate optimal electrode placement over the motor strip.47,55 Neuronavigation is typically employed to accurately determine the surgical site and to allow for anatomic localization. The procedure can be performed under either local or general anesthesia. A craniotomy or burr hole allows access to the epidural space. From here, mapping is performed to identify the N20-P20 phase reversal that characterizes the location of the central sulcus, which is considered the gold standard for identifying the motor cortex.48,55 Additional intraoperative electrophysiology with somatosensory evoked potentials (SSEPs) or motor evoked potentials can further verify the optimal location of the electrode (Figs. 97.3 and 97.4).47,48,61

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FIGURE 97.3 Blue circles correspond to position of motor cortex stimulation. Dark blue, hand; light blue, face; F, fingers; H, hand; V, abduction of fifth finger; C, cheek; M, mouth; EMG, electromyography responses. (Reprinted from Nguyen JP, Lefaucher JP, Le Guerinel C, et al. Motor cortex stimulation in the treatment of central and neuropathic pain. Arch Med Res 2000;31[3]:263– 265. Copyright © 2000 IMSS. With permission.)

FIGURE 97.4 Circles correspond to the position of motor cortex stimulation that resulted in good or excellent pain reduction. Dark blue, hand; light blue, face. (Reprinted from Nguyen JP, Lefaucher JP, Le Guerinel C, et al. Motor cortex stimulation in the treatment of central and neuropathic pain. Arch Med Res 2000;31[3]:263–265. Copyright © 2000 IMSS. With permission.)

At some centers, the dura is opened under certain circumstances. For instance, the dura may need to be opened to access the interhemispheric fissure for providing therapy to the lower extremities or if there is a significant distance between the dura and cortex.47,60 Many different types of electrodes have been used, including 4 and 8 contact electrodes, as well as grids, and both parallel and perpendicular orientations have been used.47,48,60,61,64 Electrode location can be subsequently confirmed by 4866

stimulating through the contacts, and motor threshold testing can be carried out in the operating room.55,75 Some centers choose to coagulate the dura underneath the electrode in order to avoid possible headache that can arise from dural nerve stimulation.48 Once the leads are secured in place, they can be either passed to an infraclavicular chest or abdominal pocket to a pulse generator or they can be tunneled out from the skin for postoperative testing (Fig. 97.5). Trial periods for MCS vary, with some centers not performing any trial period, and others typically trialing stimulation for 3 to 7 days, with longer periods having a possible increased infection risk.2,48,56,60,61,63,64 Patients who have a response have the electrodes permanently implanted, although improvement thresholds that would allow for permanent implantation can range at different centers. As mentioned earlier, patients may develop tolerance to the MCS and require ongoing adjustments or stimulation holiday periods.

FIGURE 97.5 Skull radiograph of a patient with an epidural electrode over the right motor cortex for motor cortex stimulation. (Reprinted from Di Lazzaro V, Oliviero A, Pilato F, et al. Comparison of descending volleys evoked by transcranial and epidural motor cortex stimulation in a conscious patient with bulbar pain. Clin Neurophysiol 2004;115[4]:834–838. Copyright © 2004 International

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Federation of Clinical Neurophysiology. With permission.)

Stimulation regimens vary widely, as reviewed recently.48,55 Voltage can range from 2 V to ≥8 V, and typically a cyclic mode is used. Generally, the best orientation arises from cathodal stimulation of the precentral gyrus and anodal stimulation of the anterior border of the central sulcus.48 Frequencies vary, from 20 to 80 Hz, with pulse duration from 90 to 450 µs.48,55 Subsequent programming after pulse generator implantation can take an extended period of time, lasting >3 months at some centers. Complications of MCS include seizures, wound infection, hardware malfunction, hematomas, and paresthesias.47,55,60,61,63,64 Seizures have typically occurred in the setting of increased voltages.60,61,64 A large number of studies have reported no adverse events,75 and the complication rate overall is considered to be about 5%, with the most common complications being seizure and wound infection.55,56 One large examination of case series published from 1991 to 2006 found that infection occurred in about 5.7% of cases and hardware-related issues were found in 5.1%, with seizures occurring in 12% of patients in the early postoperative period.74 There may be higher risk of complications with subdural placement of electrodes.55

