The ASAM Principles of Addiction Medicine [6th Edition] 9781496371010

Table of contents :
Half Title......Page 2
Title......Page 3
Copyright......Page 5
Dedictation......Page 7
Section Editors......Page 8
Contributors......Page 14
Preface......Page 70
A Note About Terminology......Page 74
Acknowledgments......Page 76
Contents......Page 77
SECTION 1: Basic Science and Core Concepts......Page 89
1 Drug Addiction: The Neurobiology of Motivation Gone Awry......Page 90
2 Recommended Use of Terminology in Addiction Medicine......Page 139
3 The Epidemiology of Substance Use Disorders......Page 151
4 The Anatomy of Addiction......Page 192
5 From Neurobiology to Treatment: Progress against Addiction......Page 222
6 Clinical Trials in Substance-Using Populations......Page 236
7 The Addiction Medicine Physician as a Change Agent for Prevention and Public Health......Page 272
SECTION 2: Pharmacology......Page 289
8 Pharmacokinetic, Pharmacodynamic, and Pharmacogenomic Principles......Page 290
9 The Pharmacology of Alcohol......Page 323
10 The Pharmacology of Nonalcohol Sedative Hypnotics......Page 364
11 The Pharmacology of Opioids......Page 390
12 The Pharmacology of Stimulants......Page 423
13 The Pharmacology of Caffeine......Page 482
14 The Pharmacology of Nicotine and Tobacco......Page 513
15 The Pharmacology of Cannabinoids......Page 555
16 The Pharmacology of Hallucinogens......Page 607
17 The Pharmacology of Dissociatives......Page 653
18 The Pharmacology of Inhalants......Page 681
19 The Pharmacology of Anabolic–Androgenic Steroids......Page 703
20 Electronic Cigarettes......Page 745
21 Novel Psychoactive Substances: Their Recognition, Pharmacology, and Treatment......Page 777
SECTION 3: Diagnosis, Assessment, and Early Intervention......Page 792
22 Screening and Brief Intervention......Page 793
SIDEBAR: Screening and Brief Intervention for Pregnant Women......Page 829
SIDEBAR: Trauma Centers, Hospitals, and Emergency Departments......Page 843
SIDEBAR: Implementation of Screening and Brief Intervention (SBI) in Clinical Settings Using Quality Improvement Principles......Page 852
SIDEBAR: Screening for Unhealthy Alcohol Use in the Elderly......Page 855
23 Laboratory Assessment......Page 869
24 Assessment......Page 897
25 Environmental Approaches to Prevention: Communities and Contexts......Page 920
SECTION 4: Overview of Addiction Treatment......Page 944
26 Addiction Medicine in America: Its Birth, Early History, and Current Status (1750-2018)......Page 945
27 Treatment of Unhealthy Alcohol Use: An Overview......Page 977
28 The Treatment of Addiction: An Overview......Page 1010
29 Integrated Care for Substance Use Disorder......Page 1041
30 The ASAM Criteria and Matching Patients to Treatment......Page 1064
31 Linking Addiction Treatment With Other Medical and Psychiatric Treatment Systems......Page 1096
32 Alternative Therapies for Substance Use Disorders......Page 1129
33 Harm Reduction, Overdose Prevention, and Addiction Medicine......Page 1156
34 Quality Improvement for Addiction Treatment......Page 1180
35 Nursing Roles in Addressing Addiction......Page 1209
36 International Perspectives on Addiction Management......Page 1227
SECTION 5: Special Issues in Addiction......Page 1249
37 Prescription Medications: Nonmedical Use, Use Disorders, and Public Health Consequences......Page 1250
38 Special Issues in Treatment: Women......Page 1278
39 Traumatic Brain Injury and Substance Use Disorders......Page 1312
40 Military Sexual Trauma......Page 1345
41 Alcohol, Prescription, and Other Drug Problems in Older Adults......Page 1353
42 Cultural Issues in Addiction Medicine......Page 1388
43 College Student Drinking......Page 1406
44 Understanding “Behavioral Addiction”......Page 1437
45 Gambling Disorder: Clinical Characteristics and Treatment......Page 1490
46 Problematic Sexual Behaviors and “Sexual Addiction”......Page 1515
47 Microprocessor-Based Disorders......Page 1556
48 Behavioral Syndromes to Consider as Forms of “Addiction”......Page 1594
49 Physician Health Programs and Addiction Among Physicians......Page 1611
SECTION 6: Management of Intoxication and Withdrawal......Page 1661
50 Management of Intoxication and Withdrawal: General Principles......Page 1662
51 Management of Alcohol Intoxication and Withdrawal......Page 1684
52 Management of Sedative–Hypnotic Intoxication and Withdrawal......Page 1725
53 Management of Opioid Intoxication and Withdrawal......Page 1772
54 Management of Stimulant, Hallucinogen, Marijuana, Phencyclidine, and Club Drug Intoxication and Withdrawal......Page 1810
SECTION 7: Pharmacological Interventions and Other Somatic Therapies......Page 1864
55 Pharmacological Interventions for Alcohol Use Disorder......Page 1865
56 Pharmacological Interventions for Sedative–Hypnotic Use Disorder......Page 1897
57 Pharmacological and Psychosocial Treatment for Opioid Use Disorder......Page 1916
58 Special Issues in Office-Based Opioid Treatment......Page 1973
59 Pharmacological Treatment of Stimulant Use Disorders......Page 2009
60 Pharmacological Interventions for Tobacco Use Disorder......Page 2045
61 Pharmacological Interventions for Other Drugs and Multiple Drug Use Disorders......Page 2074
62 Neuromodulation for Addiction-Related Disorders......Page 2091
SECTION 8: Psychologically Based Interventions......Page 2094
63 Enhancing Motivation to Change......Page 2095
64 Group Therapies......Page 2127
65 Individual Treatment......Page 2154
66 Contingency Management and the Community Reinforcement Approach......Page 2200
67 Behavioral Interventions for Nicotine/Tobacco Use Disorder......Page 2240
68 Network Therapy......Page 2281
69 Therapeutic Communities and Modified Therapeutic Communities for Co-Occurring Mental and Substance Use Disorders......Page 2308
70 Aversion Therapies......Page 2343
71 Family Involvement in Addiction, Treatment, and Recovery......Page 2378
72 Twelve-Step Facilitation Approaches......Page 2417
73 Relapse Prevention: Clinical Models and Intervention Strategies......Page 2429
74 Digital Health Interventions for Substance Use Disorders: The State of the Science......Page 2468
75 Medical Management Techniques and Collaborative Care: Integrating Behavioral with Pharmacological Interventions in Addiction Treatment......Page 2485
SECTION 9: Mutual Help, Twelve-Step, and Other Recovery Programs......Page 2521
76 Twelve-Step Programs in Addiction Recovery......Page 2522
77 Recent Research into Twelve-Step Programs......Page 2546
78 Spirituality in the Recovery Process......Page 2586
SECTION 10: Medical Disorders and Complications of Addiction......Page 2599
79 Medical and Surgical Complications of Addiction......Page 2600
80 Cardiovascular Consequences of Alcohol and Other Drug Use......Page 2653
81 Liver Disorders Related to Alcohol and Other Drug Use......Page 2691
82 Renal and Metabolic Disorders Related to Alcohol and Other Drug Use......Page 2755
83 Gastrointestinal Disorders Related to Alcohol and Other Drug Use......Page 2791
84 Respiratory Tract Disorders and Selected Critical Care Considerations Related to Alcohol and Other Drug Use......Page 2822
85 Neurological Disorders Related to Alcohol and Other Drug Use......Page 2877
86 Human Immunodeficiency Virus, Tuberculosis, and Other Infectious Diseases Related to Alcohol and Other Drug Use......Page 2935
87 Sleep Disorders Related to Alcohol and Other Drug Use......Page 2976
88 Traumatic Injuries Related to Alcohol and Other Drug Use: Epidemiology, Screening, and Prevention......Page 3020
89 Endocrine and Reproductive Disorders Related to Alcohol and Other Drug Use......Page 3040
90 Alcohol and Other Drug Use during Pregnancy: Management of the Mother and Child......Page 3080
91 Perioperative Management of Patients with Alcohol- or Other Drug Use......Page 3120
SECTION 11: Co-Occurring Addiction and Psychiatric Disorders......Page 3148
92 Substance-Induced Mental Disorders......Page 3149
93 Co-occurring Mood and Substance Use Disorders......Page 3181
94 Co-Occurring Substance Use and Anxiety Disorders......Page 3245
95 Co-Occurring Addiction and Psychotic Disorders......Page 3272
96 Co-occurring Substance Use Disorder and Attention Deficit Hyperactivity Disorder......Page 3313
97 Co-occurring Personality Disorders and Addiction......Page 3355
98 Posttraumatic Stress Disorder and Substance Use Disorder Comorbidity......Page 3390
99 Co-occurring Substance Use Disorders and Eating Disorders......Page 3427
SECTION 12: Pain and Addiction......Page 3459
100 The Pathophysiology of Chronic Pain and Clinical Interfaces With Substance Use Disorder......Page 3460
101 Psychological Issues in the Management of Pain......Page 3511
102 Rehabilitation Approaches to Pain Management......Page 3555
103 Nonopioid Pharmacotherapy of Pain......Page 3581
104 Opioid Therapy of Pain......Page 3606
105 Co-Occurring Pain and Addiction......Page 3688
106 Legal and Regulatory Considerations in Opioid Prescribing......Page 3709
SECTION 13: Children and Adolescents......Page 3728
107 Preventing Substance Use Among Children and Adolescents......Page 3729
SIDEBAR: Governmental Policy on Cannabis Legalization and Cannabis as Medicine: Impact on Youth......Page 3744
108 Translational Neurobiology of Addiction from a Developmental Perspective......Page 3765
109 Screening and Brief Intervention for Adolescents......Page 3809
110 Assessing Adolescent Substance Use......Page 3827
111 Placement Criteria and Strategies for Adolescent Treatment Matching......Page 3839
SIDEBAR: Confidentiality in Dealing with Adolescents......Page 3870
SIDEBAR: Drug Testing Adolescents in School......Page 3876
112 Adolescent Treatment and Relapse Prevention......Page 3884
113 Pharmacotherapies for Adolescents with Substance Use Disorders......Page 3906
114 Co-occurring Psychiatric Disorders in Adolescents......Page 3929
SECTION 14: Ethical, Legal, and Liability Issues in Addiction Practice......Page 3967
115 Ethical Issues in Addiction Practice......Page 3968
116 Consent and Confidentiality Issues in Addiction Practice......Page 3988
117 Clinical, Ethical, and Legal Considerations in Prescribing Drugs With Potential for Nonmedical Use and Addiction......Page 4006
SIDEBAR: Drug Control Policy: History and Future Directions......Page 4029
SIDEBAR: Guidance on the Use of Opioids to Treat Chronic Pain......Page 4037
118 Medicinal Uses of Cannabis and Cannabinoids......Page 4052
119 Practical Considerations in Drug Testing......Page 4070
SIDEBAR: Workplace Drug Testing and the Role of the Medical Review Officer......Page 4095
120 Reducing Substance Use in Criminal Justice Populations......Page 4109
SIDEBAR: Treatment of Substance Use Disorders During Incarceration......Page 4126
121 Preventing and Treating Substance Use Disorders in Military Personnel......Page 4147
SIDEBAR: Risk Factors for Military Families......Page 4168
Index......Page 4181

Citation preview

The ASAM Principles of Addiction Medicine S I X T H E D I T I O N

The ASAM Principles of Addiction Medicine S I X T H E D I T I O N Senior Editor Shannon C. Miller, MD, DFAPA, DFASAM Director, Addiction Services VA Medical Center, Cincinnati, Ohio Faculty, Neuroscience Graduate Program Professor of Clinical Psychiatry, Affiliated, University of Cincinnati College of Medicine Past Founding Co-Editor, Journal of Addiction Medicine (2006-2016), American Society of Addiction Medicine Lieutenant Colonel, United States Air Force, Retired

Associate Editors David A. Fiellin, MD, FASAM Professor of Medicine, Emergency Medicine and Public Health Director, Program in Addiction Medicine Yale School of Medicine New Haven, Connecticut

Richard N. Rosenthal, MA, MD, DFAPA, DFAAAP, FASAM Professor of Psychiatry Director of Addiction Psychiatry Department of Psychiatry Stony Brook University Medical Center Stony Brook, New York

Richard Saitz, MD, MPH, FACP, DFASAM Chairman, Department of Community Health Sciences (CHS) Professor of Community Health Sciences & Medicine Boston University Schools of Public Health and Medicine Clinical Addiction Research and Education (CARE) Unit Section of General Internal Medicine Boston Medical Center Boston, Massachusetts

Acquisitions Editor: Chris Teja Product Development Editor: Ariel S. Winter Editorial Coordinator: Ashley Pheiffer Marketing Manager: Rachel Mante Leung Production Project Manager: David Saltzberg Design Coordinator: Stephen Druding Manufacturing Coordinator: Beth Welsh Prepress Vendor: SPi Global Copyright © 2019 by (ASAM) Fifth Edition, © 2014 by (ASAM) Fourth Edition, © 2009 by (ASAM) Third Edition, © 2003 by (ASAM) Second Edition, © 1998 by (ASAM) First Edition, © 1994 by (ASAM) 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 lww.com (products and services). 9 8 7 6 5 4 3 2 1 Printed in China Library of Congress Cataloging-in-Publication Data Names: Miller, Shannon C., editor. | Fiellin, David A., editor. | Rosenthal, Richard N., editor. | Saitz, Richard, editor. | American Society of Addiction Medicine, issuing body. Title: The ASAM principles of addiction medicine / senior editor, Shannon C. Miller; associate editors, David A. Fiellin, Richard N. Rosenthal, and Richard Saitz. Other titles: Principles of addiction medicine (American Society of Addiction Medicine) | Principles of addiction medicine Description: Sixth edition. | Philadelphia : Wolters Kluwer, [2019] | Includes bibliographical references. Identifiers: LCCN 2018038924 | ISBN 9781496370983 Subjects: | MESH: Substance-Related Disorders—therapy | Substance-Related Disorders—diagnosis | Substance-Related Disorders—complications | Behavior, Addictive | Addiction Medicine Classification: LCC RC564 | NLM WM 270 | DDC 362.29—dc23 LC record available at https://lccn.loc.gov/2018038924 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. 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

Dedicated to all people whose lives have been affected by addiction and related conditions and to those who care for them based on respect and the best science available.

Section Editors

Peter Banys, MD, MSc Clinical Professor of Psychiatry University of California at San Francisco (UCSF) San Francisco, California Technical Expert, Addiction Treatment WHO and European Union EPOS Manila, Philippines

William C. Becker, MD Associate Professor of Medicine (General Internal Medicine) Yale University School of Medicine New Haven, Connecticut Co-Director, Opioid Reassessment Clinic VA Connecticut Healthcare System West Haven, Connecticut

J. Wesley Boyd, MD, PhD Associate Professor of Psychiatry and Faculty, Center for Bioethics Harvard Medical School Boston, Massachusetts Staff Psychiatrist Cambridge Health Alliance Cambridge, Massachusetts

Timothy K. Brennan, MD, MPH Assistant Professor in Psychiatry Director, Addiction Institute at Mt. Sinai West & St. Luke’s Director, Fellowship in Addiction Medicine Program Icahn School of Medicine at Mount Sinai

New York, New York

Martin D. Cheatle, PhD Associate Professor, Department of Psychiatry Perelman School of Medicine University of Pennsylvania Director, Pain and Chemical Dependency Program Center for Studies of Addiction Perelman School of Medicine University of Pennsylvania Philadelphia, Pennsylvania

Wilson M. Compton, MD, MPE Deputy Director National Institute on Drug Abuse National Institutes of Health U.S. Department of Health and Human Services Bethesda, Maryland

John A. Dani, PhD David J. Mahoney Professor of Neuroscience Perelman School of Medicine University of Pennsylvania Chair, Department of Neuroscience Director, Mahoney Institute for Neuroscience Perelman School of Medicine Philadelphia, Pennsylvania

Lori J. Ducharme, PhD Program Director for Health Services Research National Institute on Alcohol Abuse and Alcoholism Bethesda, Maryland

Robert L. DuPont, MD President, Institute for Behavior and Health, Inc. Rockville, Maryland

Clinical Professor of Psychiatry Georgetown University School of Medicine Washington, District of Columbia

Rollin M. Gallagher, MD, MPH Clinical Professor of Psychiatry and Anesthesiology Director for Pain Policy Research and Primary Care Perelman School of Medicine University of Pennsylvania Philadelphia, Pennsylvania

R. Jeffrey Goldsmith, MD Professor of Clinical Psychiatry Department of Psychiatry and Clinical Neuroscience University of Cincinnati College of Medicine Staff Psychiatrist Mental Health Care Line Cincinnati VA Medical Center Cincinnati, Ohio

Adam Joseph Gordon, MD, MPH, FACP, DFASAM, CMRO Elbert F. and Marie Christensen Endowed Research Professorship Professor of Medicine and Psychiatry University of Utah School of Medicine Section Chief, Addiction Medicine Salt Lake City VA Health Care System Salt Lake City, Utah

David A. Gorelick, MD, PhD, DLFAPA Professor of Psychiatry University of Maryland School of Medicine Baltimore, Maryland

Jon E. Grant, MD, JD, MPH Professor Department of Psychiatry & Behavioral Neuroscience

Pritzker School of Medicine University of Chicago Chicago, Illinois

John R. Knight Jr, MD Associate Professor of Pediatrics Harvard Medical School Director, Center for Adolescent Substance Abuse Research Division of Developmental Medicine Boston Children’s Hospital Boston, Massachusetts

Thomas R. Kosten, MD Waggoner Chair and Professor of Psychiatry, Neuroscience, Pharmacology, Immunology & Pathology Director, Dan Duncan Institute for Clinical and Translational Research Baylor College of Medicine, Michael E. DeBakey VAMC Houston, Texas

Kevin Kunz, MD, MPH, DFASAM Executive Vice President The Addiction Medicine Foundation Chevy Chase, Maryland

Patrick G. O’Connor, MD, MPH Dan Adams and Amanda Adams Professor of General Medicine Chief, Section of General Internal Medicine Department of Internal Medicine Yale School of Medicine New Haven, Connecticut

Theodore V. Parran Jr, MD, FACP, FASAM Isabel and Carter Wang Professor and Chair in Medical Education CWRU School of Medicine Co-Medical Director, Rosary Hall St. Vincent Charity Medical Center

Cleveland, Ohio

Richard K. Ries, MD, FASAM, FAPA Professor of Psychiatry Director Addictions Division Department of Psychiatry and Behavioral Sciences University of Washington School of Medicine Seattle, Washington

Richard N. Rosenthal, MA, MD, DFAPA, DFAAAP, FASAM Professor of Psychiatry Director of Addiction Psychiatry Department of Psychiatry Stony Brook University Medical Center Stony Brook, New York

Seddon R. Savage, MD, MS, DFASAM Adjunct Associate Professor of Anesthesiology Geisel School of Medicine at Dartmouth Hanover, New Hampshire

Andrew J. Saxon, MD Professor and Director Addiction Psychiatry Residency Program Department of Psychiatry & Behavioral Sciences University of Washington Director, Center of Excellence in Substance Abuse Treatment and Education (CESATE) Seattle, Washington

Corinne L. Shea, MA Director of Programs and Communications Institute for Behavior and Health, Inc. Rockville, Maryland

Daryl Shorter, MD

Director of Residency Education Assistant Professor Menninger Department of Psychiatry and Behavioral Sciences Staff Psychiatrist Michael E. DeBakey VA Medical Center Houston, Texas

Deborah R. Simkin, MD Adjunct Assistant Professor Emory School of Medicine Atlanta, Georgia

Jeanette M. Tetrault, MD, FACP Associate Professor of Medicine Department of Internal Medicine Yale University School of Medicine New Haven, Connecticut

Bonnie B. Wilford, MS Executive Vice President Coalition on Physician Education in Substance Use Disorders (COPE) Easton, Maryland

Christine Yuodelis-Flores, MD, FAPA, FASAM Associate Professor Department of Psychiatry and Behavioral Sciences University of Washington Harborview Medical Center Seattle, Washington

Joan E. Zweben, PhD Health Sciences Clinical Professor of Psychiatry University of California, San Francisco Staff Psychologist VA Medical Center San Francisco, California

Contributors

Muhammad A. Abbas, MD Clinical Assistant Professor Department of Psychiatry and Human Behavior Jersey Shore University Medical Center Neptune City, New Jersey Rutgers-Robert Wood Johnson Medical Center Hackensack Meridian School of Medicine New Brunswick, New Jersey

Kathleen M. Akgün, MD, MS Assistant Professor of Medicine Pulmonary, Critical Care and Sleep Medicine Section Hospice and Palliative Medicine VA Connecticut Healthcare System Yale University School of Medicine Director Medical Intensive Care Unit VA Connecticut Healthcare System West Haven, Connecticut

Daniel P. Alford, MD, MPH Professor of Medicine Director, Clinical Addiction Research and Education (CARE) Unit Boston University School of Medicine Boston Medical Center Boston, Massachusetts

Jeffrey Allgaier, MD, FACEP Ideal Option Addiction Medicine Practice Kennewick, Washington

Catreena Al Marj, MD Post-Doctoral Fellow University of Utah Salt Lake City, Utah

Laith Al-Rabadi, MD Assistant Professor of Nephrology University of Utah Hospital Salt Lake City, Utah

Hamada Hamid Altalib, DO, MPH Director Yale Epilepsy Outcomes Research Co-Director, Epilepsy Center of Excellence Connecticut VA Healthcare System Assistant Professor Departments of Neurology & Psychiatry Yale School of Medicine New Haven, Connecticut

Christopher A. Arger, PhD Postdoctoral Fellow Vermont Center on Behavior and Health University of Vermont Burlington, Vermont

Ashraf Attalla, MD Associate Professor of Psychiatry Emory University School of Medicine Atlanta, Georgia Program Director Youth Services at Ridgeview Institute Smyrna, Georgia

Reham A. Attia, MD, ABFM, ABAM Core Faculty Eisenhower Family Medicine Residency

Assistant Professor University of California Riverside, School of Medicine Rancho Mirage, California

Sanford Auerbach, MD Associate Professor of Neurology, Psychiatry and Behavioral Neurosciences Boston University School of Medicine Director Sleep Disorders Center Boston Medical Center Boston, Massachusetts

Sudie E. Back, PhD Professor of Psychiatry and Behavioral Sciences Medical University of South Carolina Director DART Residency Research Track Department of Psychiatry and Behavioral Sciences Medical University of South Carolina Charleston, South Carolina

Robert L. Balster, PhD Butler Professor of Pharmacology and Toxicology Research Professor of Psychology and Psychiatry Virginia Commonwealth University Richmond, Virginia

Emma Louise Barrett, PhD Fulbright Scholar, Psychiatry and Behavioral Sciences Medical University of South Carolina Charleston, South Carolina Research Fellow, National Drug, Alcohol Research Centre University of New South Wales Sydney, Australia

Declan T. Barry, PhD

Associate Professor of Psychiatry Yale University School of Medicine Director of Pain Treatment Services, APT Foundation Director of Research, APT Foundation New Haven, Connecticut

Kristen L. Barry, PhD Research Professor Emerita Department of Psychiatry Addiction Section University of Michigan Ann Arbor, Michigan

Andrea G. Barthwell, MD, DFASAM Clinical Professor State University of New York Stony Brook (SUNY) School of Social Welfare Stony Brook, New York Director and Founder, Two Dreams

Steven L. Batki, MD Professor, Department of Psychiatry UCSF School of Medicine Chief, Addiction Recovery Treatment Services (ARTS), SFVAHCS Director, Addiction Research Program UCSF/SFVAHCS San Francisco Veterans Affairs Health Care System (SFVAHCS) San Francisco, California

Michael H. Baumann, PhD Staff Scientist and Facility Head Designer Drug Research Unit, Intramural Research Program National Institute on Drug Abuse, National Institutes of Health Baltimore, Maryland

Louis E. Baxter Sr, MD, DFASAM President and CEO Professional Assistance Program of NJ, Inc.