Transcranial Magnetic Stimulation BASIC CONSIDERATIONS rTMS has been applied to a variety of diagnoses and has been identified as a possible therapy for neuropathic chronic pain. The procedure involves placing a stimulating coil adjacent to the scalp, with the changing magnetic fields subsequently inducing electric currents in local neurons and resulting in depolarization (Fig 97.6).81,82

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FIGURE 97.6 The use of a navigation system for repetitive transcranial magnetic stimulation (rTMS). The stimulation coil (left) is centered over the motor cortex; the numbers on the right show motor cortex (1), relative to the sensory cortex (2), the premotor area (3), and the supplementary motor area (4). (Reprinted with permission from Hirayama A, Saitoh Y, Kishima H, et al. Reduction of intractable deafferentation pain by navigation-guided repetitive transcranial magnetic stimulation of the primary motor cortex. Pain 2006;122[1–2]:22–27.)

The rationale for rTMS has been derived from MCS, in which stimulation of the motor cortex corresponding to the region of pain results in pain relief, and the two therapies may share basic mechanisms, although their different stimulation parameters may recruit different substrates.53,83,84 Specific rTMS settings can trigger varying effects; for instance, rTMS at ≥5 Hz can increase excitability and potentiate transmission, but rTMS at ≤1 Hz can decrease it, thereby leading to either long-term potentiation or depression.81,84,85 Other factors such as pulse waveform and coil orientation can also lead to differing effects.84,86 rTMS has been investigated as a therapy for several etiologies, including central pain,71,87,88 facial neuropathic pain,88 postherpetic neuralgia,81 fibromyalgia,89,90 brachial plexus and peripheral nerve related pain,71,88 spinal cord lesions,88 and phantom limb pain.91 A majority of rTMS studies have targeted primary motor cortex.82 For pain, ≥5 Hz frequency has been the most common.81,82 Intensity of the pulses is typically tailored to individual motor thresholds; the number of pulses can vary, as can the orientation of the coil. Notably, the effects of rTMS may be temporary, and maintenance protocols will need to be developed.84,86,92

EFFICACY OF REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION FOR PAIN Recent large-scale reviews of rTMS have demonstrated heterogeneous results.82,86 A notable 2014 Cochrane review suggested that although high4869

frequency stimulation of the motor cortex can result in short-term effects in single doses, multiple dose studies have not shown a significant effect. In addition, the review failed to demonstrate meaningful clinical effect of rTMS, although it was limited by significant variation among studies and conflicting results.82 Another large review similarly found that low-frequency rTMS was ineffective, but high-frequency rTMS likely results in significant analgesic effects.86 This review also suggested that comparison among studies may be affected by variation in therapy time course and posttherapy evaluation, as the effects from rTMS may be most significant after a few days. In addition, there is some debate over whether rTMS is best for particular diagnoses. An earlier meta-analysis had suggested that rTMS for pain that originates from central, rather than peripheral, sources may be more effective.93 Notably, however, it has been difficult to perform double-blind studies of rTMS because there are auditory, visual, and sensation changes that occur during the course of therapy which may be difficult to replicate.81 There are typically few complications from rTMS.94 The most important adverse events can arise from damage to or heating of implants that are nearby; otherwise, the only significant risk is seizure, which has a very small risk, 1,500 interlaminar injections.56 Dural punctures were seen in 0.2% of patients, vasovagal reactions in 0.5%, and a central steroid effect (transient flushing, sleeplessness, nonpositional headache) was observed in 2.6%. A recently reported single-center 12-year experience in >9,800 lumbar interlaminar injections identified single cases (0.01%) each of intraspinal hematoma, spondylodiscitis, and septic shock.35 Dural puncture with CSF leak was seen in six patients (0.06%); vasovagal reactions and systemic steroid effects were not described.