Princeton, New Jersey Assistant Clinical Professor of Medicine Rutgers New Jersey Medical School Newark, New Jersey Co-Program Director Howard University Addiction Medicine Fellowship Washington, District of Columbia

William C. Becker, MD Associate Professor of Medicine (General Internal Medicine) Yale University School of Medicine New Haven, Connecticut Co-Director, Opioid Reassessment Clinic VA Connecticut Healthcare System West Haven, Connecticut

Neal L. Benowitz, MD Professor of Medicine, Bioengineering and Therapeutic Sciences University of California San Francisco San Francisco, California

Nicolas Bertholet, MD, MSc Associate Physician Private Docent, Senior Lecturer Alcohol Treatment Center Department of Community Medicine and Health Lausanne University Hospital Lausanne, Switzerland

Roger L. Bertholf, PhD Medical Director of Clinical Chemistry Houston Methodist Hospital Houston, Texas

Thomas J.R. Beveridge, MSc, PhD Director, Medical Affairs—Oncology

Ipsen Biopharmaceuticals, Inc. Basking Ridge, New Jersey Assistant Professor (Adjunct) Department of Physiology and Pharmacology Wake Forest School of Medicine Winston-Salem, North Carolina

Joyce N. Bittinger, PhD University of Washington Seattle, Washington

Richard D. Blondell, MD Professor of Family Medicine Department of Family Medicine, University at Buffalo Director, DART Methadone Maintenance Clinic Buffalo, New York

Erika Litvin Bloom, PhD Assistant Professor (Research) Departments of Psychiatry and Human Behavior and Medicine Alpert Medical School of Brown University Division of General Internal Medicine—Research Rhode Island Hospital Providence, Rhode Island

Frederic C. Blow, PhD Senior Research Investigator HSR&D Center for Clinical Management Research Ann Arbor VA Healthcare System Professor and Director UM Addiction Center Department of Psychiatry University of Michigan Ann Arbor, Michigan

Michael P. Bogenschutz, MD

Professor of Psychiatry New York University School of Medicine New York, New York

Mark Bondeson, PsyD Chief of Mental Health and Homeless Operations Department of Veterans AffairsVeterans Integrated Service Network 20 (VISN 20) Northwest Network, VA Healthcare System Acting, Associate Chief of Staff for Behavioral Health Department of Veterans Affairs Boise, Veterans Administration Medical Center Boise, Idaho

Jacob T. Borodovsky, BA PhD Candidate, Center for Technology and Behavioral Health & The Dartmouth Institute for Health Policy and Clinical Practice Dartmouth Geisel School of Medicine Lebanon, New Hampshire

Gilbert J. Botvin, PhD Professor Emeritus Department of Healthcare Policy and Research Weill Cornell Medical College New York, New York

Andria M. Botzet, MA, LAMFT Department of Psychiatry University of Minnesota Minneapolis, Minnesota Project Coordinator Center for Adolescent Substance Abuse Research Boston, Massachusetts

J. Wesley Boyd, MD, PhD Associate Professor of Psychiatry and Faculty,

Center for Bioethics Harvard Medical School Boston, Massachusetts Staff Psychiatrist Cambridge Health Alliance Cambridge, Massachusetts

Maureen P. Boyle, PhD Chief, Science Policy Branch National Institute on Drug Abuse Bethesda, Maryland

Katharine A. Bradley, MD, MPH Senior Scientific Investigator Kaiser Permanente Washington Health Research Institute Kaiser Permanente Washington Associate Investigator Health Services Research and Development VA Puget Sound Affiliate Professor Department of Medicine Department of Health Services University of Washington Seattle, Washington

Kathleen T. Brady, MD, PhD Distinguished University Professor Vice-President for Research Clinical and Translational Science Department of Psychiatry and Behavioral Science Medical University of South Carolina Charleston, South Carolina

Robert M. Bray, PhD Chief Scientist, Behavioral Health/Criminal Justice Division RTI International Research Triangle Park, North Carolina

Timothy K. Brennan, MD, MPH Assistant Professor in Psychiatry Director, Addiction Institute at Mt. Sinai West & St. Luke’s Director, Fellowship in Addiction Medicine Program Icahn School of Medicine at Mount Sinai New York, New York

Traci L. Brooks, MD Instructor in Pediatrics Harvard Medical School Medical Director School Based Health Centers, Cambridge Health Alliance Staff Physician Division of Adolescent/Young Adult Medicine Boston Children’s Hospital Boston, Massachusetts

Lawrence S. Brown Jr, MD, MPH, DFASAM Chief Executive Officer START Treatment & Recovery Centers Brooklyn, New York Associate Physician The Rockefeller University Hospital Clinical Associate Professor of Medicine and Clinical Associate of Healthcare Policy and Research Department of Medicine, Weill Cornell Medical College New York, New York

Richard A. Brown, PhD Research Professor School of Nursing University of Texas at Austin Austin, Texas

Gregory C. Bunt, MD Assistant Professor Addiction Psychiatry NYU School of Medicine

New York, New York

Randy L. Calisoff, MD Assistant Professor of Physical Medicine and Rehabilitation Northwestern University Feinberg School of Medicine Attending Physician Rehabilitation Institute of Chicago Center for Pain Management Chicago, Illinois

Deepa Camenga, MD, MHS Assistant Professor of Emergency Medicine and Pediatrics Yale School of Medicine New Haven, Connecticut

James W. Campbell, MD, MS Professor of Family Medicine CASE Western Reserve University Chairman of Geriatrics MetroHealth Medical Center Cleveland, Ohio

Kathleen M. Carroll, PhD Albert E. Kent Professor of Psychiatry Yale University School of Medicine Director, Psychosocial Research, Division of Addictions Principal Investigator, Psychotherapy Development Center for Drug Abuse Yale University School of Medicine New Haven, Connecticut

Jonathan P. Caulkins, PhD University Professor of Operations Research and Public Policy Carnegie Mellon University Heinz College Pittsburgh, Pennsylvania

Martin D. Cheatle, PhD

Associate Professor, Department of Psychiatry Perelman School of Medicine University of Pennsylvania Director, Pain and Chemical Dependency Program Center for Studies of Addiction Perelman School of Medicine University of Pennsylvania Philadelphia, Pennsylvania

H. Westley Clark, MD, JD, MPH Dean’s Executive Professor of Public Health Santa Clara University Santa Clara, California

Jeffrey S. Cluver, MD Associate Professor of Psychiatry & Behavioral Sciences Deputy Chair & Vice Chair for Education & Training Medical University of South Carolina Charleston, South Carolina

John J. Coleman Assistant Administrator (Ret.) Drug Enforcement Administration Washington, District of Columbia

Peggy Compton, RN, PhD, FAAN Associate Professor of Nursing University of Pennsylvania School of Nursing Philadelphia, Pennsylvania

Wilson M. Compton, MD, MPE Deputy Director National Institute on Drug Abuse National Institutes of Health U.S. Department of Health and Human Services Bethesda, Maryland

David J. Copenhaver, MD, MPH Associate Professor Director of Cancer Pain Management Director of Pain Telehealth Programs Senior Editor Anesthesia & Analgesia Division of Pain Medicine Anesthesiology and Pain Medicine University of California at David Sacramento, California

Megan E. Crants Medical Student Touro College of Osteopathic Medicine Middletown, New York

Stanley D. Crittenden, MD Lead Medical Director Humana, Inc. Louisville, Kentucky

Rosa M. Crum, MD, MHS Professor, Department of Epidemiology, Joint Appointment, Department of Psychiatry & Behavioral Sciences Johns Hopkins Medical Institutions Baltimore, Maryland

Dennis C. Daley, PhD, LSW Senior Director, Substance Use Services, Behavioral Health Integration Division UPMC Insurance Division Professor of Psychiatry Department of Psychiatry, University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania

Kalyan Dandala, MD Chief Medical Officer

Associated Behavioral Health Care Clinical Associate Professor University of Washington Seattle Pacific University Seattle University Seattle, Washington

John A. Dani, PhD David J. Mahoney Professor of Neuroscience Perelman School of Medicine University of Pennsylvania Chair, Department of Neuroscience Director, Mahoney Institute for Neuroscience Perelman School of Medicine Philadelphia, Pennsylvania

Itai Danovitch, MD, MBA Chairman, Department of Psychiatry and Behavioral Neurosciences Associate Clinical Professor of Psychiatry Cedars-Sinai Medical Center Los Angeles, California

Danielle R. Davis, MA Predoctoral Fellow Vermont Center on Behavior & Health University of Vermont Burlington, Vermont

George De Leon, PhD Clinical Professor of Psychiatry New York University School of Medicine Science Director Behavioral Science Training School of Nursing New York University New York, New York

Christina M. Delos Reyes, MD Associate Professor, Department of Psychiatry Director, Addiction Psychiatry Fellowship University Hospitals Cleveland Medical Center Cleveland, Ohio

Adam R. Demner, MD Clinical Assistant Professor of Psychiatry New York University School of Medicine Unit Chief, Chemical Dependency Outpatient Program Bellevue Hospital Center New York, New York

Helen Dermatis, PhD Research Associate Professor of Psychiatry Department of Psychiatry Division of Alcoholism and Drug Abuse New York University School of Medicine New York, New York

Monica M. Diaz, MD Neuroinfectious & Neuroimmunology Fellow University of California, San Diego Health San Diego, California

William E. Dickinson, DO, FAAFP, ABAM, DFASAM Medical Director Providence Alcohol and Drug Treatment Services Everett, Washington

Patricia Jean Dickmann, MD Assistant Professor of Psychiatry University of Minnesota Medical School Medical Director, Addiction Recovery Services Medical Director, Opioid Treatment Program Medical Director, Community Resource and Referral Center

Minneapolis VA Medical Center Minneapolis, Minnesota

Edward F. Domino, MS, MD Active Emeritus Department of Pharmacology The University of Michigan Medical School University of Michigan Ann Arbor, Michigan

Gail D’Onofrio, MD, MS Professor and Chair Department of Emergency Medicine Yale University School of Medicine Physician-in-Chief Emergency Department Yale-New Haven Hospital New Haven, Connecticut

Dennis M. Donovan, PhD Director, Alcohol & Drug Abuse Institute Professor, Psychiatry & Behavioral Sciences Adjunct Professor, Psychology, Health Services, and Global Health University of Washington Schools of Medicine and Public Health Seattle, Washington

Antoine Douaihy, MD Professor of Psychiatry & Medicine University of Pittsburgh School of Medicine Senior Academic Director of Addiction Medicine Services Director of Addiction Psychiatry Fellowship Western Psychiatric Institute and Clinic Co-Director of Tobacco Treatment Service University of Pittsburgh Medical Center Pittsburgh, Pennsylvania

Robert L. DuPont, MD President, Institute for Behavior and Health, Inc. Rockville, Maryland Clinical Professor of Psychiatry Georgetown University School of Medicine Washington, District of Columbia

Paul H. Earley, MD, DFASAM Medical Director Georgia Professionals Health Program Atlanta, Georgia

Jon O. Ebbert, MD Professor of Medicine Mayo Clinic Rochester, Minnesota

Steven J. Eickelberg, MD, FAPA, DFASAM President Medical Education and Research Foundation for the Treatment of Addiction (MERF) San Francisco, California

A. Ahsan Ejaz, MD Division of Nephrology, Hypertension and Renal Transplantation University of Florida Gainesville, Florida

Nady el-Guebaly, MD, DPsych, DPH, FRCPC, DABAM Professor and Head, Division of Addiction Department of Psychiatry, University of Calgary Calgary, Alberta, Canada

Ralph L. Elkins Private Practitioner Augusta, Georgia

Xiaoduo Fan, MD, MPH, MSc Associate Professor of Psychiatry Director, Psychotic Disorders Program Director, China Mental Health Program UMass Memorial Health Care/UMass Medical School Worcester, Massachusetts

James L. Ferguson, DO, DFASAM Medical Director, Recovery Management Services FirstSource Solutions Chalfont, Pennsylvania

Sergi Ferré, MD, PhD Senior Investigator, Integrative Neurobiology Section National Institute on Drug Abuse, Intramural Research Program National Institutes of Health, Department of Health and Human Services Baltimore, Maryland

David A. Fiellin, MD, FASAM Professor of Medicine, Emergency Medicine and Public Health Director, Program in Addiction Medicine Yale School of Medicine New Haven, Connecticut

James W. Finch, MD, DFASAM Director of Physician Education Governor’s Institute on Substance Abuse Raleigh, North Carolina Medical Director Changes By Choice Durham, North Carolina

Deborah S. Finnell, DNS, PMHNP-BC, CARN-AP, FAAN Professor Johns Hopkins University Baltimore, Maryland

Marc Fishman, MD Assistant Professor Psychiatry Johns Hopkins University School of Medicine Medical Director Maryland Treatment Centers Baltimore, Maryland

Scott M. Fishman, MD Charles & Patricia Fullerton Endowed Chair Professor of Anesthesiology and Pain Medicine Chief, Division of Pain Medicine Vice Chair, Department of Anesthesiology and Pain Medicine Director, Center for Advancing Pain Relief (CAPR) UC David Medical Center Sacramento, California

Michael F. Fleming, MD, MPH Vice Chair for Faculty Development Northwestern University Department of Psychiatry and Behavioral Sciences Professor of Psychiatry and Behavioral Sciences and Family and Community Medicine Associate Director Northwestern University Clinical and Translational Sciences Institute (NUCATS) The Center for Education and Career Development Chicago, Illinois

James H. Ford II, PhD, FHIMSS, FACHE Associate Scientist Center for Health Systems Research and Analysis University of Wisconsin–Madison Madison, Wisconsin

P. Joseph Frawley, MD Internal Medicine/Addiction Medicine

Co-Medical Director, Recovery Road Medical Center Santa Barbara, California

Carl H. Freyer, BSc, MBBS Advanced Trainee, Gastroenterology and Addiction Medicine Drug Health Services Royal Prince Alfred Hospital Camperdown, New South Wales, Australia

Peter D. Friedmann, MD, MPH, FACP, DFASAM Chief Research Officer, Baystate Health Associate Dean for Research and Professor of Medicine University of Massachusetts Medical School (UMMS)– Baystate Professor of Quantitative Health Sciences UMMS Springfield, Massachusetts

Marc Galanter, MD, FASAM Research Professor of Psychiatry Department of Psychiatry New York University School of Medicine New York, New York

Rollin M. Gallagher, MD, MPH Clinical Professor of Psychiatry and Anesthesiology Director for Pain Policy Research and Primary Care Perelman School of Medicine University of Pennsylvania Philadelphia, Pennsylvania

Gilberto Gerra, MD Chief, Drug Prevention and Health Branch Division of Operations

United Nations Office on Drugs and Crime Vienna, Austria

Amanda K. Gilmore, PhD Assistant Professor (Research) College of Nursing and Department of Psychiatry & Behavioral Sciences Medical University of South Carolina Charleston, South Carolina

Mark S. Gold, MD 17th Distinguished Alumni Professor University of Florida Adjunct Professor Department of Psychiatry Washington University in St. Louis School of Medicine St. Louis, Missouri

Bruce A. Goldberger, PhD, F-ABFT Chief, Director and Professor Division of Forensic Medicine Department of Pathology, Immunology and Laboratory Medicine University of Florida College of Medicine Gainesville, Florida

R. Jeffrey Goldsmith, MD Professor of Clinical Psychiatry Department of Psychiatry and Clinical Neuroscience University of Cincinnati College of Medicine Staff Psychiatrist Mental Health Care Line Cincinnati VA Medical Center Cincinnati, Ohio

David A. Gorelick, MD, PhD, DLFAPA Professor of Psychiatry University of Maryland School of Medicine

Baltimore, Maryland

Praveen Gounder, MBBS (Hons) Clinical Pharmacology Advanced Trainee Royal Prince Alfred Hospital Sydney, Australia

Brian Grahan, MD, PhD Medical Director of Quality Measures Director, Minnesota Opioid and Addictions Care Project ECHO Hennepin Healthcare Assistant Professor of Medicine University of Minnesota Minneapolis, Minnesota

Jon E. Grant, MD, JD, MPH Professor Department of Psychiatry & Behavioral Neuroscience Pritzker School of Medicine University of Chicago Chicago, Illinoi

Kevin M. Gray, MD Professor and Director, Child and Adolescent Psychiatry Medical University of South Carolina Charleston, South Carolina

Kenneth W. Griffin, PhD, MPH Professor Department of Healthcare Policy and Research Weill Cornell Medical College New York, New York

Roland R. Griffiths, PhD Professor Department of Psychiatry of Behavioral Sciences

Department of Neuroscience Johns Hopkins University School of Medicine Baltimore, Maryland

Daniel F. Gros, PhD Associate Professor, Department of Psychiatry and Behavioral Sciences Medical University of South Carolina Section Chief, Supervisory Psychologist, PCMHI/CBT programs Principal Investigator, VA Clinical Sciences R&D Mental Health Service 116, Ralph H. Johnson VAMC Charleston, South Carolina

Kathleen A. Gross, MD Clinical Research Coordinator Center for Clinical Research Western Michigan University–Homer Stryker M.D. School of Medicine Kalamazoo, Michigan

Joel W. Grube, PhD Senior Research Scientist, Prevention Research Center, Pacific Institute for Research and Evaluation Oakland, California

Paul J. Gruenewald, PhD Scientific Director, Senior Research Scientist Prevention Research Center, Pacific Institute for Research and Evaluation Oakland, California

Carolina L. Haass-Koffler, PHARMD Assistant Professor Center for Alcohol and Addiction Studies Department of Psychiatry and Human Behavior Department of Behavioral and Social Sciences Brown University Providence, Rhode Island

Paul S. Haber, MD, FRACP, FAChAM Professor Drug Health Services Royal Prince Alfred Hospital Camperdown, New South Wales, Australia

Timothy M. Hall, MD, PhD, FAPA, FASAM Assistant Clinical Professor Center for Behavioral & Addiction Medicine Department of Family Medicine David Geffen School of Medicine University of California, Los Angeles Los Angeles, California

Deborah L. Haller, PhD Voluntary Professor Department of Public Health Sciences University of Miami Miller Medical School Miami, Florida Chief Psychologist NFL Program of Substances of Abuse

Colleen A. Hanlon, PhD Brain Stimulation Division Center for Biomedical Imaging Departments of Psychiatry and Neurosciences College of Medicine Medical University of South Carolina Charleston, South Carolina

Drew A. Harris, MD Fellow, Pulmonary, Critical Care and Sleep Medicine Yale University School of Medicine New Haven, Connecticut

Sion Kim Harris, PhD, CPH

Assistant Professor of Pediatrics Harvard Medical School Co-Director, Center for Adolescent Substance Abuse Research Boston Children’s Hospital Boston, Massachusetts

Karen J. Hartwell, MD Associate Professor of Psychiatry and Behavioral Sciences Addiction Sciences Division Medical University of South Carolina Medical Director Substance Treatment and Recovery Program Ralph H. Johnson VAMC Charleston, South Carolina

Kathryn Hawk, MD, MHS Assistant Professor of Emergency Medicine Yale University School of Medicine New Haven, Connecticut

Nicole A. Hayes, MS Doctoral Candidate, Psychiatry and Behavioral Sciences Northwestern University Feinberg School of Medicine Chicago, Illinois

J. Taylor Hays, MD Professor of Medicine Mayo Clinic College of Medicine and Science Director, Nicotine Dependence Center Mayo Clinic Rochester, Minnesota

Jason J. Heavner, MD Pulmonary & Critical Care Medicine University of Maryland Baltimore Washington Medical Center

Baltimore, Maryland

Sarah H. Heil, PhD Associate Professor with Tenure Vermont Center on Behavior and Health Departments of Psychiatry and Psychological Science University of Vermont Burlington, Vermont

Abigail J. Herron, DO, DFASAM, FAPA Director of Psychiatry, Director of Fellowship in Addiction Medicine The Institute for Family Health Assistant Clinical Professor of Psychiatry and Family Medicine Icahn School of Medicine at Mt. Sinai New York, New York

Stephen T. Higgins, PhD Director, Vermont Center on Behavior and Health Virginia H. Donaldson Professor of Translational Science Departments of Psychiatry and Psychological Science Vice Chair, Department of Psychiatry University of Vermont Burlington, Vermont

Kenneth Hoffman, MD, MPH Colonel (retired) Medical Corps US Army

Kim A. Hoffman, PhD Senior Research Associate OHSU-PSU School of Public Health Portland, Oregon

Matthew Owen Howard, PhD Daniel Distinguished Professor

Associate Dean for Doctoral Education School of Social Work University of North Carolina Chapel Hill, North Carolina

Mark Hrymoc, MD Assistant Clinical Professor Department of Psychiatry and Biobehavioral Sciences University of California, Los Angeles Los Angeles, California

Keith Humphreys, PhD Professor of Psychiatry Stanford University School of Medicine Stanford, California Senior Research Career Scientist Veterans Affairs Health Care System Palo Alto, California

Richard D. Hurt, MD Emeritus Professor of Medicine, College of Medicine Emeritus Director, Nicotine Dependence Center Mayo Clinic Rochester, Minnesota

Ryan T. Hurt, MD, PhD Professor of Medicine Mayo Clinic Rochester, Minnesota

Gwendolyne Anyanate Jack, MD, MPH Department of Endocrinology, Diabetes and Metabolism Department of Medicine Beth Israel Deaconess Medical Center Boston, Massachusetts

Jerome H. Jaffe, MD Friends Research Institute Baltimore, Maryland

Steven L. Jaffe, MD, DFAPA, LFACCAP Professor Emeritus of Psychiatry Emory University School of Medicine Clinical Professor of Psychiatry Morehouse School of Medicine Atlanta, Georgia Clinical Director The Insight Program Roswell, Georgia

Julie K. Johnson, PhD Postdoctoral Fellow Department of Mental Health Johns Hopkins Bloomberg School of Public Health Baltimore, Maryland

Kimberly Johnson, MBA, PhD Associate Professor Louis De La Parte Florida Mental Health Institute Department of Mental Health Law and Policy College of Behavioral and Community Sciences Tampa, Florida

Christopher M. Jones, PharmD, MPH Acting Associate Deputy Assistant Secretary (Science and Data Policy) Office of the Assistant Secretary for Planning and Evaluation U.S. Department of Health and Human Services Washington, District of Columbia

Hendrée E. Jones, PhD Executive Director, UNC Horizons Professor, Department of Obstetrics and Gynecology

Carrboro, North Carolina

Laura M. Juliano, PhD Professor Department of Psychology American University Washington, District of Columbia

Christopher W. Kahler, PhD Professor of Behavioral and Social Sciences Center for Alcohol and Addiction Studies Brown University School of Public Health Providence, Rhode Island

David Kan, MD, DFASAM Associate Clinical Professor University of California, San Francisco Medical Director, Bright Heart Health San Ramon, California Private Practice Walnut Creek, California

Lori D. Karan, MD, FACP, DFASAM Professor of Internal Medicine and Preventive Medicine Loma Linda University School of Medicine & VA Loma Linda Health Care System Loma Linda, California

Jag H. Khalsa, MS, PhD Chief, Medical Consequences Branch Division of Therapeutics and Medical Consequences National Institute on Drug Abuse National Institutes of Health Bethesda, Maryland

Therese K. Killeen, PhD, APRN, BC

Research Professor Department of Psychiatry and Behavioral Sciences Addictions Sciences Division Medical University of South Carolina Charleston, South Carolina

Beau Kilmer, PhD Co-Director, RAND Drug Policy Research Center RAND Corporation San Francisco, California

Jason R. Kilmer, PhD Associate Professor Psychiatry & Behavioral Sciences, School of Medicine Assistant Director of Health & Wellness for Alcohol & Other Drug Education Health & Wellness, Division of Student Life University of Washington Seattle, Washington

Simeon D. Kimmel, MD, MA Infectious Disease and Addiction Fellow Boston Medical Center Boston University School of Medicine Boston, Massachusetts

Drew D. Kiraly, MD, PhD Assistant Professor, Psychiatry & Neuroscience Icahn School of Medicine at Mount Sinai Attending Physician, Psychiatry The Mount Sinai Hospital New York, New York

Barbara M. Kirrane, MD, MPH Medical Toxicology Consultant Department of Emergency Medicine Saint Barnabas Medical Center

Physician Advisor Department of Case Management Saint Barnabas Medical Center Livingston, New Jersey

John R. Knight Jr, MD Associate Professor of Pediatrics Harvard Medical School Director, Center for Adolescent Substance Abuse Research Division of Developmental Medicine Boston Children’s Hospital Boston, Massachusetts

Brian B. Koo, MD Associate Professor of Neurology Yale University School of Medicine New Haven, Connecticut Director, Sleep Laboratory Connecticut Veterans Affairs Health Care Systems West Haven, Connecticut

George F. Koob, PhD Director National Institute on Alcohol Abuse and Alcoholism National Institutes of Health Bethesda, Maryland

Thomas R. Kosten, MD Waggoner Chair and Professor of Psychiatry, Neuroscience, Pharmacology, Immunology & Pathology Director, Dan Duncan Institute for Clinical and Translational Research Baylor College of Medicine, Michael E. DeBakey VAMC Houston, Texas

Walker H. Krepps

Graduate Student, Stem Cell Biology University of Minnesota, Stem Cell Institute Minneapolis, Minnesota

Kevin Kunz, MD, MPH, DFASAM Executive Vice President The Addiction Medicine Foundation Chevy Chase, Maryland

Matthew M. LaCasse, DO Instructor, Department of Psychiatry Western Michigan University–Homer Stryker M.D. School of Medicine Kalamazoo, Michigan

Maritza E. Lagos, MD, DABAM Associate Professor Department of Psychiatry Western Michigan University–Homer Stryker M.D. School of Medicine Kalamazoo, Michigan

Cynthia L. Lancaster, PhD Assistant Professor, Clinical Psychology University of Nevada, Reno Reno, Nevada

Mary E. Larimer, PhD Professor of Psychiatry & Behavioral Sciences and Psychology University of Washington University School of Medicine Director, Center for the Study of Health & Risk Behaviors University of Washington Seattle, Washington

Celine Larkin, PhD Postdoctoral Research Fellow, Department of Emergency Medicine University of Massachusetts Medical School Worcester, Massachusetts

David Y.W. Lee, PhD Associate Professor Harvard Medical School/McLean Hospital Boston, Massachusetts Director Bio-Organic & Natural Products Laboratory McLean Hospital Belmont, Massachusetts

Janet H. Lenard, EdD, LCSW, CCS, CAC II Department of the Army Clinical Program Manager (retired) Army Substance Abuse Program Installation Management Headquarters Command Fort Sam Houston, Texas

Adam M. Leventhal, PhD Associate Professor of Preventive Medicine and Psychology University of Southern California, Keck School of Medicine Director, Health, Emotion, and Addiction Laboratory University of Southern California, Keck School of Medicine Los Angeles, California

Frances R. Levin, MD Kennedy Leavy Professor of Psychiatry at CUMC Columbia University Medical Center New York, New York

Petros Levounis, MD, MA Professor and Chair, Department of Psychiatry Rutgers New Jersey Medical School Chief of Service University Hospital Newark, New Jersey

Aron H. Lichtman, PhD

Professor of Pharmacology and Toxicology and Medicinal Chemistry Associate Dean of Research and Graduate Studies, School of Pharmacy Virginia Commonwealth University Richmond, Virginia

Michael R. Liepman, MD, DFAPA, FASAM† Professor, Psychiatry Addiction Psychiatry Director Department Director of Research Western Michigan University School of Medicine Kalamazoo, Michigan

Ty W. Lostutter, PhD Assistant Professor Center for the Study of Health & Risk Behaviors Department of Psychiatry & Behavioral Sciences University of Washington Director, Psychology Internship Program Department of Psychiatry & Behavioral Sciences University of Washington’s School of Medicine Seattle, Washington

Scott E. Lukas, PhD Professor of Psychiatry (Pharmacology) Harvard Medical School Boston, Massachusetts Director, McLean Imaging Center Director, Behavioral Psychopharmacology Research Laboratory McLean Hospital Belmont, Massachusetts

Brian C. Mac Grory, MB, BCh, BAO, MRCP Staff Neurologist, Rhode Island Hospital Comprehensive Stroke Center Assistant Professor of Neurology Warren Alpert Medical School at Brown University Providence, Rhode Island

Alan Ona Malabanan, MD, CCD, FACE Assistant Professor of Medicine Harvard Medical School Program Director, Endocrinology Fellowship Training Program Beth Israel Deaconess Medical Center Boston, Massachusetts

Robert Malcolm, MD Professor of Psychiatry Family Medicine and Pediatrics Associate Dean for SME Medical University of South Carolina Charleston, South Carolina

Marianne T. Marcus, EdD, RN, FAAN Professor Emerita University of Texas Health Science Center School of Nursing Houston, Texas

John J. Mariani, MD Associate Professor of Clinical Psychiatry Division on Substance Use Disorders Department of Psychiatry Columbia University Medical Center Director, Substance Treatment and Research Service Columbia University Medical Center New York, New York

G. Alan Marlatt, PhD† Professor of Psychology University of Washington Seattle, Washington

Lisa A. Marsch, PhD Director, Center for Technology and Behavioral

Health Professor, Department of Psychiatry Dartmouth Geisel School of Medicine Lebanon, New Hampshire

Suena H. Massey, MD Associate Professor of Psychiatry & Behavioral Sciences and Medical Social Sciences Northwestern University Feinberg School of Medicine Northwestern Memorial Hospital Chicago, Illinois

Elinore F. McCance-Katz, MD, PhD Professor of Psychiatry and Human Behavior Alpert Medical School Brown University Providence, Rhode Island Chief Medical Officer Rhode Island Department of Behavioral Healthcare Developmental Disabilities and Hospitals

John J. McCarthy, MD Associate Professor of Psychiatry University of California Davis School of Medicine Davis, California Volunteer Clinical Faculty

Richard A. McCormick, PhD Senior Scholar Center for Healthcare Research and Policy MetroHealth/Case Western Reserve University Cleveland, Ohio

Barbara S. McCrady, PhD Distinguished Professor of Psychology Director, Center on Alcoholism, Substance Abuse and Addictions

University of New Mexico Albuquerque, New Mexico

David D. McFadden, MD Assistant Professor of Medicine, College of Medicine General Internal Medicine Mayo Clinic Rochester, Minnesota

Mark McGovern, PhD Professor, Department of Psychiatry & Behavioral Sciences and Department of Medicine Stanford University School of Medicine Co-Chief, Division of Public Mental Health and Population Sciences, Department of Psychiatry & Behavioral Sciences Medical Director, Integrated Behavioral Health, Division of Primary Care and Population Health Stanford Health Care Palo Alto, California

A. Thomas McLellan, PhD Professor Emeritus Perelman School of Medicine University of Pennsylvania Philadelphia, Pennsylvania

David Mee-Lee, MD, FASAM President DML Training and Consulting Davis, California

Delinda E. Mercer, PhD, MSCP, MAC Licensed Psychologist Regional West Health Systems Scottsbluff, Nevada

Contributing Faculty, School of Psychology Walden University Minneapolis, Minnesota

Jessica S. Merlin, MD, PhD, MBA Visiting Associate Professor of Medicine Divisions of General Internal Medicine and Infectious Diseases University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania

Lisa J. Merlo, PhD, MPE Associate Professor of Psychiatry University of Florida College of Medicine Gainesville, Florida

Shannon C. Miller, MD, DFAPA, DFASAM Director, Addiction Services VA Medical Center, Cincinnati, Ohio Faculty, Neuroscience Graduate Program Professor of Clinical Psychiatry, Affiliated, University of Cincinnati College of Medicine Past Founding Co-Editor, Journal of Addiction Medicine (2006-2016), American Society of Addiction Medicine Lieutenant Colonel, United States Air Force, Retired

Margaret R. Moon, MD, MPH Associate Professor of Pediatrics Johns Hopkins University, School of Medicine Chief Medical Officer, The Johns Hopkins Children’s Center Core Faculty, The Johns Hopkins Berman Institute of Bioethics Baltimore, Maryland

Hugh Myrick, MD Acting Chief Mental Health Officer VISN 7 ACOS, Mental Health Service Lince Ralph H. Johnson VAMC

Associate Professor of Psychiatry Director, Addiction Sciences Division Director, Military Sciences Division Medical University of South Carolina Charleston, South Carolina

Edgar P. Nace, MD Clinical Professor of Psychiatry University of Texas Southwestern Medical School Dallas, Texas

Eric J. Nestler, MD, PhD Nash Family Professor of Neuroscience Director, Friedman Brain Institute Dean for Academic and Scientific Affairs Icahn School of Medicine at Mount Sinai New York, New York

David E. Nichols, PhD Adjunct Professor of Chemical Biology and Medicinal Chemistry University of North Carolina at Chapel Hill Chapel Hill, North Carolina

Tatjana Novakovic-Agopian, PhD Director Rehabilitation Neuropsychology San Francisco VA Medical Center Assistant Professor of Psychiatry University of California San Francisco School of Medicine San Francisco, California

Edward V. Nunes, MD Professor of Psychiatry Columbia University–New York State Psychiatric Institute New York, New York

Patrick G. O’Connor, MD, MPH

Dan Adams and Amanda Adams Professor of General Medicine Chief, Section of General Internal Medicine Department of Internal Medicine Yale School of Medicine New Haven, Connecticut

Brian L. Odlaug, PhD, MPH Visiting Researcher Faculty of Health & Medical Sciences University of Copenhagen Adjunct Faculty Science & Health Department Danish Institute for Study Abroad (DIS) Copenhagen, Denmark

Dennis E. Orwat, MD Fellow, Addiction Psychiatry Medicine University of South Carolina Charleston, South Carolina

James A.D. Otis, MD, FAAN Associate Professor of Neurology Boston University School of Medicine Director, Pain and Headache Group Boston Medical Center Boston, Massachusetts

Simy K. Parikh, MD Jefferson Headache Center Thomas Jefferson University Philadelphia, Pennsylvania

Theodore V. Parran Jr, MD, FACP, FASAM Isabel and Carter Wang Professor and Chair in Medical Education CWRU School of Medicine Co-Medical Director, Rosary Hall

St. Vincent Charity Medical Center Cleveland, Ohio

Mallie J. Paschall, PhD Senior Research Scientist Prevention Research Center, Pacific Institute for Research and Evaluation Oakland, California

Huned S. Patwa, MD Associate Professor of Neurology Yale University School of Medicine New Haven, Connecticut Chief, Neurology Service VA Connecticut Healthcare System West Haven, Connecticut

David L. Pennington, PhD Assistant Professor, Department of Psychiatry University of California San Francisco Assistant Director, Addiction Research Program San Francisco VA Medical Center San Francisco, California

India Perez-Urbano, BA Study Coordinator Division of General and Internal Medicine Albert Einstein College of Medicine Bronx, New York Founder and Executive Director Rockland Connects, Inc. Nyack, New York

Michael Perloff, MD, PhD Assistant Professor Neurology Department of Neurology and the Pain Management Group

Boston University Medical Center Boston, Massachusetts

Steven Pfau, MD Associate Professor of Medicine Department of Medicine (Cardiology) Yale University School of Medicine New Haven, Connecticut

Karran A. Phillips, MD, MSc Senior Clinician and Clinical Director National Institute on Drug Abuse National Institutes of Health Baltimore, Maryland

Javier Ponce Terashima, MD Adult Psychiatry Resident University Hospitals Cleveland Medical Center– Case Western Reserve University Cleveland, Ohio

Adrian Popescu, MD Assistant Professor of Clinical Physical Medicine and Rehabilitation Department of Physical Medicine and Rehabilitation Assistant Professor of Anesthesiology and Critical Care Perelman School of Medicine University of Pennsylvania Philadelphia, Pennsylvania

Marc N. Potenza, MD, PhD Professor of Psychiatry, Child Study and Neuroscience Yale University School of Medicine Director, Center of Excellence on Gambling Research Director, Women and Addictions Core, Women’s Health Research at Yale Director, Impulsivity and Impulse Control Disorder Research Program Yale University School of Medicine

New Haven, Connecticut

Vladimir Poznyak, MD, PhD Coordinator, Management of Substance Abuse Department of Mental Health and Substance Abuse World Health Organization Geneva, Switzerland

Wesley Prickett, MD Pain Physician/Anesthesiologist U.S. Department of Veterans Affairs Nebraska-Western Iowa Healthcare System Omaha, Nebraska

James O. Prochaska, PhD Professor and Director Cancer Prevention Research Center University of Rhode Island Kingston, Rhode Island

Yelena Gorfinkel Pyatkevich, MD Instructor of Neurology Boston University School of Medicine Boston, Massachusetts

Gary M. Reisfield, MD Associate Professor of Psychiatry University of Florida School of Medicine Gainesville, Florida

Richard K. Ries, MD, FAPA, FASAM Professor of Psychiatry Director Addictions Division Department of Psychiatry and Behavioral Sciences University of Washington School of Medicine Seattle, Washington

Paul J. Rinaldi, PhD Clinical Psychologist Adjunct Assistant Professor of Psychiatry Mount Sinai Icahn School of Medicine New York, New York

David C.S. Roberts, PhD Professor Emeritus, Department of Physiology and Pharmacology Wake Forest School of Medicine Winston-Salem, North Carolina

Richard N. Rosenthal, MA, MD, DFAPA, DFAAAP, FASAM Professor of Psychiatry Director of Addiction Psychiatry Department of Psychiatry Stony Brook University Medical Center Stony Brook, New York

Stephen Ross, MD Associate Professor of Psychiatry & Child and Adolescent Psychiatry NYU Langone Medical Center Bellevue Hospital Center Department of Psychiatry Senior Consultant, Division of Alcoholism & Drug Abuse, Bellevue Hospital Center Senior Consultant, Division of Addiction Psychiatry, NYU Tisch Hospital New York, New York

Stanley Sacks, PhD Senior Research Scientist Emeritus National Development and Research Institutes, Inc. New York, New York

Michael E. Saladin, PhD Professor Department of Health Sciences and Research

College of Health Professions Medical University of South Carolina Charleston, South Carolina

Richard Saitz, MD, MPH, FACP, DFASAM Chairman, Department of Community Health Sciences (CHS) Professor of Community Health Sciences & Medicine Boston University Schools of Public Health and Medicine Clinical Addiction Research and Education (CARE) Unit Section of General Internal Medicine Boston Medical Center Boston, Massachusetts

Robert F. Saltz, PhD Senior Scientist Prevention Research Center Pacific Institute for Research & Evaluation Berkeley, California

Jeffrey H. Samet, MD, MA, MPH Vice Chair for Public Health, Department of Medicine John Noble MD Professor of Medicine and Professor of Community Health Sciences Boston University Schools of Medicine and Public Health Chief, Section of General Internal Medicine Boston Medical Center Boston, Massachusetts

Friedhelm Sandbrink, MD Clinical Associate Professor in Neurology Uniformed Services University Bethesda, Maryland Assistant Clinical Professor of Neurology George Washington University Director, Pain Management Program Department of Neurology Washington VA Medical Center

Washington, District of Columbia

Christine L. Savage, PhD, RN, CARN, FAAN Adjunct Professor Johns Hopkins University School of Nursing Baltimore, Maryland

Andrew J. Saxon, MD Professor and Director Addiction Psychiatry Residency Program Department of Psychiatry & Behavioral Sciences University of Washington Director, Center of Excellence in Substance Abuse Treatment and Education (CESATE) Seattle, Washington

Emmanuelle A.D. Schindler, MD, PhD Veterans Affairs Special Fellow, Neurosciences Veterans Affairs Connecticut Healthcare System West Haven, Connecticut Clinical Instructor, Neurology Yale School of Medicine New Haven, Connecticut

Simone H. Schriger, BA Center for Behavioral & Addiction Medicine Department of Family Medicine University of California, Los Angeles Los Angeles, California