TRANSFORAMINAL INJECTIONS Caudal and interlaminar injections rely on medication spreading to the target nerve or nerve roots from the point of injection. Because the spread of injectate into the epidural space is uncontrolled and unpredictable, only a fraction of the medication administered may actually reach the target nerve. TF injections differ in that the needle is placed next to the target 4936

nerve, virtually or actually touching it. Thereby, all the medication is delivered onto the target nerve. There is no “blind” version of TF injections. They are performed under image guidance.57 Image guidance is also critical for safety. The most serious danger of TF injections is injection into a radicular artery that reinforces the blood supply of the conus medullaris. Therefore, steps must be taken to guard against complications from such intra-arterial injections. When lumbar spinal nerves are the target, the target zone is the intervertebral foramen that lodges that nerve. Along a posterior or posterior oblique view, a spinal needle is delivered into that foramen, at a location where the target spinal nerve does not lie (Fig. 99.5). The classical placement is subpedicular (i.e., tangential to the inferior surface of the pedicle) as deeply as the back of the vertebral body (see Fig. 99.5).

FIGURE 99.5 Fluoroscopy views of stages in the conduct of a lumbar transforaminal injection. A: Posterior view showing a needle directed to a subpedicular position in a right L5–S1 intervertebral foramen. B: Lateral view showing the needle tangential to the pedicle, with its tip (arrow) resting on the back of the vertebral body. C: Posterior view after injection of contrast medium which outlines the parapedicular course of the L5 spinal nerve and the dural sleeve covering its roots. D: Lateral view after injection of contrast medium. The contrast medium (arrows) surrounds the nerve and flows rostrally, around the pedicle and under the lamina. (Images from International Spine Intervention Society. Lumbar interlaminar access. In: Bogduk N, ed. Practice Guidelines for Spinal Diagnostic and Treatment Procedures. 2nd ed. San Francisco, CA: International Spine Intervention Society; 2013:443–456.)

Alternative placements are supraneural, retroneural, and infraneural (Fig. 99.6). These can be used if and when the spinal nerve is displaced onto the pedicle, in patients with foraminal stenosis, or to avoid arteries in 4937

the rostral sectors of the foramen.

FIGURE 99.6 Alternative placements of a needle in the intervertebral foramen for transforaminal injections. In the supraneural placement, the tip of the needle lies above the nerve. For the retroneural placement, the tip of the needle lies behind the nerve. For infraneural placement, the tip of the needle lies below the nerve, opposite the intervertebral disk. (Images reproduced with permission from International Spine Intervention Society. Lumbar interlaminar access. In: Bogduk N, ed. Practice Guidelines for Spinal Diagnostic and Treatment Procedures. 2nd ed. San Francisco, CA: International Spine Intervention Society; 2013:443–456.)

When sacral nerves are the target, a technique analogous to that for lumbar nerves is used. The needle is inserted through the posterior sacral foramen and placed in a retroneural position (Fig. 99.7).

FIGURE 99.7 Fluoroscopy views of stages in the conduct of a sacral transforaminal injection. A: Posterior view showing a needle directed to a subpedicular position through a left S1 posterior sacral foramen. B: Lateral view showing the needle tangential to the pedicle, with its tip resting on the floor of the sacral canal. C: Posterior view after injection of contrast medium which outlines the parapedicular course of the S1 spinal nerve and the dural sleeve covering its roots. D: Lateral view

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after injection of contrast medium showing contrast medium surrounding the nerve and flowing rostrally.

Once the needle has been placed, one or more safety checks are performed to avoid injection into a radicular artery. Such tests are necessary because infarction of the conus medullaris is the most catastrophic complication of TF injection of steroids, and circumstantial evidence implicates intra-arterial injection of particulate steroids as the cause. Laboratory studies have shown that agents such as triamcinolone, betamethasone, and methylprednisolone form particles or aggregates that are large enough to block end arteries or capillaries.58 By implication, these particles could act as emboli if injected into an artery that supplies the spinal cord. More recent evidence suggests that particulate steroids may cause stasis in a microvascular bed due to red blood cell agglutination as a consequence of red cell membrane effects.59 Studies in animals have shown that injection of particulate steroids into cerebral arteries universally causes fatal stroke, whereas the nonparticulate steroid, dexamethasone, does not.60,61 In virtually all cases of spinal cord infarction after lumbar TF injection of steroids, a particulate steroid was used.62 Only one case report records this complication after the use of dexamethasone.63 Dexamethasone, however, is known to precipitate into particles if mixed with ropivacaine.64,65 Additionally, there is some evidence that steroid preparations can have a direct neurotoxic effect without forming emboli.60 The foremost test for intra-arterial injection is the injection of a test dose of contrast medium. In the first instance, contrast medium is injected in order to show that injectate will flow in the appropriate direction, which is centrally, along the course of the target nerves and the dural sleeve that encloses its roots (see Fig. 99.5). It also serves to reveal aberrant flow if the needle has not been placed correctly. Aberrant flow can be into the subarachnoid space or the subdural space if the dural sleeve has been punctured; it may be externally, away from the nerve, if the intervertebral foramen is blocked or stenosed; or it may be into an epidural vein. Guidelines for what to do in the face of aberrant flow are elaborated elsewhere.57 4939

Notwithstanding normal flow, if the needle has punctured a radicular artery, the contrast medium will briefly flow within the artery before it is washed away. Intra-arterial injection is an indicated to terminate the procedure in order to avoid the risk of injecting potentially offensive medications into the artery and, therefore, into the circulation of the spinal cord. However, given that these arteries are tiny, it may be difficult to visualize arterial uptake of the contrast medium against a background of contrast medium in the epidural space (Fig. 99.8A). For this reason, some physicians repeat the injection of contrast medium under digital subtraction imaging (DSI). Under DSI, tiny arteries are brought into stark relief (Fig. 99.8B). Although adding DSI increases the amount of radiation to which the patient is exposed, the amount is small and well within notionally safe limits.66

FIGURE 99.8 Injection into a radicular artery during a lumbar transforaminal injection. A: Posterior view during injection of contrast medium. The tiny artery (arrow) is difficult to see. B: Digital subtraction imaging brings the artery into starker relief (arrows). (Images kindly provided by Dr. Way Yin, Bellingham, WA and reproduced with permission from International Spine Intervention Society. Lumbar interlaminar access. In: Bogduk N, ed. Practice Guidelines for Spinal Diagnostic and Treatment Procedures. 2nd ed. San Francisco, CA: International Spine Intervention Society; 2013:443–456.)

Some physicians perform an additional test, although its validity is contentious. The test is to administer a small dose (1 mL) of lidocaine 2%; wait 2 minutes and examine the patient for sensory of motor loss in the lower limbs. The rationale for this test is that if the needle has punctured a radicular artery but the artery has not been noticed during the injection of contrast medium, the local anesthetic will be injected into the artery and will cause temporary neurologic deficits on the spinal cord being anesthetized. Incurring a temporary neurologic deficit protects the patient from permanent damage that would occur had hazardous medications been 4940

administered. The test is loosely based on a single case report of temporary neurologic deficit after injection of local anesthetic during a cervical TF injection67 and a retrospective study of cervical TF injections that found that four patients in a series of 532 were positive to the local anesthetic test even though contrast medium had not shown arterial uptake.68 Once the needle has been correctly placed and safety checks have reduced the likelihood of intra-arterial injection, the chosen medication can be administered. In the past, the agents used had been methylprednisolone (40 or 80 mg), triamcinolone (40, 50, or 80 mg), or betamethasone (5.7, 8.55, or 11.4 mg). Until recently, these particulate steroids were preferred over dexamethasone (6 or 7.5 mg) because they were regarded as being more effective. Indeed, the early literature supported this view because the studies with the best outcome data all used particulate steroids, whereas outcomes were poor in the few studies that used dexamethasone. However, that situation has changed. Multiple large studies69–71 and reviews72,73 have shown that the success rates of TF injection of steroids are not significantly different statistically when dexamethasone is used instead of particulate steroids. This has promoted dexamethasone as a safer alternative for lumbar TF injections. Concerned about the safety profile of TF injections, the FDA commissioned an expert panel to publish recommendations designed to reduce the risk of spinal cord injury.45 In the essence, those recommendations are the following: • All lumbar interlaminar ESIs should be performed using image guidance, with appropriate anteroposterior (AP), lateral, or contralateral oblique views and a test dose of contrast medium. • Lumbar TF ESIs should be performed by injecting contrast medium under real-time fluoroscopy and/or DSI, using an AP view, before injecting any substance that may be hazardous to the patient. • A nonparticulate steroid (e.g., dexamethasone) should be used for the initial injection in lumbar TF epidural injections. • There are situations where particulate steroids could be used in the performance of lumbar TF ESIs.