Frank J. Schwebel, MS Graduate Student, Department of Psychology University of Washington Seattle, Washington

Mark F. Seltzer Esq

Founder Seltzer and Associates, P.C. Philadelphia, Pennsylvania

Samit Shah, MD, PhD Clinical Fellow in Cardiovascular Disease Yale University School of Medicine New Haven, Connecticut

Steven Shoptaw, PhD Vice Chair and Professor, Family Medicine Professor, Psychiatry and Biobehavioral Sciences David Geffen School of Medicine University of California, Los Angeles Director, Center for Behavioral and Addiction Medicine Director, Center for HIV Identification, Prevention and Treatment Services University of California, Los Angeles Los Angeles, California

Daryl Shorter, MD Director of Residency Education Assistant Professor Menninger Department of Psychiatry and Behavioral Sciences Staff Psychiatrist Michael E. DeBakey VA Medical Center Houston, Texas

Gerald D. Shulman, MA, MAC, FACATA Trainer & Consultant Shulman & Associates Training and in Behavioral Health Jacksonville, Florida

Jason J. Sico, MD, MHS, FAHA, FACP Director, Stroke Care VA Connecticut Healthcare System

Assistant Professor, Departments of Neurology and Internal Medicine (General Medicine) Yale University School of Medicine New Haven, Connecticut

Deborah R. Simkin, MD Adjunct Assistant Professor Emory School of Medicine Atlanta, Georgia

Girish Singhania, MBBS Assistant Professor of Medicine Division of Nephrology & Hypertension University of Utah Salt Lake City, Utah

David Smelson, PsyD Professor and Vice Chair Department of Psychiatry University of Massachusetts Medical School Worcester, Massachusetts Director, Translational Research Bedford VA Medical Center Bedford, Massachusetts

Tricia H. Smith, PhD Faculty Instructor Department of Biology Virginia Commonwealth University Richmond, Virginia

Ramon Solhkhah, MD Founding Chairman, Department of Psychiatry & Behavioral Health Professor of Psychiatry & Behavioral Health and Pediatrics Hackensack Meridian School of Medicine at Seton Hall University Nutley, New Jersey

Chairman, Department of Psychiatry Jersey Shore University Medical Center Neptune, New Jersey

Sharon Stancliff, MD, FAAFP, FASAM Medical Director Harm Reduction Coalition New York, New York

Steven P. Stanos, DO Pain Medicine Specialist & Physiatrist Medical Director, Swedish Pain Services Swedish Health System President American Academy of Pain Medicine Seattle, Washington

Joanna L. Starrels, MD, MS Associate Professor of Medicine Albert Einstein College of Medicine and Montefiore Medical Center Bronx, New York

Gideon St. Helen, PhD Assistant Professor Division of Clinical Pharmacology Department of Medicine University of California, San Francisco San Francisco, California

Randy Stinchfield, PhD Department of Psychiatry University of Minnesota Medical School Minneapolis, Minnesota

Susan M. Stine, MD, PhD Professor Emeritus

Department of Psychiatry and Behavioral Neurosciences Wayne State University School of Medicine Detroit, Michigan

Susan A. Storti, PhD, RN, NEA-BC, CARN-AP Administrator of Health Homes and Mental Health Policy Substance Use and Mental Health Leadership Council of RI Warwick, Rhode Island

Geetha A. Subramaniam, MD, DFAPA, DFAACAP Deputy Director Center for Clinical Trials Network National Institute on Drug Abuse Bethesda, Maryland

Carol A. Sulis, MD Associate Professor of Medicine Boston University School of Medicine Medical Director, Infection Control and Hospital Epidemiology Boston Medical Center Boston, Massachusetts

Mary M. Sweeney, PhD Department of Psychiatry and Behavioral Sciences Johns Hopkins University School of Medicine Baltimore, Maryland

Zebulon Charles Taintor, MD Adjunct Professor of Psychiatry New York University School of Medicine New York, New York

Jenni Teeters, MS Clinical Psychology Doctoral Candidate University of Memphis

Memphis, Tennessee

Jeanette M. Tetrault, MD, FACP Associate Professor of Medicine Department of Internal Medicine Yale University School of Medicine New Haven, Connecticut

Federico E. Vaca, MD, MPH Professor and Vice Chair Department of Emergency Medicine Yale University, School of Medicine New Haven, Connecticut

Frank Vocci, PhD President and Senior Research Scientist Friends Research Institute, Inc. Baltimore, Maryland

Nora D. Volkow, MD Director National Institute on Drug Abuse National Institutes of Health Bethesda, Maryland

Darren C. Volpe, MD Assistant Professor of Neurology Yale University School of Medicine New Haven, Connecticut

Alexander Y. Walley, MD, MSc Associate Professor of Medicine Director, Addiction Medicine Fellowship Clinical Addiction Research and Education Unit Boston Medical Center/Boston University School of Medicine Boston, Massachusetts

Eric M. Wargo, PhD Office of Science Policy and Communication, Science Policy Branch National Institute on Drug Abuse National Institutes of Health Bethesda, Maryland

Elizabeth A. Warner, MD Clinical Associate Professor Department of Internal Medicine University of South Florida Morsani College of Medicine Tampa, Florida

Alan A. Wartenberg, MD, FACP, DFASAM Affiliated Faculty Brown University Center for Alcohol and Addiction Studies Providence, Rhode Island

Michael F. Weaver, MD, DFASAM Professor of Psychiatry and Behavioral Science McGovern Medical School University of Texas Health Science Center at Houston Medical Director, Center for Neurobehavioral Research on Addiction University of Texas Health Science Center at Houston Houston, Texas

Julia Megan Webb, MD Pain Medicine Fellowship Graduate Department of Anesthesiology and Pain Medicine University of California Davis Sacramento, California

Zoe M. Weinstein, MD, MS Assistant Professor of Medicine

Boston University School of Medicine Director, Addiction Consult Service Boston Medical Center Boston, Massachusetts

Roger D. Weiss, MD Professor of Psychiatry Harvard Medical School Chief, Division of Alcohol and Drug Abuse McLean Hospital Belmont, Massachusetts

Arthur F. Weissman, MD Clinical Assistant Professor Addiction Medicine Department of Family Medicine University at Buffalo Buffalo, New York

Sandra P. Welch, PhD Professor, Department of Pharmacology and Toxicology Virginia Commonwealth University Richmond, Virginia

Joseph Westermeyer, MD, MPH, PhD Professor of Psychiatry, Adjunct Professor of Anthropology University of Minnesota Staff Psychiatrist Addiction Recovery Service Minneapolis, Minnesota

Norman W. Wetterau, MD, FAAFP, DFASAM Clinical Associate Professor of Family Medicine University of Rochester School of Medicine Rochester, New York

Physician Tri-county Family Medicine Nunda, New York

William L. White, MA Emeritus Senior Research Consultant Chestnut Health Systems Punta Gorda, Florida

Ursula Whiteside, PhD Clinical Faculty, Department of Psychiatry and Behavioral Sciences University of Washington Medical Center Seattle, Washington

Bonnie B. Wilford, MS Executive Vice President Coalition on Physician Education in Substance Use Disorders (COPE) Easton, Maryland

Jeffery N. Wilkins, MD, DFAPA, DFASAM Lincy/Heyward-Moynihan Endowed Chair in Addiction Medicine Department of Psychiatry and Behavioral Neurosciences Cedars-Sinai Medical Center Los Angeles, California

Mark Willenbring, MD CEO and Founder Alltyr Clinics Saint Paul, Minnesota

Emily C. Williams, PhD, MPH Investigator, Center of Innovation for Veteran-Centered and Value-Driven Care Veterans Affairs, Health Services Research & Development Associate Professor, Department of Health Services University of Washington Seattle, Washington

Ken C. Winters, PhD Senior Scientist, Oregon Research Institute Adjunct Faculty, Department of Psychology University of Minnesota Falcon Heights, Minnesota

John J. Woodward, BS, MS, PhD Professor Department of Neuroscience Department of Psychiatry & Behavioral Sciences Medical University of South Carolina Charleston, South Carolina

Tara M. Wright, MD Assistant Professor of Psychiatry Addiction Psychiatry Fellowship Director Medical University of South Carolina Assistant Chief Mental Health Service Line Ralph H. Johnson VAMC Charleston, South Carolina

Martha J. Wunsch, MD Chief of Addiction Medicine Fellowship Director, Addiction Medicine Kaiser Permanente, GSAA, Northern California Union City, California

Stephen A. Wyatt, DO Professor of Psychiatry Carolinas HealthCare System Medical Director, Addiction Medicine Atrium Health Charlotte, North Carolina

Yvonne H.C. Yau, MSc Montreal Neurological Institute

McGill University Montreal, Quebec, Canada

Elmira Yessengaliyeva, MD Assistant Professor of Psychiatry Western Michigan University–Homer Stryker M.D. School of Medicine Kalamazoo, Michigan

Sarah W. Yip, MSc, PhD Assistant Professor Department of Psychiatry Yale School of Medicine New Haven, Connecticut

Christine Yuodelis-Flores, MD, FAPA, FASAM Associate Professor Department of Psychiatry and Behavioral Sciences University of Washington Harborview Medical Center Seattle, Washington

Anne Zajicek, MD, PharmD, FAAP Deputy Director, Office of Clinical Research Office of the Director National Institutes of Health Bethesda, Maryland

Aleksandra E. Zgierska, MD, PhD Assistant Professor Department of Family Medicine and Community Health University of Wisconsin-Madison, School of Medicine and Public Health Madison, Wisconsin

Douglas Ziedonis, MD, MPH Associate Vice Chancellor for Health Sciences Professor of Psychiatry

University of California San Diego San Diego, California

Joan E. Zweben, PhD Health Sciences Clinical Professor of Psychiatry University of California, San Francisco Staff Psychologist VA Medical Center San Francisco, California † Deceased

Preface

Welcome to the sixth edition of Principles of Addiction Medicine. Our goal, as with previous editions of Principles, is to provide a reference text that reflects the state of the art in the science and practice of addiction medicine. This goal is supported through the textbook’s link to the American Society of Addiction Medicine (ASAM), the world’s largest addiction medicine professional association, and through the involvement of the world’s leading researchers and experts in our field. This edition of Principles is being released soon after the American Board of Medical Specialties has formally recognized addiction medicine as a medical specialty, more than half a century after the formation of the American Society of Addiction Medicine. The text is organized pyramidally under senior editor, coeditors, section editors, and authors. As in previous editions, a new coeditor has joined the editorial team. Richard Rosenthal provides his strengths in psychiatry and cooccurring psychiatric disorders, behavioral and 12-step approaches, and collaborative team-based care for addiction-related disorders. He returns to the textbook after previous service as a section editor. Both Richard Saitz, MD, and David Fiellin, MD, return as coeditors (having previously served as such in the fourth and fifth editions) and provide cornerstones to our links to patientoriented research, screening and brief intervention, and the management of opioid use disorders, while sharing their wide-ranging expertise in internal medicine and primary care. Dr. Saitz also serves as senior editor of ASAM’s peer-reviewed medical journal, Journal of Addiction Medicine (JAM). Shannon Miller, MD, returns from the fourth and fifth editions where he served as coeditor, and now serves as senior editor of this sixth edition of Principles. He provides strengths in psychiatry and neuroscience, and his editorial link as a founding coeditor of ASAM’s peer-reviewed medical journal, JAM. The editors have updated, deleted, added, and moved chapters to provide more coherence and completeness to the textbook experience, with updates to all chapters and substantial revisions of most. Importantly, this edition has aimed to incorporate DSM-5 language throughout its chapters, while attempting to preserve linkages to previous DSM editions. To maintain Principles as a

reference textbook that remains current and relevant to readership as our field rapidly expands in breadth and depth, a substantial number of new chapters have been added with this sixth edition; several of which are first-time appearances for these topics within any addiction-related textbook. Kevin Kunz, MD, leads Section 1, “Basic Science and Core Concepts.” The opening chapter, “Drug Addiction: The Neurobiology of Behavior Gone Awry,” is written by Nora Volkow, MD, and George Koob, PhD, directors of the National Institute on Drug Abuse (NIDA) and the National Institute on Alcohol Abuse and Alcoholism (NIAAA), respectively. In addition to orienting the reader to basic principles in neurobiology and epidemiology of addiction, important new chapters have been added on recommended use of terminology in the field of addiction medicine (Chapter 2), understanding research in addictionrelated clinical trials (Chapter 6), and the addiction medicine physician as a change agent toward public health (Chapter 7). Thomas Kosten, MD, leads Section 2 on pharmacology along with David Gorelick, MD, PhD, John Dani, PhD, and Daryl Shorter, MD. This team has worked to better elucidate the clinical relevance of this section’s content to readers. Expansion into increasingly important topics such as electronic recreational drug delivery vehicles such as e-cigarettes (Chapter 20), synthetic cannabis (Chapter 15), and dextromethorphan (Chapter 17) have been incorporated; and the chapter on newly emerging recreational drugs has been enriched (Chapter 21). Section 3, Diagnosis, Assessment, and Early Intervention, is led by Theodore Parran Jr, MD, and features expanded material on screening and brief interventions in a variety of settings, laboratory testing, assessment, and community-based prevention. Wilson Compton, MD, MPE, from NIDA and Lori Ducharme, PhD, from NIAAA lead Section 4 on Overview of Addiction Treatment. The section includes chapters on historical and international perspectives on addiction treatment with contributions from individuals affiliated with the United Nations Office of Drug Control, the World Health Organization and the ASAM’s international companion, the International Society of Addiction Medicine. Issues such as treatment matching, integrated care, and quality improvement are addressed. In addition, Chapter 33 on harm reduction includes pivotal content on opioid overdose education and naloxone distribution—significantly expanded in parallel with this national crisis. In Section 5, “Special Issues in Addiction Medicine,” led by Joan Zweben,

PhD, Peter Banys, MD, MSc, and John Grant, MD, JD, MPH, places an increased focus on nonsubstance addictions as a collective whole, while still maintaining focus on special populations such as older adults, women, college students, impaired providers, and cultural issues. Military-relevant new chapters have been added on traumatic brain injury (Chapter 39) and military sexual trauma (Chapter 40). Chapter 45 covering gambling disorder has been significantly updated to reflect the acceptance of this disorder as an addiction disorder in DSM-5. A new chapter on microprocessor-based disorders (Chapter 47) include the latest neuroimaging and neuropsychological findings supporting the Internet gaming disorder diagnosis. Adam Gordon, MD, and Andrew Saxon, MD, continue as the section editors of Sections 6 and 7, respectively. The management and pharmacologic treatment chapters in these sections have all been fully updated to include the most current information. Section 6 includes discussion of not only FDA-approved pharmacotherapies (such as buprenorphine and intramuscular naltrexone for opioid use disorder) but also off-label uses of pharmacotherapies for addictionrelated disorders. Section 7 includes a novel chapter on neuromodulation as a treatment approach to addiction disorders (Chapter 62), including transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). Richard Rosenthal, MD, leads Section 8 on psychologically based interventions. The section incorporates the latest research in behavioral therapies and adds a new chapter on digital health interventions for substance use disorders (Chapter 74). Richard Ries, MD, leads Section 9 on mutual help and 12-step recovery programs with chapters on process and research evidence and contributes a chapter on spirituality and recovery. Section 10 is led by Jeanette Tetrault, MD, along with Patrick O’Connor, MD, MPH, and includes fully updated content to include the latest research about medical disorders and complications of addiction. This includes important updates to the treatment of medical consequences of addiction, such as hepatitis C and HIV; as well as approaches to the pregnant patient. Section 11, led by R. Jeffrey Goldsmith, MD, and Christine Yuodelis-Flores, MD, includes updated chapters on co-occurring addiction and mood, anxiety, psychotic, personality, eating, and substance-induced disorders, respectively, as well as ADHD and PTSD. Section 12 maintains the support from Seddon Savage, MD, from past editions but is now led by Rollin Gallagher, MD, along with William Becker,

MD, and Martin Cheatle, PhD, all of whom have also contributed chapters to the section. The biopsychosocial intersections between pain and addiction are explored in a comprehensive and cohesive manner. Legal and regulatory issues in opioid prescribing are also addressed for the reader. Deborah Simkin, MD, John Knight, MD, and Wes Boyd, MD, lead Section 13 on children and adolescents. This section has been interwoven with content in other sections relating to subject matter on addiction-related issues in children and adolescents. Relevant to today’s policy-making climate, the impact of cannabis legalization and cannabis as medicine on youth are presented (Sidebar to Chapter 107). Bonnie Wilford, MS, Robert DuPont, MD, and Timothy Koehler Brennan, MD, MPH, lead Section 14, “Ethical, Legal, and Liability Issues in Addiction Practice,” which features an opening chapter by Timothy Brennan, MD, MPH, and H. Westley Clark, MD, JD, former Director of the Center for Substance Abuse Treatment under the Substance Abuse and Mental Health Services Administration (Chapter 115), and a new chapter on cannabis use in medical settings (Chapter 118).

A Note About Terminology The editors of Principles of Addiction Medicine recognize that addiction is a medical condition with its own terminology used by not only clinicians and researchers but also patients, policy makers, the press, families, and other stakeholders. There are certain key terms that can have several meanings and, often unintended, effects. Most importantly, such terms can further the stigma about people and patients with addiction disorders. The terms “alcoholic” and “addict” are examples of such terms—they can be used by health care workers in a pejorative manner to label a problem medical patient, by family to label a member’s violent and irresponsible behavior, by persons with a substance use disorder attending 12-step meetings as a positive label defining themselves as actively participating in recovery, by the general public to define anybody “who drinks too much” or “is a drug user,” and by addiction professionals to indicate a patient’s substance use disorder. Pejorative terms can erode the motivation of people affected by these disorders to come forward for help from family, friends, or professionals. Inaccurate terms can cause confusion and lead to unclear research results, difficulty translating such results into practice, and inappropriate clinical care. Furthermore, inappropriate and imprecise terms can dehumanize patients as well as undermine and erode efforts toward scientifically informed and ethically appropriate public policy or legislation, including funding for research, treatment, or graduate medical education. However, we must confess that consensus definitions of the many terms in addiction medicine have not yet been reached. As such, ASAM has commissioned The Descriptive and Diagnostic Terminology Action Group to continue to address these issues. This group has identified a number of terms that have the potential to be inaccurate or even stigmatizing. In this sixth edition of Principles, we are attempting to avoid such terms, in particular those that can be stigmatizing, and instead use more medically appropriate and less stigmatizing terms. This is among the first textbooks in the field to embark more formally upon this aim, including dedicating a chapter to introduce this issue (Chapter 2). Addiction medicine is shaped by constantly evolving science and practical clinical experience. It is our sincere hope that this book will embody the best of what both of these can offer to clinicians as we work to serve our patients and

society.

Acknowledgments

The editors wish to thank the American Society of Addiction Medicine (ASAM) for the opportunity to work on this textbook. Our section editors and authors generously lent their time and expertise. Chris Teja and Rebecca Gaertner at Lippincott Williams & Wilkins helped bring the project to fruition. Yemsrach Kidane, MA, Manager of Quality and Science at ASAM skillfully nurtured most every aspect of this textbook from beginning to end; and under the sage stewardship and tireless advocacy of Brendan McEntee, Director of Quality and Science at ASAM. Finally, we wish to acknowledge the contributions of the editors of previous editions of Principles of Addiction Medicine; with enduring respect and recognition Norman S. Miller, MD; Martin C. Doot, MD; Bonnie B. Wilford, MS; Allan W. Graham, MD, FACP; Terry K. Schultz, MD; Michael F. Mayo-Smith, MD, MPH; and Richard K. Ries, MD.