TRANSFORAMINAL INJECTIONS UNDER 4941

FLUOROSCOPIC GUIDANCE: EVIDENCE TF injections require image guidance, but fluoroscopy facilities are not generally available to pain physicians for relatively minor injections. Therefore, the practice of TF injections has not been as widespread as the practice of blind caudal injections or blind interlaminar injections. Nevertheless, there is an abundant literature on the outcomes of TF injections of steroids for radicular pain. A systematic review reviewed all of the literature until 2013, covering observational studies as well as pragmatic trials and explanatory trials.74 It found that the evidence differed in volume and in conclusions for radicular pain due to disk herniation compared with neurogenic claudication associated with spinal stenosis. For spinal stenosis, the literature and evidence were largely limited to observational studies. There was one pragmatic trial but no explanatory trials. Several observational studies did not provide meaningful evidence because, although they claimed success, they did not define successful relief of pain or because follow-up was only for 2 weeks. Two outcome studies respectively reported 26 of 48 patients75 and 6 of 10 patients76 having 50% relief of pain at 6 months. From the single, pragmatic trial data on success rates could not be calculated, but outcomes were not significantly different between patients treated with either TF injections or fluoroscopically guided interlaminar epidural injections of methylprednisolone.77 For disk herniation, the review74 found that the literature is sufficiently abundant to show that lumbar TF injection of steroids is not universally effective but, nevertheless, benefits a substantial proportion of patients and is not a placebo. The original study of TF steroids reported that 47% of 30 patients obtained complete relief of pain, which was maintained for 2 years, and only 20% of patients required surgery.78 The surgery-sparing effect was corroborated by a subsequent study in which 53 (77%) of 69 patients avoided surgery for 12 months after treatment.79 Seven other observational studies provided reliable estimates of success rates for achieving at least 50% relief of pain at the times after treatment indicated: 100% of 53 patients at 1 month80; 52% of 40 patients81 and 62% 4942

of 41 patients at 90 days; 60% of 20 patients76 and 62% of 191 patients75 at 6 months; 75% of 69 patients at 12 months82; and 78% of 40 patients at 1 month, reducing to 67% at 6 months and 55% at 12 months.83 Although the review74 found several pragmatic studies, most did not provide data on success rates. Of the two that did, one reported 66% of patients achieved 50% relief of pain at 2 months,84 and the other reported 33% having this outcome at 6 months.11 These results are consistent with those of the observational studies. Of the five explanatory trials, three85–87 used TF injection of bupivacaine as the comparison treatment, but it is not known if TF bupivacaine is strictly an inactive treatment. Ostensibly, local anesthetic might have only a temporary relieving effect on pain, but long-lasting effects have not been formally excluded. A fourth study used intramuscular saline as the control treatment,88 which should be acceptable as a suitably inactive treatment for radicular pain, but this control treatment was administered in a different manner—as an office procedure—from that of fluoroscopically guided TF steroids. As well, patients were randomized according to patient choice. Both of these factors compromise the internal validity of the study and demote it to providing only weak evidence of efficacy of TF steroids. A fifth study used TF normal saline as the control treatment.89 With respect to pharmacologic activity, this served as an appropriate, inactive control, but it does not control for possible irrigation effects of TF injections. The sixth study90 addressed all of these concerns. It randomized patients to TF steroids or TF bupivacaine, TF normal saline, intramuscular steroids, or intramuscular normal saline, each performed in a fluoroscopy suite with intramuscular injections mimicking TF injections. Under these conditions, TF bupivacaine controlled for the addition of steroids to a TF injection, TF normal saline controlled for the possible effects of simply irrigating the affected nerve, intramuscular steroids controlled for systemic effects of steroids, and intramuscular saline served as a credible sham control. The first explanatory study85 did not report on relief of pain or other conventional outcomes. It used avoidance of surgery as the single outcome measure. It showed that TF steroids spared patients from surgery 4943

significantly more often than did TF bupivacaine alone. Only 29% (±17%) of 29 patients required surgery during the 13 months after treatment with TF steroids compared with 66% (±18%) of those treated with bupivacaine. Furthermore, the surgery-sparing effect was maintained during a subsequent 5-year follow-up.91 The weak explanatory study88 found that 84% (±14%) of 25 patients treated with TF steroids achieved at least 50% reduction of pain, accompanied by improvements of at least 5 points on the Roland-Morris Disability Questionnaire, persisting for 12 months. In comparison, only 48% (±20%) achieved these outcomes after intramuscular injections of normal saline. The double-blind trial that compared TF steroids and TF bupivacaine followed patients for 12 weeks86 and was supplemented by a 1-year follow-up.87 It found no differences in outcome, based on group scores, but success rates were not reported. However, patients who underwent surgery or a repeat injection before 3 months were excluded from the analysis, as were 16 patients who failed to attend for review at 3 months. It is not evident the extent to which these exclusions may have compromised the comparisons of outcomes. The study that compared TF steroids with TF normal saline initially found no differences between outcomes based on group data.89 However, a later analysis revealed several features.92 First, TF steroids were not universally successful. They were no more effective than sham treatment in patients with extruded or sequestrated disk herniations, but they were effective in those patients with contained disk herniations. TF steroids were significantly more effective than control treatment for reducing leg pain at 2 weeks and 1 month. As well, patients treated with TF steroids tended to have fewer sick days, fewer resorted to surgery, and twice as many had at least 75% reduction in pain (44% ± 20% compared with 21% ± 16%), but for these latter differences, statistical significance did not emerge because of the small sample sizes involved (25 and 24). However, what did emerge is that for those patients with contained herniations, TF steroids were significantly cost-effective at 12 months, achieving a cost reduction of $12,666 per responder. The sixth randomized, controlled study was designed primarily to test if 4944

the effects of TF steroids could be attributed to placebo.90 For that purpose, it evaluated responses at 1 month after treatment, but it also provided subsequent 12-month data. It found that the various control treatments had success rates for providing at least 50% relief of pain that were statistically indistinguishable. Some 15% (8% to 22%) of patients obtained at least 50% relief after treatment with TF bupivacaine, TF normal saline, intramuscular steroids, or intramuscular saline. The success rate for TF steroids was significantly greater at 54% (36% to 72%). Furthermore, this study showed that successful relief of pain was accompanied by restoration of function and clinically significant reduction —or elimination—of the need for other health care for radicular pain. All patients recruited for the study came from a neurosurgery unit, and all were destined for surgical treatment. Successful relief of pain by transforaminal injection of steroid (TFIS) avoided the need for surgery. During the 12 months after treatment, the success rate from the initial treatment deteriorated, but at 12 months, 11% of patients still had at least 50% relief of pain and a further 14% still had complete relief. This latter study also revealed a pertinent feature about reporting outcomes. The study clearly showed that TF steroids had a success rate that was significantly greater than those of any of the compared treatments, both statistically and clinically. However, the distribution of outcomes was distinctly bimodal: success or no success. Consequently, the group data did not produce a statistically significant difference because they camouflaged this bimodal distribution. Only if and when success rates were compared did significant differences appear. For these reasons, studies that report only group data may miss detecting statistically and clinically significant data. Since the publication of this review,74 a systematic review reinforced the surgery-sparing effects of TF injection of steroids for radicular pain due to disk herniation,93 and several studies have corroborated the observed success rates. One study found success rates of 70% at 3 months and at 6 months, with success defined as greater than 50% reduction of pain, coupled with 50% reduction in disability.70 A large study of 2,634 patients had a success rate of 52% at 2 months and 50% reduction in pain, coupled with 40% improvement in disability.69 A companion study of 4945

1,078 patients had a success rate of 45% for these same outcomes.94 An additional study demonstrated that repeat injection could increase the success rate of an initial injection that provided partial relief or could reinstate relief if initial relief waned.95 Importantly, this study also showed that if TF steroids were used in a disciplined manner, few patients actually required more than three injections per year in order to benefit from repeat injections. In patients with neurogenic claudication due to spinal stenosis, a large double-blind multisite pragmatic trial (N = 400) compared epidural administration of corticosteroid plus lidocaine versus lidocaine alone by both TF and interlaminar routes.96 In this patient population, there was no detectable difference between the groups in pain reduction or functional recovery.