Contents

Section Editors Contributors Preface A Note About Terminology Acknowledgments

SECTION 1 Basic Science and Core Concepts 1 Drug Addiction: The Neurobiology of Motivation Gone Awry Nora D. Volkow and George F. Koob

2 Recommended Use of Terminology in Addiction Medicine Richard Saitz, Shannon C. Miller, David A. Fiellin, and Richard N. Rosenthal

3 The Epidemiology of Substance Use Disorders Rosa M. Crum

4 The Anatomy of Addiction Thomas J.R. Beveridge, Colleen A. Hanlon, and David C.S. Roberts

5 From Neurobiology to Treatment: Progress against Addiction Drew D. Kiraly and Eric J. Nestler

6 Clinical Trials in Substance-Using Populations Frank Vocci

7 The Addiction Medicine Physician as a Change Agent for Prevention and Public Health

Kevin Kunz

SECTION 2 Pharmacology 8 Pharmacokinetic, Pharmacodynamic, Pharmacogenomic Principles Anne Zajicek and Lori D. Karan

9 The Pharmacology of Alcohol John J. Woodward

10 The Pharmacology of Nonalcohol Sedative Hypnotics Carolina L. Haass-Koffler and Elinore F. McCance-Katz

11 The Pharmacology of Opioids Daryl Shorter and Thomas R. Kosten

12 The Pharmacology of Stimulants David A. Gorelick and Michael H. Baumann

13 The Pharmacology of Caffeine Mary M. Sweeney, Laura M. Juliano, Sergi Ferré, and Roland R. Griffiths

14 The Pharmacology of Nicotine and Tobacco John A. Dani, Thomas R. Kosten, and Neal L. Benowitz

15 The Pharmacology of Cannabinoids Sandra P. Welch, Tricia H. Smith, Robert Malcolm, and Aron H. Lichtman

16 The Pharmacology of Hallucinogens Michael P. Bogenschutz and David E. Nichols

17 The Pharmacology of Dissociatives Edward F. Domino and Shannon C. Miller

18 The Pharmacology of Inhalants Robert L. Balster

19 The Pharmacology of Anabolic–Androgenic Steroids Scott E. Lukas

20 Electronic Cigarettes

and

Gideon St.Helen and Neal L. Benowitz

21 Novel Psychoactive Substances: Pharmacology, and Treatment

Their

Recognition,

Kathryn Hawk, Barbara M. Kirrane, and Gail D’Onofrio

SECTION 3 Diagnosis, Assessment, and Early Intervention 22 Screening and Brief Intervention Suena H. Massey, Nicole A. Hayes, Michael F. Fleming, and Aleksandra E. Zgierska SIDEBAR: Screening and Brief Intervention for Pregnant Women Nicolas Bertholet and Richard Saitz SIDEBAR: Trauma Centers, Hospitals, and Emergency Departments Arthur F. Weissman and Richard D. Blondell SIDEBAR: Implementation of Screening and Brief Intervention (SBI) in Clinical Settings Using Quality Improvement Principles Emily C. Williams and Katharine A. Bradley SIDEBAR: Screening for Unhealthy Alcohol Use in the Elderly James W. Campbell

23 Laboratory Assessment Jessica S. Merlin, Elizabeth A. Warner, and Joanna L. Starrels

24 Assessment Theodore V. Parran Jr, Mark Bondeson, Richard A. McCormick, and Christina M. Delos Reyes

25 Environmental Approaches to Prevention: Communities and Contexts Paul J. Gruenewald, Joel W. Grube, Robert F. Saltz, and Mallie J. Paschall

SECTION 4 Overview of Addiction Treatment 26 Addiction Medicine in America: Its Birth, Early History, and Current Status (1750-2018) Kevin Kunz and William L. White

27 Treatment of Unhealthy Alcohol Use: An Overview

Mark Willenbring and Brian Grahan

28 The Treatment of Addiction: An Overview Andrea G. Barthwell, Lawrence S. Brown Jr and Megan E. Crants

29 Integrated Care for Substance Use Disorder Keith Humphreys, Mark McGovern and A. Thomas McLellan

30 The ASAM Criteria and Matching Patients to Treatment David Mee-Lee and Gerald D. Shulman

31 Linking Addiction Treatment With Other Medical and Psychiatric Treatment Systems Karran A.Phillips, Peter D. Friedmann, Richard Saitz, and Jeffrey H. Samet

32 Alternative Therapies for Substance Use Disorders David Y.W. Lee

33 Harm Reduction, Overdose Prevention, and Addiction Medicine Alexander Y. Walley, Sharon Stancliff, and India Perez-Urbano

34 Quality Improvement for Addiction Treatment James H. Ford II, Kim A. Hoffman, Kimberly Johnson, and Javier Ponce Terashima

35 Nursing Roles in Addressing Addiction Deborah S. Finnell, Marianne T. Marcus, and Christine L. Savage

36 International Perspectives on Addiction Management Nady el-Guebaly, Vladimir Poznyak, and Gilberto Gerra

SECTION 5 Special Issues in Addiction 37 Prescription Medications: Nonmedical Use, Use Disorders, and Public Health Consequences Wilson M. Compton, Christopher M. Jones, Maureen P. Boyle, and Eric M. Wargo

38 Special Issues in Treatment: Women Joan E. Zweben

39 Traumatic Brain Injury and Substance Use Disorders David L. Pennington, Tatjana Novakovic-Agopian, and Steven L. Batki

40 Military Sexual Trauma Joan E. Zweben

41 Alcohol, Prescription, and Other Drug Problems in Older Adults Frederic C. Blow and Kristen L. Barry

42 Cultural Issues in Addiction Medicine Joseph Westermeyer and Patricia Jean Dickmann

43 College Student Drinking Frank J. Schwebel, Ursula Whiteside, Joyce N. Bittinger, Jason R. Kilmer, Ty W. Lostutter, and Mary E. Larimer

44 Understanding “Behavioral Addiction” Yvonne H.C. Yau, Sarah W. Yip, and Marc N. Potenza

45 Gambling Disorder: Clinical Characteristics and Treatment Jon E. Grant and Brian L. Odlaug

46 Problematic Sexual Behaviors and “Sexual Addiction” Timothy M. Hall, Simone H. Schriger, and Steven Shoptaw

47 Microprocessor-Based Disorders Richard N. Rosenthal, Zebulon Charles Taintor, and Jon E. Grant

48 Behavioral Syndromes to Consider as Forms of “Addiction” Abigail J. Herron, Paul J. Rinaldi, and Petros Levounis

49 Physician Health Programs and Addiction Among Physicians Paul H. Earley

SECTION 6 Management of Intoxication and Withdrawal 50 Management of Intoxication and Withdrawal: General Principles Tara M. Wright, Jeffrey S. Cluver, and Hugh Myrick

51 Management of Alcohol Intoxication and Withdrawal Alan A. Wartenberg

52 Management of Sedative–Hypnotic Intoxication and Withdrawal Steven J. Eickelberg, William E. Dickinson, and Reham A. Attia

53 Management of Opioid Intoxication and Withdrawal Jeanette M. Tetrault and Patrick G. O’Connor

54 Management of Stimulant, Hallucinogen, Marijuana, Phencyclidine, and Club Drug Intoxication and Withdrawal Jeffery N. Wilkins, Itai Danovitch, and David A. Gorelick

SECTION 7 Pharmacological Interventions and Other Somatic Therapies 55 Pharmacological Interventions for Alcohol Use Disorder Hugh Myrick, Andrew J. Saxon, and Jerome H. Jaffe

56 Pharmacological Interventions for Sedative–Hypnotic Use Disorder Jeffrey S. Cluver, Tara M. Wright, and Hugh Myrick

57 Pharmacological and Psychosocial Treatment for Opioid Use Disorder David Kan, Joan E. Zweben, Susan M. Stine, Thomas R. Kosten, Elinore F. McCance-Katz, and John J. McCarthy

58 Special Issues in Office-Based Opioid Treatment Andrew J. Saxon

59 Pharmacological Treatment of Stimulant Use Disorders David A. Gorelick

60 Pharmacological Interventions for Tobacco Use Disorder Jon O. Ebbert, J. Taylor Hays, David D. McFadden, Ryan T. Hurt, and Richard D. Hurt

61 Pharmacological Interventions for Other Drugs and Multiple Drug Use Disorders Jeffery N. Wilkins, Mark Hrymoc, and David A. Gorelick

62 Neuromodulation for Addiction-Related Disorders David A. Gorelick

SECTION 8 Psychologically Based Interventions 63 Enhancing Motivation to Change James O. Prochaska

64 Group Therapies Dennis C. Daley, Antoine Douaihy, Roger D. Weiss, and Delinda E. Mercer

65 Individual Treatment Deborah L. Haller and Edward V. Nunes

66 Contingency Management Reinforcement Approach

and

the

Community

Sarah H. Heil, Danielle R. Davis, Christopher A. Arger, and Stephen T. Higgins

67 Behavioral Interventions for Nicotine/Tobacco Use Disorder Erika Litvin Bloom, Christopher W. Kahler, Adam M. Leventhal, and Richard A. Brown

68 Network Therapy Marc Galanter and Helen Dermatis

69 Therapeutic Communities and Modified Therapeutic Communities for Co-Occurring Mental and Substance Use Disorders George De Leon and Stanley Sacks

70 Aversion Therapies P. Joseph Frawley, Matthew Owen Howard, Ralph L. Elkins, and Kalyan Dandala

71 Family Involvement in Addiction, Treatment, and Recovery Kathleen A. Gross, Maritza E. Lagos, Elmira Yessengaliyeva, Matthew M. LaCasse, and Michael R. Liepman (deceased)

72 Twelve-Step Facilitation Approaches Kathleen M. Carroll

73 Relapse Prevention: Clinical Models and Intervention Strategies Antoine Douaihy, Dennis C. Daley, G. Alan Marlatt, and Dennis M. Donovan

74 Digital Health Interventions for Substance Use Disorders:

The State of the Science Lisa A. Marsch and Jacob T. Borodovsky

75 Medical Management Techniques and Collaborative Care: Integrating Behavioral with Pharmacological Interventions in Addiction Treatment Richard N. Rosenthal, Richard K. Ries, and Joan E. Zweben

SECTION 9 Mutual Help, Twelve-Step, and Other Recovery Programs 76 Twelve-Step Programs in Addiction Recovery Edgar P. Nace

77 Recent Research into Twelve-Step Programs Barbara S. McCrady

78 Spirituality in the Recovery Process Marc Galanter

SECTION 10 Medical Disorders and Complications of Addiction 79 Medical and Surgical Complications of Addiction Richard Saitz

80 Cardiovascular Consequences of Alcohol and Other Drug Use Steven Pfau and Samit Shah

81 Liver Disorders Related to Alcohol and Other Drug Use Paul S. Haber and Carl H. Freyer

82 Renal and Metabolic Disorders Related to Alcohol and Other Drug Use Laith Al-Rabadi, Catreena Al Marj, Girish Singhania, A. Ahsan Ejaz, and Stanley D. Crittenden

83 Gastrointestinal Disorders Related to Alcohol and Other Drug Use Paul S. Haber and Praveen Gounder

84 Respiratory Tract Disorders and Selected Critical Care Considerations Related to Alcohol and Other Drug Use Drew A. Harris, Jason J. Heavner, and Kathleen M. Akgün

85 Neurological Disorders Related to Alcohol and Other Drug Use Emmanuelle A.D. Schindler, Monica M. Diaz, Brian C. Mac Grory, Brian B. Koo, Darren C. Volpe, Hamada Hamid Altalib, Huned S. Patwa, and Jason J. Sico

86 Human Immunodeficiency Virus, Tuberculosis, and Other Infectious Diseases Related to Alcohol and Other Drug Use Carol A. Sulis and Simeon D. Kimmel

87 Sleep Disorders Related to Alcohol and Other Drug Use Sanford Auerbach and Yelena Gorfinkel Pyatkevich

88 Traumatic Injuries Related to Alcohol and Other Drug Use: Epidemiology, Screening, and Prevention Federico E. Vaca, Deepa Camenga, and Gail D’Onofrio

89 Endocrine and Reproductive Disorders Related to Alcohol and Other Drug Use Alan Ona Malabanan and Gwendolyne Anyanate Jack

90 Alcohol and Other Drug Use during Pregnancy: Management of the Mother and Child Michael F. Weaver, Hendrée E. Jones, and Martha J. Wunsch

91 Perioperative Management of Patients with Alcohol- or Other Drug Use Daniel P. Alford and Zoe M. Weinstein

SECTION 11 Co-Occurring Addiction and Psychiatric Disorders 92 Substance-Induced Mental Disorders Christine Yuodelis-Flores, R. Jeffrey Goldsmith, and Richard K. Ries

93 Co-occurring Mood and Substance Use Disorders Edward V. Nunes and Roger D. Weiss

94 Co-Occurring Substance Use and Anxiety Disorders Karen J. Hartwell, Dennis E. Orwat, and Kathleen T. Brady

95 Co-Occurring Addiction and Psychotic Disorders Douglas Ziedonis, Xiaoduo Fan, Celine Larkin, Stephen A. Wyatt, and David Smelson

96 Co-occurring Substance Use Disorder and Attention Deficit Hyperactivity Disorder Frances R. Levin and John J. Mariani

97 Co-occurring Personality Disorders and Addiction Stephen Ross and Adam R. Demner

98 Posttraumatic Stress Disorder and Substance Use Disorder Comorbidity Michael Saladin, Jenni Teeters, Daniel F. Gros, Amanda K. Gilmore, Kevin M. Gray, Emma Louise Barrett, Cynthia L. Lancaster, Therese Killeen, and Sudie Back

99 Co-occurring Substance Use Disorders and Eating Disorders Lisa J. Merlo and Mark S. Gold

SECTION 12 Pain and Addiction 100 The Pathophysiology of Chronic Pain and Clinical Interfaces With Substance Use Disorder Rollin M. Gallagher, Peggy Compton, and Adrian Popescu

101 Psychological Issues in the Management of Pain Martin D. Cheatle

102 Rehabilitation Approaches to Pain Management Steven P. Stanos and Randy L. Calisoff

103 Nonopioid Pharmacotherapy of Pain Simy K. Parikh, Michael Perloff, and James A.D. Otis

104 Opioid Therapy of Pain Peggy Compton and Friedhelm Sandbrink

105 Co-Occurring Pain and Addiction

William C. Becker and Declan T. Barry

106 Legal and Regulatory Considerations in Opioid Prescribing Julia Megan Webb, David J. Copenhaver, Wesley Prickett, and Scott M. Fishman

SECTION 13 Children and Adolescents 107 Preventing Substance Use Among Children and Adolescents Kenneth W. Griffin and Gilbert J. Botvin SIDEBAR: Governmental Policy on Cannabis Legalization and Cannabis as Medicine: Impact on Youth Sion Kim Harris, Julie K. Johnson, and John R. Knight Jr

108 Translational Neurobiology Developmental Perspective

of

Addiction

from

a

Deborah R. Simkin

109 Screening and Brief Intervention for Adolescents Traci L. Brooks, John R. Knight Jr, and Sion Kim Harris

110 Assessing Adolescent Substance Use Ken C. Winters, Andria M. Botzet, Randy Stinchfield, and Walker H. Krepps

111 Placement Criteria and Strategies for Adolescent Treatment Matching Marc Fishman SIDEBAR: Confidentiality in Dealing with Adolescents Margaret R. Moon SIDEBAR: Drug Testing Adolescents in School J. Wesley Boyd and John R. Knight Jr

112 Adolescent Treatment and Relapse Prevention Steven L. Jaffe and Ashraf Attalla

113 Pharmacotherapies for Adolescents with Substance Use Disorders Geetha A. Subramaniam and Kevin M. Gray

114 Co-occurring Psychiatric Disorders in Adolescents Ramon Solhkhah and Muhammad A. Abbas

SECTION 14 Ethical, Legal, and Liability Issues in Addiction Practice 115 Ethical Issues in Addiction Practice Timothy K. Brennan and H. Westley Clark

116 Consent and Confidentiality Issues in Addiction Practice Louis E. Baxter Sr, Mark F. Seltzer Esq, and Bonnie B. Wilford

117 Clinical, Ethical, and Legal Considerations in Prescribing Drugs With Potential for Nonmedical Use and Addiction Theodore V. Parran Jr, James W. Finch, and Bonnie B. Wilford SIDEBAR: Drug Control Policy: History and Future Directions John J. Coleman and Robert L. DuPont SIDEBAR: Guidance on the Use of Opioids to Treat Chronic Pain James W. Finch and Bonnie B. Wilford

118 Medicinal Uses of Cannabis and Cannabinoids Jag H. Khalsa, Gregory C. Bunt, Marc Galanter, and Norman W. Wetterau

119 Practical Considerations in Drug Testing Gary M. Reisfield, Roger L. Bertholf, Bruce A. Goldberger, and Robert L. DuPont SIDEBAR: Workplace Drug Testing and the Role of the Medical Review Officer James L. Ferguson and Robert L. DuPont

120 Reducing Substance Use in Criminal Justice Populations Beau Kilmer, Jonathan P. Caulkins, Robert L. DuPont, and Keith Humphreys SIDEBAR: Treatment of Substance Use Disorders During Incarceration Lori D. Karan

121 Preventing and Treating Substance Use Disorders in Military Personnel Kenneth Hoffman, Robert M. Bray, and Janet H. Lenard SIDEBAR: Risk Factors for Military Families Joan E. Zweben and Susan A. Storti

Index

SECTION 1

Basic Science and Core Concepts

CHAPTER 1

Drug Addiction: The Neurobiology of Motivation Gone Awry Nora D. Volkow and George F. Koob

CHAPTER OUTLINE Introduction Addiction: A Developmental Disorder Neurobiology of Addictive Drugs: Binge–Intoxication Stage Neurobiology of Drug Addiction: Withdrawal–Negative Affect Stage Neurobiology of Drug Addiction: Preoccupation–Anticipation (“Craving”) Stage Vulnerability to Addiction Strategies to Combat Addiction Challenges for Society Summary

INTRODUCTION Drug addiction manifests as a chronic relapsing disorder, characterized by a compulsive drive to take a drug despite serious adverse consequences, the loss of control over intake, and the emergence of a negative emotional state during abstinence. This aberrant behavior has traditionally been viewed as a bad “choice” that is made voluntarily by the addicted person, a view that engendered the lingering stigma of addiction as a moral failure. However, addiction researchers have collected converging evidence that shows that frequent drug misuse changes the brain in ways that can lead to the profound behavioral disruptions that are seen in addicted individuals. This is because addictive drugs impact many neuronal circuits, including those that are involved in processing responses to rewarding stimuli and motivating behavioral actions, negative emotions, interoception, decision-making, and cognitive control, turning drug use into compulsive behavior. The fact that these changes are progressive but that, once developed, are long lasting, persisting even after years of drug use discontinuation, is what makes addiction a chronic and relapsing disease but also one that offers unique opportunities for prevention. New knowledge about vulnerability factors that increase the risk for drug use and addiction, including genetic, developmental, and environmental factors, and our much better understanding of the effects of drugs in the brain has started to bring about changes in our approaches to the prevention, diagnosis, and treatment of substance use disorders (SUDs; new terminology used by the Diagnostic and

Statistical Manual of Mental Disorders, 5th edition [DSM-5]), including addiction (corresponding roughly to moderate to severe SUD). Drugs, both legal (eg, alcohol, nicotine) and illegal (eg, cocaine, methamphetamine, heroin, marijuana), and psychotherapeutics (opioid analgesics, stimulant medications, benzodiazepines, and barbiturates) can be used for various reasons, including to experience pleasure, alter mental states, improve performance, and self-medicate negative emotional states or a mental disorder. The repeated use of a psychoactive drug in vulnerable individuals can result in addiction, which is characterized by an intense desire for the drug, combined with an impaired ability to control that urge, even in the face of wellknown adverse, even catastrophic consequences (eg, incarceration, loss of child custody, loss of medical license, adverse health effects). It is important to emphasize the distinct difference between a state of addiction and a state of physical dependence. Physical dependence results in strong withdrawal symptoms when drugs, such as alcohol and heroin, are discontinued, but the adaptations that are responsible for these effects are relatively short lasting and distinct from those that underlie addiction, which are much longer lasting and are described in detail in this chapter. Partly because this distinction has often led to confusion, the DSM-5 eliminated the categories of substance abuse and dependence and uses instead the category of “addiction and related disorders.” This nomenclature strategy, which includes SUD (with each drug identified in its own category along with its severity), may better capture the dimensionality of the disease, variations in disease severity, and the complex progression of neural and behavioral impairments that afflict addicted individuals. A growing body of basic research in animal models and imaging evidence in humans provides critical insights that help explain the aberrant behavioral manifestations that characterize addiction. The convergent results suggest that individuals with addiction undergo progressive structural and functional disruption in brain regions that underlie normal processes of reward and motivation, emotional regulation, inhibitory control, and self-awareness (1,2). Drug addiction has been conceptualized as a cycle of three stages, each representing basic neurocircuitry linked to a functional domain and associated brain functional networks, but with the recognition that brain networks interact with one another (Fig. 1-1). The binge–intoxication stage via the neurocircuitry of the basal ganglia reflects the rewarding effects of drugs and the ways in which drugs impart motivational significance to cues and contexts in the environment, termed incentive salience, which is experienced as “well-being,” “high,”

“euphoria,” or “relief,” depending on the degree of tolerance to the rewarding effects of the drug (see Fig. 1-1). The withdrawal–negative affect stage via the extended amygdala and habenula reflects the loss of reward and motivation and the enhanced sensitivity and recruitment of the brain stress systems, termed a negative emotional state, which is experienced as dysphoria, anhedonia, and irritability (see Fig. 1-1). The preoccupation–anticipation (“craving”) stage via the neurocircuitry of the prefrontal cortex (PFC) reflects the impulsivity and loss of control over drug taking, termed loss of executive control, and the input from the default mode network (DMN) that reflects the enhanced interoceptive awareness of the desire for the drug, which is experienced as drug craving (see Fig. 1-1) (3).

Figure 1-1. Conceptual framework for Neurobiology of Addiction. The three stages of the addiction cycle (see text) are linked to three domains of neurocircuity, which mediate three domains of dysfunction: binge–intoxication (basal ganglia–incentive salience), withdrawal–negative affect

(extended amygdala–negative emotional states), preoccupation–anticipation (“craving”) (prefrontal cortex– executive dysfunction). In parallel, the disruption of the default mode network (DMN) necessary for interoceptive awareness makes it harder to ignore drug craving as well as the negative emotional states during the withdrawal-negative affect stage. See eBook for color images. This provides a compelling rationale for the argument that drug addiction is a chronic disease of the brain (because the changes are long-lasting, persisting months or years after drug discontinuation) and that the associated abnormal behaviors (such as those that are associated with opioid, cocaine or alcohol use disorders) are the result of dysfunctions in brain functional networks that are necessary for everyday activities and in that way not different from cardiac insufficiency, which is the result of impaired myocardial function that is necessary for the heart to provide proper circulation to the rest of the body (4) (Fig. 1-2). Therefore, although initial drug experimentation and recreational use may be controllable in most cases, once addiction develops, behavioral control becomes markedly disrupted. Importantly, although imaging studies consistently show specific abnormalities in the brain in individuals with addiction, not all people with addiction present these abnormalities, and the severity is not the same across all addicted subjects. The dimensional and heterogeneous nature of this disease has implications for its prevention and treatment and for public health policy, highlighting the need for further research to delineate the nature and diversity of genetic, neurobiological, and social factors that are involved in addiction.