TRANSFORAMINAL INJECTIONS: DETERMINANTS OF EFFICACY It would be clinically useful to identify patient, imaging, or procedural characteristics which are predictive of a positive response to TF ESIs. Spinal cord physiologic changes of central sensitization may amplify intensity and duration of perceived pain; pain chronicity may be a clinical marker of this process. A systematic review74 pooled data from three studies and noted a significant, although weak, association; patients having pain less than 6 months had better outcomes after TF injections. Another study of >2,000 lumbar TF injections had ~60% responders for pain and functional recovery in patients with pain 22,000 lumbar TF injections; there were no major adverse events.35 Symptom aggravation was described in 0.43%. In another single-center study of 1,300 lumbar TF injections, there were no major adverse events; minor events, primarily vasovagal reactions, were reported in 11.5%.103 An additional singlecenter study reported on nearly 4,000 lumbar TF injections.104 There were no major adverse events; the most common minor adverse event was transient increase in pain in 0.01% of injections. Thus, despite the 4947

concerns raised by case reports, TF injections are very safe when performed according to evidence-based procedural guidelines.

TRANSFORAMINAL INJECTIONS UNDER COMPUTED TOMOGRAPHY GUIDANCE: EVIDENCE, ADVERSE EVENTS A systematic review found that, although there were several publications that promoted the use of TF injections under CT guidance, most did not provide evidence either of efficacy or of effectiveness.105 Variously, the published studies assessed several interventions but without stratifying outcomes, claimed success but without defining success, and claimed success but did not provide baseline data or numerical outcome data to corroborate that claim. Of the four accepted studies, the first treated patients with radicular pain due to disk herniation106 and second treated patients with spinal stenosis.107 Both reported significant decreases in pain scores but did not provide any data on success rates. The third study treated patients with disk herniation or foraminal stenosis.108 It reported that 62% (±16%) had 50% relief at 6 months. The fourth study109 reported results in a confusing manner. A distillation of those results suggests the following: • Of 49 patients with disk herniation, 24 obtained lasting relief, with 90% of these having at least 50% relief, which amounts to a success rate of 44% ± 14%. • Of 59 patients with foraminal stenosis, 22 had lasting relief, with 90% of these having at least 50% relief, which amounts to a success rate of 34% ± 12%. • Of those patients with lasting relief, only 78% also ceased medications. Thus, the success rate for relieving pain and also ceasing medications may be lower than the success rates for relieving pain alone. Conspicuously, the review105 found no evidence to support the claims of proponents that CT-guided TF injections were “more accurate” and “safer” than fluoroscopically guided injections. Although CT shows the target nerve, this feature does not make the procedure “more accurate” than placing a needle under fluoroscopy. Meanwhile, the existing literature 4948

actually refutes claims of CT guidance being safer. In the first instance, CT guidance incurs radiation exposure that is some five times greater than that of fluoroscopic guidance.105 Secondly, CT guidance is not immune to serious vascular complications. At least half of the complications described in case reports have occurred under CT guidance, but all were prior to the recognition of the risks associated with particulate steroids. Critical to the avoidance of vascular complications is the administration of a test dose of contrast medium in order to check for arterial uptake. Conventional CT guidance does not allow for this safety check.105 The single-plane, axial view of conventional CT guidance does not show arteries running cephalad of the point of injection. However, if multislice CT fluoroscopy is employed, with image acquisition as the injection is performed, and immediately following cessation of the injection, vascular uptake can be evaluated under CT.110 When performed in this fashion, rates of detection of vascular uptake approached those seen with DSI. In a large prospective series of consecutive patients using this technique, in all spine segments, no major adverse events were noted.56

TRANSFORAMINAL EPIDURAL STEROID INJECTIONS: THEIR ROLE IN TREATING THE RADICULAR PAIN PATIENT ESIs can never be seen as an isolated therapeutic intervention; they must be part of a holistic spine care program. Their role in the disk herniation patient is to diminish the inflammatory response that causes neural irritation and to allow time for the natural history of involution of the herniated disk material to play out. TF ESIs have also been demonstrated to enable more vigorous and effective participation in a rehabilitation program. In a prospective cohort study, patients who had failed conservative therapy and were consented for surgery were offered up to two TF injections followed by a rigorous rehabilitation program.111 At 1 year, 78% had avoided surgery, and 62% had minimal pain (Visual Analog Scale [VAS]