Figure 1-2. Drug addiction as a disease of the brain. Images of the brain in a healthy control and in an individual addicted to cocaine (top panel) and in an individual acutely exposed to placebo or alcohol (middle panel) and parallel images of the heart in a healthy control and in an individual with a myocardial infarction (bottom panel). The images were obtained with positron emission tomography (PET) and [18F]fluoro-2-deoxyglucose (FDG-PET) to measure glucose metabolism, which is a sensitive indicator of damage to the tissue in the brain and the heart. Note the decreased glucose metabolism in the orbitofrontal cortex (OFC) of the addicted

person and the decreased metabolism in the myocardial tissue in the person with a myocardial infarct. Damage to the OFC will result in improper inhibitory control and compulsive behavior, and damage to the myocardium will result in improper blood circulation. Although abnormalities in the OFC are some of the most consistent findings in imaging studies of addicted individuals (including alcohol addiction), they are not detected in all addicted individuals. This implies that disruption of this frontal region is not the only mechanism that underlies the addictive process. See eBook for color images. (Heart images courtesy of H. Schelbert, University of California at Los Angeles. Images of glucose metabolism during alcohol intoxication reprinted from Volkow ND, et al. Acute alcohol intoxication decreases glucose metabolism but increases acetate uptake in the human brain. Neuroimage. 2013;64:277-283. Ref. (5).) Drug addiction develops as a progressive process that involves complex interactions between biological and environmental factors (6). This can help explain why some individuals become addicted and why others do not and why attempts to understand addiction as a purely biological or environmental disease have been largely unsuccessful. Recently, important discoveries have provided a means of explaining this environmental/biological interaction via our better knowledge of the ways in which drugs affect the epigenome, the expression patterns of specific genes, their protein products, neuronal communication and plasticity, and neural circuitry (7) and the ways in which these biological factors might conflate to affect human behavior. This also sets the stage for a better understanding of the ways in which different environmental factors influence molecular traits (eg, through epigenetic modifications (8)) and contribute to patterns of behavior that facilitate the establishment of addiction. Here, we summarize new methodologies that allow us to study how drugs affect genes, their products, and the function of the human brain and how they have provided us with a better understanding of drug addiction along with their implications for the prevention and treatment of SUD.

ADDICTION: DISORDER

A

DEVELOPMENTAL

Normal developmental processes might result in a higher risk of drug use at certain times in life than others. Experimentation often starts in adolescence, as does the process of addiction (9,10) (Fig. 1-3). Normal adolescent-specific behaviors (such as risk taking, novelty seeking, and heightened sensitivity to peer pressure) increase the likelihood of experimenting with legal and illegal drugs (11,12), which likely reflects the incomplete development and connections between brain regions (eg, pruning of frontal cortical regions and myelination of projections that connect cortical and limbic brain regions) (13,14) that are involved in the processes of executive control and necessary for regulating emotions and desires. The frontal lobes and connections between the frontal lobes do not fully develop until the age of 25 (13). This is relevant because drug experimentation emerges in adolescence, and the highest rates of drug use for most substances occur between 18 and 24 years of age, when the connectivity between functional networks is still developing. Preclinical studies with animal models and human imaging studies indicate that drug exposure during adolescence might result in different neuroadaptations from those that occur during adulthood. For example, adolescent rats that are exposed to nicotine exhibit significant changes in nicotinic receptors, with greater reinforcement value for nicotine later in life (15). Lasting reductions of synaptic metabotropic glutamate receptor type 2 are also observed in the medial PFC, leading to attention deficits later in adulthood (16). Similarly, recent studies in both humans and animals have demonstrated that the adolescent period is distinctly sensitive to long-term alterations by chronic alcohol and drug exposure (17–20) and may explain the greater vulnerability to alcohol use disorder among individuals who start using alcohol and drugs, including marijuana, early in life (19,21). For example, adolescents who had engaged in episodes of heavy drinking presented faster declining volumes in lateral frontal and temporal cortex gray matter regions and smaller increases in regional white matter volumes relative to nondrinking adolescents (22).

Figure 1-3. Mean age at first use for specific illicit drugs among past year initiates aged 12-49, in 2011. (Data from SAMHSA. Results from the 2011 National Survey on Drug Use and Health: Summary of National Findings and Detailed Tables. Rockville, MD: Substance Abuse and Mental Health Services Administration, Office of Applied Studies, 2012.)

NEUROBIOLOGY OF ADDICTIVE DRUGS: BINGE–INTOXICATION STAGE During the binge–intoxication stage, large surges of dopamine (DA) and the release of opioid peptides have been consistently associated with the reinforcing effects of most addictive drugs. Addictive drugs induce large increases in extracellular DA concentrations in the basal ganglia, including the nucleus accumbens (NAc) (23,24). Specifically, the reinforcing effects of these drugs are seemingly attributable to their ability to surpass the magnitude and duration of the fast DA increases that occur in the NAc when triggered by natural reinforcers, such as food and sex, that are necessary to stimulate DA D1

receptors that are needed for reward (25). Such drugs as cocaine, amphetamine, methamphetamine, and ecstasy increase DA in the synaptic space by inhibiting DA reuptake or by promoting the release of intravesicular DA into the cytoplasm (26–28). Other drugs, such as nicotine, alcohol, opioids, and marijuana, work directly or indirectly to modulate DA cell firing through their effects on nicotinic, γ-aminobutyric acid (GABA), opioid, and cannabinoid receptors (predominantly CB1), respectively (29,30). For example, alcohol has prominent effects on DA and opioid peptide release in the basal ganglia (Fig 1-4 (31) and Fig. 1-5 (32)), whereas heroin directly stimulates μ opioid receptors (MORs), resulting in increases in DA in brain reward regions.

Figure 1-4. Neuroimaging of reward activation (binge– intoxication stage). Alcohol releases DA in the striatum in humans. Left, striatal change in [11C]raclopride nondisplaceable binding potential (BPND) maps and subjective activation in response to alcohol. The placebo consisted of cranberry juice and soda alone, while the alcohol

drink in addition contained the equivalent of three standard drinks of 100 proof vodka designed to deliver an average of 0.75 g alcohol per kg body water. BAL peaked at 55 minutes after drink (1.15 ± 0.3 mg/mL in men and 1.02 ± 0.4 mg/mL in women). BPND maps averaged across men (n = 11, top) and women (n = 10, bottom) following placebo drink (left) and alcohol drink (right). The MRI images (center) are averaged across all 21 subjects. Images were all nonlinearly warped into MNI space in the SPM2 software environment (31). The ROIs on the coronal MRI image (left) are the preDCA, preDPU, and VST. The line through the sagittal MRI slice (right) shows the coronal slice level of the other images. The graphs on the right show the correlation between subjective activation at 30 minutes after drink (total score post alcohol minus total score post placebo, not adjusted for baseline) and absolute Δ BPND (reflecting changes in DA). The relationship is stronger for men (top). Note that the absolute value of Δ BPND is presented here. See eBook for color images. (Taken from Urban NB, et al. Sex differences in striatal dopamine release in young adults after oral alcohol challenge: a positron emission tomography imaging study with [11C]raclopride. Biol Psychiatry. 2010;68:689-696, with permission.)

Figure 1-5. Neuroimaging of reward activation (binge– intoxication stage). Alcohol consumption induces opioids in

the NAc in humans. Changes in MOR binding in ROIs following alcohol consumption A. (Top). Spatially coregistered coronal MRI (left) and PET (right) images from a single representative control subject indicating designation of individually drawn NAc ROIs. Left: Coronal section MRI with the NAc ROI in orange. Right: [11C]carfentanil binding potential, with highest binding potential in hot colors (see color scale). (B) Binding potential (BP = Bmax/Kd − 1) for the NAc region *p < 0.05; **p < 0.01, paired t tests for heavy drinking (n = 12) and control subjects (n = 13) before and after alcohol consumption. Alcohol consumption of one standard drink in fruit juice resulted in blood alcohol levels of 0.04-0.05 gm%. It is common to describe the effects of DA in the NAc as one that signals “reward,” but this traditional concept is an oversimplification (33). Rather, DA is a versatile modifier of motivation and a predictor of reward, and its effects depend on the receptor through which it signals (there are five different DA receptors). Psychopharmacological studies show that, depending on the magnitude and time course of DA-mediated neuronal activity, the system can encode different kinds of information to subcortical and cortical brain structures that convey different messages about stimulus–response, approach behavior, learning, and decision-making (34–36). For example, abrupt and large increases in DA stimulate D1 receptors and are related to reward-predictive stimuli, whereas slower and lower increases in DA stimulate D2 receptors and are related to preparedness of the neuronal system to stimulation and are necessary for sustaining effort and attention. Dopaminergic neurons also respond to aversive stimuli or the absence of an expected reward by decreasing DA release, thus influencing subsequent behaviors to avoid aversive stimuli or to avoid placing effort on nonrewarding stimuli. Interestingly, imaging studies with individuals who are diagnosed with cocaine addiction have shown the expected, druginduced fast increases in DA in the striatum (including the NAc) associated with the drug’s rewarding effect, and such increases are markedly blunted compared with controls (37) (see below). These same subjects with drug addiction, however, present significant increases in DA in the striatum in response to drug-

conditioned cues that are associated with self-reports of drug craving and appear to have a greater magnitude than DA responses to consumption of the drug itself. We postulate that the discrepancy between the expectation for the drug’s effects (ie, conditioned responses) and the blunted pharmacological effects of the drug’s consumption maintain drug taking in an attempt to obtain the expected reward (see Preoccupation-Anticipation Stage section). Another important question can be posed: If natural reinforcers increase DA, then why would they not lead to addiction? The difference might be attributable to qualitative and quantitative differences in the increases in DA that are induced by drugs, which are greater in magnitude (by at least 5- to 10-fold as measured by microdialysis) and duration than are those that are induced by natural reinforcers (25). Additionally, increases in DA that are produced by natural reinforcers in the NAc undergo satiation, whereas those that are induced by drugs of abuse do not (23). For natural reinforcers (but not for drugs) lower DA release in NAc is associated with satiety (highly rewarding food that is rich in fat and sugar is a special case that is discussed elsewhere in more detail) (38). Finally, engagement of the dorsal striatum during addiction is thought to help solidify habitual behaviors that are associated with drug seeking and taking. Neuroadaptations in the dorsal striatum and NAc involve changes in glutamate, GABA, and the endocannabinoid system (39,40).

NEUROBIOLOGY OF DRUG ADDICTION: WITHDRAWAL– NEGATIVE AFFECT STAGE Addiction to drugs has been conceptualized as a reward deficit disorder (41). More specifically, a defining characteristic of drug addiction is the transition from impulsive drug intake to compulsive intake that is mediated by positive and negative reinforcement, respectively. Once a person transitions to compulsive drug use, negative reinforcement mechanisms play a substantial role in continued, escalated drug use. Negative reinforcement is a behavioral mechanism whereby greater drug taking is strengthened by the alleviation of a negative emotional state that is precipitated by absence of the drug. In recent years, attention has focused on understanding the neurobiological mechanisms, including specific neuroadaptations that underlie this negative emotional state that is produced by drug withdrawal and abstinence because of its central role in

relapse. Neuroadaptations in the brain reward, executive, and stress systems are key drivers of the compulsion to continue drug intake despite adverse consequences. Decreases in DA and GABA in the ventral striatum (where NAc is located) are coupled with the recruitment of brain stress systems in the extended amygdala and habenula, which in turn inhibit DA cell firing and DA release (42). The extended amygdala is a composite structure that comprises the central nucleus of the amygdala (CeA), the bed nucleus of the stria terminalis (BNST), and a transition area in the medial and caudal portions of the NAc (43). A key player in the brain stress systems is dysregulation of the hypothalamic– pituitary–adrenal (HPA) axis and the recruitment of extrahypothalamic corticotropin-releasing factor (CRF) in the extended amygdala (44). In animal models, CRF receptor antagonists blocked alcohol self-administration in dependent rats during both acute withdrawal and protracted abstinence and also blunted compulsive-like responding for all major drugs of abuse, and many of these effects have been localized to the extended amygdala (44). Withdrawal from all addictive drugs that have been studied to date leads to an activated HPA stress response. However, repeated withdrawal and the repeated activation of glucocorticoids (effectors of the HPA axis) can lead to a blunted HPA stress response along with sensitization of the CRF–CRF1 receptor systems of the extended amygdala, causally linking the neuroendocrine and extrahypothalamic CRF system stress responses in the development of addiction (44). Consistent with a functional role for the HPA axis component of the opponent process, glucocorticoid receptor antagonists reduced the development and expression of excessive alcohol self-administration that resulted from repeated, intermittent alcohol intoxication (45) and alcohol seeking in a human laboratory study (46).The excessive release of DA and opioid peptides produces the subsequent activation of dynorphin systems, which through their activation of κ opioid receptors decreases DA release. A decrease in DA release contributes to the dysphoria that is associated with addiction (47) and more generally to negative emotional states (48). Indeed, κ opioid receptor antagonists block the depression-like, aversive responses to stress, and dysphoric-like responses during drug withdrawal and compulsive-like responding in animal models (49). Additionally there is evidence that norepinephrine, vasopressin, substance P, hypocretin (orexin), and inflammatory cytokines also contribute to negative emotional states of drug withdrawal, which are most prominent for alcohol and opioids (50). Recruitment of the brain stress systems in the extended amygdala is also accompanied by compensatory mechanisms that oppose these effects. Such “buffer systems” include neuropeptide Y (NPY), nociceptin, and the

endocannabinoid system, which act to restore homeostasis to extended amygdala circuits and modulate stress responses (51,52). Thus, one can envision stress system recruitment (the overactivation of CRF or dynorphin-κ opioid receptors) or buffer system failure (low activation of NPY, nociceptin, or endocannabinoids) that contributes to vulnerability, severity, and relapse in addiction under the conceptual framework that is conveyed by negative reinforcement. In human imaging studies, hyperactivity of the amygdala, thalamus, and hippocampus and a decrease in amygdala connectivity with the anterior cingulate gyrus were observed in response to angry and fearful facial expressions in people with a current cocaine use disorder compared with controls (Fig. 1-6 (54)). Increases in amygdala activation were also independently associated with an earlier age of first cocaine use and longer exposure to cocaine (54).

Figure 1-6. Neuroimaging showing sensitization of amygdala during fear responses (withdrawal–negative affect stage). Brain image of a cocaine-dependent individual showing significantly increased activation in the left amygdala in response to fearful and angry faces during an emotional facematching task. Amygdala activity and amygdala connectivity during the emotional face-matching task, known to activate the amygdala (Morris JS, et al. A neuromodulatory role for the human amygdala in processing emotional facial expressions. Brain. 1998;121(Pt 1):47-57. Ref. (53)) were assessed in 51 cocaine-using males and 32 non–drug-using healthy males using functional magnetic resonance imaging

(fMRI). Male healthy non–drug-using controls and male current cocaine users, 22-50 years old, were included when using at least 1 g of cocaine during at least two occasions per week for the last 6 consecutive months. (Crunelle CL, et al. Dysfunctional amygdala activation and connectivity with the prefrontal cortex in current cocaine users. Hum Brain Mapp. 2015;36:4222-4230.) There is also evidence of impairments in ancillary circuits that are likely to contribute to compulsive-like behaviors that are seen in individuals with addiction. For example, insular dysfunction can affect the ability to properly evaluate internal states (55), and impairments in the lateral habenula can compromise the ability to properly process and learn from disappointments and might disrupt mood (56). Finally, in addition to classic neurotransmitter systems, recent studies link neuroinflammatory signaling in the brain to drug use and addiction. For example, central immune signaling activation is associated with the abuse of alcohol, opioids, cocaine, and methamphetamine (57). Alterations of neuroimmune signaling regulate alcohol drinking behavior and may contribute to negative affect and depression-like behaviors that are induced by alcohol (58,59) and opioids (60,61) and additionally contribute to the toxicity associated with alcohol (62) and other drugs, such as methamphetamine and opioids (63,64).

NEUROBIOLOGY OF DRUG ADDICTION: PREOCCUPATION– ANTICIPATION (“CRAVING”) STAGE A hallmark of addiction involves poor inhibitory control and poor executive function, which are mediated by prefrontal cortical regions in the brain. For example, regions of the PFC are selectively damaged by chronic intermittent drug use (alcohol, cocaine, marijuana) use and result in poor decision-making that can perpetuate the addiction cycle. Indeed, gray matter volume deficits in specific medial frontal and posterior parietal–occipital brain regions are predictive of relapse risk, suggesting a significant role for gray matter atrophy in poor clinical outcomes in alcoholism (see Fig. 1-7 (65)). Similar, although not

identical, findings have been observed for opioid, cocaine, and cannabis use disorders (66–69). Adaptations also appear to occur in regions that are innervated by mesolimbic DA circuits (including the NAc, amygdala, hippocampus, and PFC), which may contribute to greater salience of the drug and drug stimuli and the lower sensitivity to natural reinforcers (7). Whether tested during early or protracted withdrawal, individuals with addiction present lower levels of DA D2 receptors in the striatum (including the NAc), which are associated with decreases in the baseline activity of frontal brain regions that are implicated in salience attribution (orbitofrontal cortex [OFC]), inhibitory control, and error monitoring (anterior cingulate gyrus [ACC]), the disruption of which results in compulsivity and impulsivity (70). These results point to an imbalance between dopaminergic circuits that underlie reward and conditioning and those that underlie executive function (emotional control and decision-making). We postulate that this imbalance contributes to compulsive drug use and the loss of control in addiction. For example, increases in DA are likely to play a role in error prediction that is important for stimulus–reward learning (71) and the assignment of salience (35). Salience refers to stimuli or environmental changes that are arousing or that elicit an attentional–behavioral switch (72). Salience, which applies not only to reward but also to aversive, new, or unexpected stimuli, affects the motivation to seek the anticipated reward and facilitates conditioned learning and engages DA D1 receptors (73,74). This provides a different perspective about drugs because it implies that drug-induced increases in DA will inherently motivate further procurement of more drug (regardless of whether the effects of the drug are consciously perceived to be pleasurable). Indeed, some addicted individuals report that they seek the drug even though its effects are no longer pleasurable. Drug-induced increases in DA through D1 receptor stimulation will also facilitate conditioned learning, in which previously neutral stimuli that are associated with the drug become salient. These previously neutral stimuli then increase DA by themselves and elicit the desire for the drug (75). This may explain why the person with addiction is at risk of relapse when exposed to an environment where he previously administered the drug.

Figure 1-7. Neuroimaging showing decreased frontal activity correlated with relapse vulnerability (preoccupation– anticipation stage), with significant clusters of gray matter volume deficit in alcohol-dependent patients relative to healthy comparison subjects. Panel A presents estimated survival risk functions (with mean age, IQ, and baseline total amount of alcohol consumed held constant) for mean gray matter volumes as well as for volumes one and two standard deviations above and below the mean for the medial frontal cluster (cluster χ2 = 6.7, p < 0.009; hazard ratio = 0.52, 95% CI = 0.31-0.85). Although the survival function was a 90-day analysis, the graphs are cut off at day 60 because all alcoholdependent patients with gray matter volumes two standard deviations below the mean for each of the two regions relapsed by day 60. For patients with volumes two standard deviations above the mean in the medial frontal cluster, the estimated survival function at day 60 spans a 0.68 (68%) proportion of surviving relapse, whereas for patients with volumes two standard deviations below the mean, the estimated survival function at day 60 for both regions spans only a 0.02% chance of surviving relapse. Panel B shows the

right lateral prefrontal cortex with crosshairs at Montreal Neurological Institute (MNI) coordinates x = 51, y = 40, z = 19 (Brodmann area 46; dorsolateral prefrontal cortex). (Taken from Rando K, et al. Association of frontal and posterior cortical gray matter volume with time to alcohol relapse: a prospective study. Am J Psychiatry. 2011;168:183-192, with permission.) At the neurotransmitter level, addiction-related adaptations have been reported not only for DA but also for glutamate, GABA, opioids, serotonin, cannabinoids, and various neuropeptides (76). These changes contribute to the abnormal function of brain circuits. For example, in individuals who are addicted to cocaine, imaging studies have shown that disruptions of DA activity in the brain (reflected by reductions of D2 receptors in the striatum and reductions of DA release) (77) are associated with lower baseline activity in the OFC and anterior CG (brain regions that are involved in salience attribution and inhibitory control (70); Fig. 1-8). Abnormal function of these cortical regions has been particularly revealing in furthering our understanding of addiction because their disruption is linked to compulsive behavior (OFC) and disinhibition (CG) (70). The combined research of the last decade reveals that drug-induced impairments in areas of the PFC exert a twofold greater impact on addiction, first through its perturbed regulation of limbic reward regions and second through its involvement in higher-order executive function (eg, self-control, salience attribution, and awareness) (79). Therefore, abnormalities in these PFC regions could underlie both the compulsive nature of drug administration in individuals with addiction and their inability to control their urges to take the drug when they are exposed to it (80). They are also likely to contribute to the impaired judgment and cognitive deficits that are seen in many people with addiction. Additionally, animal studies have shown that drug-related adaptations in these PFC regions result in greater activity of the glutamatergic pathway that regulates DA release in the NAc (81). Adaptations in this pathway appear to play a role in the relapse that occurs after drug withdrawal in animals that are previously trained to selfadminister a drug when they are again exposed to the drug, a drug-related stimulus, or stress (81). Moreover, brain imaging studies have shown that the more that individuals with a cocaine use disorder can engage the PFC, the more they can inhibit activation of the NAc that follows exposure to cocaine-related cues (82).

Figure 1-8. Dopamine D2 receptors and glucose metabolism in addiction. A, B: Positron emission tomography (PET) images showing DA D2 receptors and brain glucose metabolism in the OFC (orbitofrontal cortex) in controls (A) and in individuals who use cocaine (B). Note that the individuals using cocaine have reductions in both D2 receptors and in OFC metabolism. C: Correlation between measures of D2 receptors and brain glucose metabolism in the OFC and anterior cingulate gyrus (CG) of both cocaine and methamphetamine users. The lower the D2-receptor expression, the lower the metabolism in the OFC and CG. Decreased activity in the OFC, a brain region that is implicated in salience attribution and whose disruption results in compulsive behavior, could underlie the compulsive drug administration that occurs in addiction. Decreased activity in the CG, a brain region that is involved in inhibitory control, could underlie the inability to restrain from taking the drug when the addicted person is exposed to it. (Volkow ND, Fowler JS, Wang GJ, et al. Dopamine in drug abuse and addiction: results of imaging studies and treatment implications. Arch Neurol.. 2007;64:1575-1579. Ref. (78).) At the molecular-cellular level, drugs have been reported to alter the expression of certain transcription factors (nuclear proteins that bind to regulatory regions of genes, thereby regulating their transcription into mRNA), and a wide variety of proteins that are involved in neurotransmission in several key brain regions. Growing evidence suggests that epigenetic mechanisms mediate many druginduced changes in gene expression patterns that lead to structural, synaptic, and behavioral plasticity in the brain (83). The dynamic and often long-lasting changes that occur in the transcription factors ΔFosB, cAMP-responsive element-binding protein (CREB), and nuclear factor κB after chronic drug administration are particularly interesting because they appear to modulate the synthesis of proteins that are involved in key aspects of the addiction phenotype, such as synaptic plasticity (84). Indeed, chronic drug exposure can alter the

morphology of neurons in DA-regulated circuits. For example, in rodents, chronic cocaine, alcohol, or amphetamine administration alters neuronal dendritic branching and spine density in the NAc and PFC. This adaptation is thought to play a role in the greater incentive motivational value of the drug in addiction (85–87). These molecular changes can influence all three stages of the addiction cycle, thereby loading the circuits that contribute to neuroadaptations in reward-motivation, stress-emotion, executive function-self regulation, and interoceptive-self awareness networks in the brain whose dysfunction coalesce to drive compulsive alcohol and drug intake.

VULNERABILITY TO ADDICTION Genetic Factors It is estimated that 40-60% of the vulnerability to addiction is attributable to genetic factors (88). In animal studies, several genes have been identified that are involved in drug responses, and their experimental modifications markedly affect drug self-administration (89). Animal studies have identified candidate genes and genetic loci for alcohol responses that overlap with genes and loci that are identified in human studies (90,91). For example, genes on mouse chromosome 1 and human chromosome 1q are associated with alcohol withdrawal responses. Genome-wide association studies (GWASs), which interrogate all of the common genetic variants for correlations with alcohol phenotypes, have proven to be a useful approach to identify novel variants (92). A GWAS of alcohol consumption identified the autism susceptibility candidate 2 (AUTS2) gene in a large population-based sample (93). A family-based GWAS of frontal theta oscillations, an endophenotype of alcoholism, found that the potassium channel gene KCNJ6 was responsible for a significant amount of variations in that measure (94). Progress in identifying candidate genes for alcoholism and alcohol-related responses continues at a rapid pace (95). However, identifying the biological function of these new candidate genes will be a major challenge in the next decade. The hope is that a better understanding of the myriad interacting genetic factors and networks that influence addiction risk and trajectory will help increase the efficacy of addiction treatments and reduce the likelihood of relapse (96). A prime example of a successful move from gene identification to biological function is the association between drugmetabolizing genes and protection against alcohol use disorder. Some of these

polymorphisms interfere with drug metabolism, influencing the amount of time a drug circulates through the body. For example, specific alleles of the genes that encode alcohol dehydrogenases ADH1B and ALDH2 (enzymes that are involved in the metabolism of alcohol) are reportedly protective against alcoholism (97). Similarly, polymorphisms in the gene that encodes cytochrome P-450 2A6 (an enzyme that is involved in nicotine metabolism) are reportedly protective against nicotine addiction (98). Furthermore, genetic polymorphisms in the cytochrome P-450 2D6 gene (an enzyme that is involved in the conversion of codeine to morphine) appear to provide a degree of protection against the nonmedical use of codeine (99). These polymorphisms of drug-metabolizing genes operate by modulating the accumulation of toxic metabolites that are aversive; therefore, if alcohol or drugs are consumed by individuals who carry variants that convert their substrate at high rates, then the accumulation of toxic metabolites serves as a negative stimulus to prevent further consumption. Some polymorphisms of receptor genes that mediate effects of drug have also been associated with a higher risk of addiction. For example, a number of convergent results support a CHRNA5/CHRNA3/CHRNB4 gene cluster association with nicotine dependence (100–103) and the risk of such smokingrelated diseases as lung cancer and peripheral arterial disease (104). Similarly, polymorphisms of the MOR gene have been associated with a higher risk for an opioid or alcohol use disorder (105,106). Associations have also been found between alcohol dependence and the genes that encode GABAA (GABRG3 (107) and GABRA2 (108)). Particularly interesting in this context are findings related to the association between DRD4 variable number tandem repeat polymorphisms and attention-deficit/hyperactivity disorder (ADHD), personality traits that influence risk taking, addiction, and addiction-related phenotypes (109). The likely involvement of DRD4 in addiction trajectories is potentially very important in light of its alleged ability to moderate the impact of environments on behavior and health (110). The replication of many of the genetic findings in SUDs is still pending, but such techniques as exome sequencing (where one sequences all of the protein-coding regions of the genome) will identify variants that may play a direct role in altering the function of the corresponding protein.

Environmental Factors Environmental factors that have been consistently associated with a propensity to drug use include low socioeconomic class, poor parental support, within–peer group deviancy, and drug availability, all of which contribute to stress, which

may be a common feature of a wide variety of environmental factors that increase the risk for drug use. The mechanisms that are responsible for stressinduced increases in vulnerability to drug use and relapse in people who are addicted are not yet well understood. However, there is strong evidence that dysregulation of stress-responsive CRF, vasopressin, dynorphin, hypocretin, norepinephrine, and neuroinflammatory systems may contribute to a variety of psychiatric disorders and SUDs (111), likely through their effects on the HPA axis, extended amygdala, and other stress-responsive regions, such as the insula and habenula (112) (see Withdrawal-Negative Affect Stage section above). A recent study showed that social isolation during a critical period of adolescence increases the vulnerability to addiction (113). Social isolation in adolescence also increases anxiety and alcohol intake (114). Imaging techniques now allow us to investigate the ways in which environmental factors affect the brain and the ways in which these affect behavioral responses to addictive drugs. For example, in nonhuman primates, social status affects D2 receptor expression in the brain, which in turn affects the propensity for cocaine self-administration in males (115) but not females (116). Animals (males and females) that achieve a dominant status in the group show greater numbers of D2 receptors in the striatum and are reluctant to administer cocaine (males only), whereas animals that are subordinate have fewer D2 receptors and readily administer cocaine. Because studies in male rodents have shown that increasing D2 receptors in the NAc markedly decreases drug consumption (which has been shown for alcohol and cocaine) (117,118), this could provide a mechanism by which a social stressor can modify the propensity to self-administer drugs, at least for males. These results also highlight the need to understand potential gender differences in the neurobiological responses of the brain to stressors and their subsequent contribution to drug taking. Long-lasting changes in gene expression that are induced by environmental events, such as drug or alcohol exposure, are now being studied as a means to identify the ways in which the environment can contribute to drug and alcohol addiction. These long-lasting changes in gene expression are mediated by epigenetic mechanisms, including DNA methylation, histone modification, and microRNAs. For example, the acute anxiolytic effects of alcohol in rats were associated with a decrease in histone deacetylase (HDAC) activity and an increase in the acetylation of histones H3 and H4. CREB-binding protein (CBP) and NPY expression levels increased in the amygdala, a major brain region that is implicated in stress and anxiety.

Conversely, anxiety-like behaviors during withdrawal after chronic alcohol exposure were highly correlated with an increase in HDAC activity and decreases in the acetylation of H3 and H4 and levels of CBP and NPY in the amygdala (85). Treatment with the HDAC inhibitor trichostatin A in rats reversed the deficits in H3, H4, and NPY expression and prevented the development of alcohol withdrawal–related anxiety in the elevated plus maze and light/dark box test. Based on the effect of trichostatin A, the authors suggested the possibility that neuroadaptations in the amygdala during chronic alcohol exposure may involve both histone acetyltransferases and HDACs in the dynamic process of chromatin remodeling (119). An increasingly relevant example of an environmental factor that negatively impacts brains that are hardwired to respond and seek immediate rewards can be found in the ubiquitous availability of high-calorie “junk” food, which can hijack deeply entrenched (evolved) homeostatic mechanisms to easily override inhibitory controls in vulnerable individuals and facilitate behaviors that lead to obesity (38). A similarly deleterious relationship between greater availability and negative impacts on health can also be found in the more widespread nonmedical use of stimulant (eg, ADHD) medications (120,121), high rates of opioid analgesic prescriptions and overdose deaths (122,123), and the steady increase in marijuana use among young people (124).

Comorbidity with Mental Illness The risk for a SUD in individuals with mental illness is significantly higher than for the general population (125). The high comorbidity probably reflects, in part, overlapping environmental, genetic, and neurobiological factors that influence drug use and mental illness (126–128). Alcohol use disorder also often presents in combination with the use of other drugs and psychiatric disorders, including mood, anxiety, sleep, and psychotic disorders. Among individuals with alcohol use disorder, nearly 40% have at least one lifetime psychiatric diagnosis and more than 20% have another SUD. Similarly, individuals with a mood disorder are at increased risk for an opioid use disorder, which in turn increases their risk for overdose fatalities and suicidality (129), Almost 30% of people with psychiatric disorders present with a SUD, and 25% have an alcohol use disorder and 15% have another drug use disorder. These comorbidities are problematic because they can complicate treatment and lead to synergistic negative effects on health that are worse than any of the disorders alone. For example, depression can deplete patients of the

motivation that is required to maintain recovery from alcohol. Depressed individuals with alcohol use disorder have 59% more severe suicidal symptoms compared with depressed nondependent individuals, and depression is predictive of relapse to drinking. It is likely that different neurobiological factors are involved in comorbidity, depending on the temporal course of its development (ie, mental illness followed by drug use or vice versa). In some instances, the mental illness and addiction appear to co-occur independently (130). In others, there might be sequential dependency. It has been proposed that comorbidity might be attributable to use of the drugs to self-medicate the mental illness in cases in which the onset of mental illness is followed by the use of some types of drug. When drug use is followed by mental illness, chronic excessive drug exposure could lead to neurobiological changes, which might explain the greater risk of mental illness (131). For example, the high prevalence of smoking that is initiated after individuals experience depression could at least partially reflect the antidepressant effects of nicotine and the antidepressant effects of monoamine oxidase A and B inhibition by cigarette smoke (132). The reported risk for depression with early drug use (133) could reflect neuroadaptations of the DA systems and the recruitment of brain stress systems that might make individuals more vulnerable to depression. Also in this category are the multiple observations that suggest that cannabis exposure may be a “component cause” that, in combination with other factors (eg, preexisting/genetic vulnerabilities), could contribute to schizophrenia or other psychotic disorders (134). The higher risk of drug use in individuals with mental illness highlights the relevance of the early evaluation and treatment of mental diseases as an effective strategy to prevent drug addiction that starts as self-medication.

STRATEGIES TO COMBAT ADDICTION Knowledge of the neurobiology of drugs and the adaptive changes that occur with SUDs is guiding new strategies for prevention and treatment and identifying areas in which further research is required.

Preventing Addiction The greater vulnerability of adolescents to experimentation with addictive drugs and to subsequent addiction underscores why the prevention of early exposure is

such an important strategy to combat drug addiction. Epidemiological studies show that the prevalence of drug use in adolescents has changed significantly over the past 30 years, and some of the decreases appear to be related to education about the risks of drugs, but some of the increases may be related to changes in the perception of such risks. For example, for marijuana, the prevalence rates of use in the United States in 1979 were as high as 50%. In 1992, they were as low as 20% (135) (Fig. 1-9) but now have increased significantly among 18-25 year olds, although these rates have remained stable among adolescents. Interestingly, in contrast to the stable levels of marijuana use among teenagers, the use of other drugs, both legal (alcohol and nicotine) and illegal (cocaine, methamphetamine, heroin, ecstasy, and inhalants), and prescription medications (stimulants, opioids, benzodiazepines) has continued to decrease in the United States (136). Moreover, in the past, we had observed a strong relationship between perception of the risks that are associated with marijuana consumption and its use. When adolescents perceived the drug to be risky, the rate of use was low, whereas when they did not, the rate of use was high. This is no longer the case. Despite the significant decreases over the past 5 years in the perception of marijuana as risky, its use has not changed during this time period (136). Some of the significant decreases in ecstasy use and cigarette smoking in adolescents (135) reflect effective prevention campaigns, which provide evidence that, despite the fact that adolescents are more likely to take risks, interventions that educate them about the harmful effects of drugs through age-appropriate messages can decrease the rate of drug use (137–139). Nevertheless, there is evidence that despite the decrease in alcohol use, there has been a dramatic increase in high-intensity drinking (defined as 10-15 drinks in a given setting) in the United States, as shown by steady increases in emergency room visits that are linked to alcohol in the last 8 years (140). Thus, not all media campaigns and school-based educational programs have been successful in preventing hazardous or unhealthy substance use (141,142). Tailored interventions that take into account socioeconomic, cultural, and age and gender characteristics of children and adolescents are more likely to improve the effectiveness of the interventions.

Figure 1-9. Use and risk perception of marijuana. The prevalence rate for marijuana use in the past 12 months and the perception of marijuana as a dangerous drug in 12th graders (18-19 years old) between 1975 and 2012. When teenagers perceived marijuana as dangerous, the prevalence of drug use was low and vice versa. (From Johnston LD, O'Malley PM, Bachman JG, et al. Monitoring the Future National Survey Results on Drug Use. 2012 Overview. Publication No. 07-6205. Bethesda, MD: National Institutes of Health, 2012.) Currently, prevention strategies include not only educational interventions that are based on comprehensive school-based programs and effective media campaigns and strategies that decrease access to drugs and alcohol but also strategies that provide supportive community activities that engage adolescents in productive and creative ways. However, as we begin to understand the neurobiological consequences that underlie the adverse environmental factors that increase the risks for drug use and addiction, we will be able to develop interventions to counteract these changes. As we deepen our knowledge of the ways in which different genes (and their encoded proteins) make a person more or less vulnerable to taking drugs and addiction, more targets will be available to tailor interventions for those at higher risk. Finally, we can also expect a renewed focus in the near future in the research and development of interventions that increase general resilience that leads to

universally better outcomes. Particularly promising in this context are the recent results of a major longitudinal study that showed a dramatic positive influence of childhood self-control on a wide range of life outcomes, including substance use risk, overall health, and financial status (143). Future studies are needed to investigate whether there are other factors that also contribute to the significant reduction of the consumption of alcohol and other drugs among adolescents in the United States (ie, some [prosocial] forms of interactions among teenagers through social media rather than in physical venues that favor peer pressure for drug consumption, alternative sources of rewarding behaviors such as some video games).

Treating Addiction The adaptations in the brain that result from chronic drug exposure are long lasting; therefore, addiction must be viewed as a chronic disease (51). This is why long-term treatment will be required for most people with addiction, just as it is for other chronic diseases, like hypertension, diabetes, or asthma (144). By recognizing the likelihood of relapse, this perspective radically modifies our expectations of addiction treatment outcomes, establishing the need for a more rational, chronic management model for addiction treatment (145). The discontinuation of treatment, as for other chronic diseases, is likely to result in relapse. As for other chronic medical conditions, relapse should not be interpreted as a failure of treatment (as is the prevailing view for most people who are diagnosed with addiction), but instead as a temporary setback due to a lack of compliance or tolerance to an effective treatment (144). It is rather telling that the rates of relapse and recovery in the treatment of drug addiction are equivalent to those of other medical diseases (144). The involvement of multiple brain circuits (reward, motivation, memory, learning, stress, emotion, interoception, inhibitory control, and executive function) and the associated behavioral disruptions point to the need for a multimodal approach to the treatment of addiction. Therefore, interventions should not be limited to inhibiting the rewarding effects of a drug—they should include strategies to enhance the salience of natural reinforcers (including social support), strengthen inhibitory control, decrease conditioned responses, improve mood, reduce stress, and strengthen executive function and decision-making. Among the recommended multimodal approaches, the most obvious rely on the combination of pharmacological and behavioral interventions, which might target different underlying factors and thus have synergistic effects. Such

combined treatments are strongly recommended because behavioral and pharmacological treatments are thought to operate through different yet complementary mechanisms that can have additive or even synergistic effects. Thus, it could be expected that addiction treatments that use behavioral interventions would be more effective when complemented with medications to help the patient remain drug-free. For example, behavioral approaches complement most tobacco addiction treatment programs. They can amplify the effects of medications by teaching people how to manage stress, recognize and avoid high-risk situations for smoking relapse, and develop alternative coping strategies (eg, cigarette refusal skills, assertiveness, and time management skills) that they can practice in treatment, social, and work settings (146,147).

Pharmacological Interventions Pharmacological interventions can be grouped into two classes. First, there are those that interfere with the reinforcing effects of addictive drugs (ie, medications that interfere with binding to a target, drug-induced DA increase, postsynaptic responses, or the drug’s delivery to the brain, like antidrug antibodies or medications that trigger aversive responses). Second, there are those that compensate for the adaptations that either preceded or developed after long-term use (ie, medications that decrease the prioritized motivational value of the drug, enhance the salience of natural reinforcers, or interfere with conditioned responses, stress-induced relapse, or motivational aspects of withdrawal). The usefulness of some addiction medications has been clearly validated; for others, the data are still preliminary. For these, most results are limited to promising preclinical findings. Table 1-1 summarizes U.S. Food and Drug Administration (FDA) approved medications and medications for which there are preliminary clinical/preclinical data. Many of these promising new medications target different neurotransmitters (such as GABA, serotonin, or glutamate) relative to older drugs, offering a wider range of therapeutic options. Combining medications may increase their efficacy, as recently shown for a tobacco (nicotine) use disorder treatment (184).

TABLE 1-1 Medications for Treating Drug and Alcohol Addiction

Medications used for physical withdrawal are not included. aAntiepileptic drugs that have been shown to decrease drug-induced DA increases as well as conditioned response. FDA, Food and Drug Administration; GABA, γ-aminobutyric acid; GABAB, GABA type B; 5HT3, 5hydroxytryptamine (serotonin) receptor subtype 3; MAO-B, monoamine oxidase B.

Behavioral Interventions In a similar fashion, behavioral interventions can be classified according to their intended remedial function, such as to strengthen inhibitory control circuits, provide alternative reinforcers, reduce stress, improve mood, or strengthen executive function. Traditionally, behavioral therapy has focused on symptombased targets rather than underlying causes of addiction. However, for other brain disorders, new views of brain plasticity that recognize the capacity of neurons in the adult brain to increase synaptic connections and in certain instances to regenerate (185) have resulted in more focused cognitive–behavioral interventions that are designed to increase the efficiency of dysfunctional brain circuits. This has been applied to attempts to improve reading in children with learning disabilities (186), improve memory-related brain activity in Alzheimer’s disease patients (187), strengthen voluntary cortical control in children with ADHD (188), and facilitate motor and memory rehabilitation after brain injury (88). We are beginning to see the first glimpses of this general approach as potentially applicable to the treatment of drug addiction. For example, a small positive relationship was found between cognitive-specific strategies, such as using positive self-talk and a better ability to cope with the urge to smoke (189). Similarly, a recent imaging study of people who used cocaine showed that specific instructions to purposefully inhibit cue-induced craving were associated with inhibition in the (limbic) NAc, insula, and orbitofrontal and cingulate cortices and reduced cocaine craving (82). Dual approaches that pair cognitive– behavioral strategies with medications to compensate for or counteract the neurobiological changes that are induced by chronic drug exposure are also a promising area of translational research that might, in the near future, provide more robust and longer-lasting treatments for addiction than either when given in isolation (190). A new and exciting area of research in this context is the emerging area of translational research that focuses on understanding how and why behavioral interventions work in terms of neurobiological function and structure (191,192).

Treating Comorbidities The use of multiple substances (eg, alcohol + nicotine or alcohol + cocaine) should be considered in the proper management of individuals with addiction. Similarly, comorbidities with other mental illnesses will require treatment for the mental illness concurrent with treatment for drug use. Because addictive drugs adversely affect many organs in the body (Fig. 1-10), they can contribute to the

burden of many medical diseases, including death from overdoses, cancer, cardiovascular and pulmonary diseases, HIV/AIDS, and hepatitis C, as well as to accidents and violence. Therefore, substance use treatment will help to prevent or improve the outcome for many medical diseases. The HIV/AIDS epidemic provides one of the best examples. Drug use and addiction have been fueling the global spread of HIV from the very beginning of the AIDS epidemic. This inextricable connection is predicated on at least three major threads: (a) the direct effects of contaminated injection drug use on infection rates, (b) the indirect impact of addictive drugs on high-risk sexual behaviors and treatment adherence, and (c) the drugs’ ability to worsen neurological complications that stem from HIV infection. Fortunately, recent research has now shown conclusively that (a) HIV prevention among drug users (which includes HIV treatment) is effective in reducing HIV prevalence and (b) treating SUDs (particularly with the aid of new and more effective medications) improves HIV treatment outcomes and should be parlayed into global instruments for severing those threads once and for all. A particularly promising approach in this context has emerged in the form of the Seek, Test, Treat, and Retain paradigm that seeks out hard-to-reach/high-risk populations, including drug users and those in the justice system, tests them for HIV, links those who test positive to HIV treatment and other services, and provides the necessary support to ensure these individuals remain in the care system (193,194). Similarly, the treatment of SUD decreases the incidence of hepatitis C infection (195).

Figure 1-10. Monoamine oxidase B concentration and cigarette smoking. Positron emission tomography (PET) images of the concentration of the enzyme MAO-B (monoamine oxidase B) in the body of a healthy control and of a cigarette smoker. There are significant decreases in the concentration of the enzyme throughout the body of the smoker. (Reproduced from Fowler JS, Logan J, Wang GJ, Volkow ND. Monoamine oxidase and cigarette smoking. Neurotoxicology. 2003;24:75-82, with permission.)

CHALLENGES FOR SOCIETY In most cases, SUD alienates individuals from both their families and communities, increasing isolation and interfering with treatment and recovery. Because both the family and the community provide integral aspects of effective

treatment and recovery, this identifies an important challenge: to reduce the stigma of addiction that interferes with intervention and proper rehabilitation. The effective treatment of drug addiction in many individuals requires the consideration of social policy, such as the treatment of people with addiction in the justice system, the role of unemployment in the vulnerability to drug use, and family dysfunctions that contribute to stress and that might block the efficacy of otherwise effective interventions. For example, studies have shown that providing drug treatment to prisoners who had a SUD and continuing treatment after they leave prison dramatically reduced not only their rate of relapse to drug use but also their rate of reincarceration (196,197) and overdose (198–200). Similarly, drug courts in the United States, which incorporate drug treatment into the judicial system, have proved to be beneficial in decreasing drug use and arrests of offenders who are involved in drug taking (201). However, despite these preliminary positive results, there are many lingering challenges (202). There are also many unanswered questions that future research should address. For example, what are the active ingredients in the treatment of the drug offender? How does the system address the fact that few offenders stay in treatment long enough to receive the minimally required services? What are the implications of these findings for pretrial diversion laws, postprison reentry initiatives, and so on? The recognition of addiction as a chronic disease that affects the brain is essential for large-scale prevention and treatment programs that require participation of the medical community. The engagement of primary care physicians (internists, family physicians, pain specialists, obstetricians/gynecologists, and pediatricians) and emergency medicine and preventive medicine physicians will facilitate the early detection of drug use in childhood and adolescence. A prerequisite for this will be the implementation of adequate competencies and curricula in medical school education and postgraduate residency training in addiction medicine. These models should be replicated across all health professional training (nursing, physician assistants, dental, pharmacy). Moreover, screening for drug use could help clinicians better manage medical diseases that are likely to be adversely affected by the concomitant use of drugs, such as cardiac and pulmonary diseases. Unfortunately, physicians, nurses, psychologists, and social workers receive little training in the management of addiction, despite being one of the most common chronic disorders, a situation that the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism are trying to address through the

development and deployment of such products as a Screening, Brief Intervention, and Referral to Treatment (SBIRT) service program (203,204), as well as a Web-based tutorial to train substance use healthcare providers. Participation of the medical community in many countries, including the United States, is further curtailed by the lack of reimbursement by most private medical insurance policies for the evaluation or treatment of drug use and addiction. This lack of reimbursement limits the treatment infrastructure and the choices that the addicted person has with respect to their treatment. It also sends a negative message to medical students who are interested in clinical practice, discouraging them from choosing a specialty for which the reimbursement of their services is limited by the lack of parity. Another considerable obstacle in the treatment of addiction is the limited involvement of the pharmaceutical industry in the development of new medications. Such issues as stigmatization, the lack of reimbursement for drug use treatment, and the perceived lack of a large market all contribute to the limited involvement of the pharmaceutical industry in the development of medications to treat drug addiction (205). The importance of this issue had been identified by the Institute of Medicine of the United States, which recommended in 1995 a program to provide incentives to the pharmaceutical industry as a way of helping address this problem (206). The translation of scientific findings in drug use into prevention and treatment initiatives clearly requires partnerships with federal agencies, such as the Substance Abuse and Mental Health Services Administration (which is responsible for US programs to prevent and treat drug use) and the Office of National Drug Control Policy (which is responsible for US programs to control availability and reduce demand for addictive drugs). A good example of progress in this area is the recent publication of the Surgeon General’s Report: Facing Addiction: Alcohol Drugs and Health (U.S. Department of Health and Human Services (HHS), Office of the Surgeon General, 2016). Furthermore, improvements in prevention and treatment programs could result from collaborations with other agencies and groups, such as the Department of Education (which can bring prevention interventions into the school environment), the Department of Justice (which can implement treatment strategies that will minimize the chances of recidivism and reincarceration of inmates with substance use problems), and state and local agencies (which can bring evidence-based and science-based treatments into the communities). As we learn more about the neurobiology of normal and pathological human

behavior, a challenge for society will be to harness this knowledge to effectively guide public policy. For example, as we improve our understanding of the neurobiological underpinnings of voluntary actions, how will society define the boundaries of personal responsibility in those individuals who have impairments in these very same brain circuits? The answer to this and other questions will have implications not only for the management of drug offenders but also for other offenders with such diagnoses as antisocial personality disorder and conduct disorder. Critics of the medical model of addiction argue that this model removes the responsibility of the addicted individual from his behavior. However, the value of the medical model of addiction as a public policy guide is not to excuse the behavior of the individual with a SUD but rather to provide a framework to understand it and to treat it more effectively.

SUMMARY Remarkable scientific advances have been made in the neurobiology of SUD in the domains of genetics, molecular biology, behavioral neuropharmacology, and brain imaging that offer critical new insights into the ways in which the human brain engages in self-destructive compulsive drug seeking that characterizes addiction and the ways in which the human brain engages executive and motivational functional networks that allow us to optimize everyday decisions and plan for the future. Drug addiction engages fundamental neurocircuits of motivation in three stages: the basal ganglia in the binge–intoxication stage to drive incentive salience and habits, the extended amygdala in the withdrawal– negative affect stage to drive stress and negative emotional states, and the PFC in the preoccupation–anticipation (“craving”) stage to drive executive dysfunction, while at the same time enhancing the engagement of interoceptive brain networks that make it difficult to ignore the craving and negative emotional states that dominate the mental state of the addicted person. However, the field is at a crossroads where major advances in understanding the neurobiology of addiction have helped identify promising new medications and improve behavioral treatments but where the translation of these findings into clinical practice is limited by several factors, including the limited involvement of the medical community in the treatment of addiction, the restricted involvement of the pharmaceutical industry, the lack of reimbursement by private insurance policies, and the stigma associated with drug addiction. One of the main challenges for agencies like the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism is to develop and

disseminate knowledge that will help to overcome these obstacles (207).

ACKNOWLEDGMENTS The authors thank M. Arends, R. Baler, M. Egli, R. Huebner, R. Litten, A. Noronha, and M Reilly for thoughtful comments and editorial assistance. This chapter has been adapted and updated from Volkow ND, Li TK. Drug addiction: the neurobiology of behavior gone awry. Nat Rev Neurosci. 2004;5(12):963-970, and Volkow ND and Warren, KR. Drug addiction: the neurobiology of behavior gone awry. Principles of Addiction Medicine. 5th ed.

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CHAPTER 2

Recommended Use of Terminology in Addiction Medicine Richard Saitz, Shannon C. Miller, David A. Fiellin and Richard N. Rosenthal

CHAPTER OUTLINE Introduction Recommended Concepts and Terminology by Construct Conclusions

INTRODUCTION Addiction medicine specialists are uniquely positioned to be “change agents” toward public health. Each should lead by example with the use of medically clear, accurate, and nonstigmatizing terminology. Words reflect and impact the way we think. Nowhere is this perhaps more evident than in the field of addiction medicine. The terminology used in addiction medicine has appropriately evolved with a changing understanding of the condition and evolving attitudes. This is less a reflection of political correctness than it is a response to a need for greater clarity and objectivity. Terminology used by clinicians and researchers should be both scientifically accurate and nonstigmatizing. This chapter serves only to introduce and briefly discuss key issues in terminology, provide references for further exploration, and make recommendations. It is not exhaustive in its coverage of all possible terms related to addiction and its treatment. The American Society of Addiction Medicine’s Journal of Addiction Medicine and other leading journals have encouraged the use of precise nonstigmatizing terminology (1–4). Furthermore, the International Society of Addiction Journal Editors (ISAJE) published a recommendation statement against the use of stigmatizing terms (5). The American Society of Addiction Medicine has published policy statements on the issue of terminology (6,7). Most recently, the U.S. Office of National Drug Control Policy posted a draft statement on changing the language in our field (8).

RECOMMENDED CONCEPTS TERMINOLOGY BY CONSTRUCT

AND

Avoid Stigmatizing the Patient or the Condition, and Seek Medically Defined Terminology Stigmatizing terms can negatively impact quality of care (9–11). For example, research demonstrates that when patients are described as having substance “abuse” instead of a “disorder,” clinicians are more likely to recommend punitive approaches (9,10). While there may not be consensus on exactly which terms in and of themselves are stigmatizing versus which are not, clearly using terminology in a way that ignores the many human aspects of the patient beyond their substance use and defines them by their behavior or condition is potentially stigmatizing. Examples include the use of the terms “alcoholic,” “abuser,” “drunk,” “user,” “addict,” or “junkie.” While some may view the use of age-old terms such as “alcoholic” and “addict” as acceptable in 12-step or other nonmedical settings, these terms could easily be replaced with more medically defined and less stigmatizing terms that incorporate person-first language (eg, patient with “alcohol use disorder” and not “alcoholic,” etc.). Our patients are people first, who secondarily have a disease or disorder; using proper terminology can remind clinicians, families, and patients of that fact.

The Spectrum of Use Several terms are preferred when discussing the spectrum of unhealthy alcohol and other drug use (12). Much of this section appears in an ASAM policy statement (6). 1. Low- or lower-risk use (and nonuse) 2. Unhealthy (alcohol, other drugs) use a. Hazardous use (13,14) or at-risk use b. Harmful use c. Addiction and substance use disorder 3. Low-risk use (or lower risk) or no use refers to consumption of an amount of alcohol or other drugs below the amount identified as physically hazardous and use in circumstances not defined as psychosocially hazardous. This amount could be any (even a small) amount and is empirically derived for each substance. 4. “Unhealthy” covers the entire spectrum including all use related to health

consequences including addiction. Unhealthy alcohol and other drug (substance) use is any use that increases the risk or likelihood for health consequences (hazardous use) or has already led to health consequences (harmful use). Unhealthy use is an umbrella term that encompasses all levels of use relevant to health, from at-risk use through addiction. Unhealthy use is a useful descriptive term referring to all the conditions or states that should be targets of preventive activities or interventions. The exact threshold for unhealthy use is a clinical and/or public health decision based on epidemiological evidence for measurably increased risks for the occurrence of use-related injury, illness, or other health consequences. The term “unhealthy” (just as with the descriptors “unsafe” or “hazardous” or “harmful” or “misuse”) does not imply the existence of “healthy” or “safe” or “nonhazardous” or “harmless” use or that there is a way to use the substances properly (ie, without “misuse”). a. Hazardous or at-risk use is use that increases the risk for health consequences. These terms refer only to use that increases the risk or likelihood of health consequences. They do not include use that has already led to health consequences. Thresholds are defined by the amount and frequency of use and/or by circumstances of use. Some of these thresholds are substance specific and others are not. For example, use of a substance that impairs coordination, cognition, or reaction time while driving or operating heavy machinery is hazardous. Nonmedical use or use in doses more than what is prescribed of prescription drugs can be hazardous. Use of substances that interact (eg, two medications with sedative effects like benzodiazepines and opioids) is hazardous. Use of substances contraindicated by medical conditions is hazardous (eg, alcohol use and hepatitis C virus infection or alcohol use and postgastrectomy states). Any cocaine use can increase risk for myocardial infarction; one-time use of hydrocarbon inhalants can lead to sudden cardiac death; no known level of tobacco use is considered risk-free; any alcohol or nicotine use during pregnancy is hazardous; any use by youth likely increases risk for later consequences; use of any potentially addictive substance is more hazardous for persons with a family history or genetic predisposition to addiction than it is to those at average risk in the general population. Alcohol is a known carcinogen, so there is likely no use that is completely risk-free. On the other hand, there are thresholds at which the risk increases for alcohol, and these

hazardous or at-risk amounts have been specified (12). The exact definitions may change with evolving epidemiological evidence and can also vary by preferences of those making clinical or public health decisions regarding thresholds. In addition, individual factors beyond age, sex, and other characteristics can affect risk (eg, weight), and thresholds are not individualized; although they are useful guides clinically, they cannot be thought of as absolute. For example, it is not the case that drinking just under the threshold is associated with no risk or that drinking just above the threshold confers a substantially greater risk. Finally, some drugs (including alcohol) may have beneficial effects (just like medications have risks and benefits), and these may accrue to different conditions (eg, possible benefits for pain or heart disease, risks for cancer). b. Harmful substance use is the use that has resulted in health consequences. The ICD-10 definition of harmful use can be summarized as repeated use that has caused physical or mental damage (15). Hazardous and harmful are mutually exclusive of each other. These terms apply also to prescription (and nonprescription or over-thecounter medications). The terms could also apply to potentially addictive behaviors. c. See “The Disease” below. The WHO lexicon defines misuse as use for a purpose not consistent with legal or medical guidelines (16). However, “misuse” is also a term used to describe not taking (nonaddictive or others) medication as directed or missing doses (eg, of an antihypertensive medication). The U.S. Department of Veterans Affairs describes misuse as the target of alcohol screening and intervention, including disorder and addiction (and labels that severe misuse). “Misuse” is not an appropriate descriptor for “substance dependence,” “addiction,” or “substance use disorder” because it minimizes the seriousness of the disorder (to “misuse” the substance). “Misuse” also seems to have a value judgment at least potentially implied, as if it were an accident, mistake, or alternatively purposeful (a choice), neither of which would be appropriate for describing the varied states of unhealthy use. As such, “misuse” can be seen as pejorative or stigmatizing. “Problem” use is not preferred because it is not well-defined, used sometimes to refer to harmful use but other times to encompass the spectrum, and can lead to stigmatizing discussion (eg, “you have a problem” or “you are a problem”). “Inappropriate” is not well-defined and carries a pejorative nuance. “Binge or binge drinking” can be useful for public health messaging but needs to

be clearly defined as it is sometimes used to mean a heavy drinking episode but also used to mean a several day long episode of heavy drinking or other drug use (eg, cocaine). “Moderate” drinking (or use) is not preferred as a term because it implies safety, restraint, avoidance of excess, and, even, health. Since alcohol is a carcinogen and cancer risk appears at amounts lower than those generally defined as hazardous, and lower limit amounts harmful to the fetus are not welldefined, better terms for amounts lower than amounts defined as risky or hazardous include “lower-risk” or “low-risk” amounts or simply the term “alcohol use.”

The Disease When referring to the disease, terms that have been defined and agreed upon should be used. This specificity is essential in allowing clinicians to accurately communicate with each other and researchers and policy makers to accurately compare populations. Examples of terms that typically indicate a medical disease and that are roughly synonymous include “addiction,” “substance use (or gambling) disorder,” and “substance dependence.” “Addiction” is a term long used by laypeople, patients, and healthcare providers to indicate a condition that can be described as “characterized by an inability to consistently abstain, impairment in behavioral control, craving, diminished recognition of significant problems with one’s behaviors and interpersonal relationships, and a dysfunctional emotional response” (7). However, the term “addicted” can be problematic because it often incorrectly conflates addiction and physical dependence. In past decades, the American Psychiatric Association (APA) and the World Health Organization International Classification of Diseases developed criteria to provide a consensus definition of this disease known commonly as addiction (15–18). We provide some historical context here. The APA’s Diagnostic and Statistical Manual of Mental Disorders (DSM) Committee on Substance-Related Disorders had “good agreement among committee members as to the definition of the medical disease known as addiction, but there was disagreement as to the label that should be used” (19). “Addiction” was a consideration; however, there was concern that labeling it as such could be pejorative and invite stigma. While there was agreement that the term “addiction” would “convey the appropriate meaning of the compulsive drug-taking condition and would distinguish it well from ‘physical’ dependence,” the concern for stigma resulted in changing the term from

“addiction” to (substance) “dependence.” Thus, “addiction” and “substance dependence” were considered as synonymous and describing the same clinical disease. In fact, a vote for (substance) “dependence” to be used and not “addiction” was won by only one committee member vote. Years later, the DSM’s committee chair as well as the directors of the National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism published an editorial recognizing that the use of “substance dependence” and not “addiction” as the label for this clinical disease was “a serious mistake,” as “this has resulted in confusion among clinicians regarding the difference between ‘dependence’ in a DSM sense, which is really ‘addiction,’ and (physical) ‘dependence’ as a normal physiological adaptation to repeated dosing of a medication.” As such, they urged the APA to adopt the word “addiction” for DSM-5. With the publication of DSM-5 in 2013, the previous DSM terms “substance abuse” and “substance dependence” were made obsolete (18). This was after consistent findings from studies of over 200 000 study participants revealing that these two terms “abuse” and “dependence” were clinically and statistically recognized as representing a single disease with varying degrees of severity, renamed in DSM-5 as “substance use disorder” with mild, moderate, or severe severity ratings. Criteria for the disorder no longer included legal problems but did (newly) include craving. In addition, rather than have the threshold as one or more criteria (as in “substance abuse”) or three or more criteria (as in “substance dependence”), the threshold was set at two or more criteria for “substance use disorder” (20). Again, the Committee on Substance-Related Disorders chose against using the term “addiction” to avoid possible stigma, even though feedback to the committee from the College on Problems of Drug Dependence in 2009 and the Research Society on Alcoholism (2010) supported the use of the term “addiction” (21). “Substance use disorder” is well-defined (18), and the features of “addiction” are carefully described (7). Each can be appropriately used if referenced. The terms overlap and have similar meaning. However, DSM-5 criteria do not define “addiction.” The DSM-5 clarifies “addiction” was not chosen as the label for substance use disorder, not only because of stigma but also because of a desire to avoid conflict with the varied ways the construct is used. While “addiction” is “in common usage in many countries to describe severe problems” (not necessarily DSM criteria) “related to compulsive and habitual use of substances,” and “some clinicians will choose to use the word addiction to describe more extreme presentations” (18), p. 485 the DSM-5 does not

state that addiction should only be used to represent a “severe” substance use disorder. The DSM-5 does not exclude addiction as present in a “moderate” or “mild” substance use disorder, nor does a diagnosis of addiction require that six (or more) criteria of a substance use disorder be present (O’Brien CP Chair, DSM5 Substance-Related Disorders Committee. Personal Communication. 2016). Finally, with respect to the term “dependence,” if this term is used, it should be clearly defined as the ICD-10 disorder, as the DSM-IV disorder, or as physical dependence, which does not necessarily indicate any disorder or addiction and may simply reflect a pharmacological effect.

Treatment Medication (including opioid agonist) treatment of addiction has been mislabeled “drug,” “medication assisted,” “substitution,” or “replacement.” These terms are inaccurate; their pejorative nature and their implicit communication that pharmacotherapy is in some way inferior to psychosocial or mutual help pathways to remission of substance use disorders may be partly responsible for the slow uptake in practice of these efficacious treatments. These treatments do not substitute for, reproduce the effects of, or replace illicit drugs. And medications do not “assist” treatment, they are treatments shown to be efficacious on their own, and studies often fail to show additional benefits of added psychosocial therapies (22–26). More accurate alternatives would be medication treatment, treatment, opioid agonist treatment, or even psychosocially assisted pharmacotherapy (27). The jarring nature of the sound of this last example (from a guide published by the World Health Organization [WHO] in 2009) demonstrates how important language and terminology are in shaping how patients and treatments are viewed. Describing patients as “using” medications, rather than “taking” medications, reflects an even subtler stigma that equates receipt of medications with drug use. Also, during treatment, testing is often performed for addictive substances. In these cases, results should be presented like other medical tests—“positive” versus “negative” and “detected” versus “not detected”—and not “dirty” or “clean,” which are then often used to describe people in a highly stigmatizing way (“I am clean,” “your urine was dirty,” “I tested you today and you were dirty”) (28).

CONCLUSIONS This chapter does not make recommendations regarding what terms people with disorders should use. Some patients (eg, those succeeding in part with participation in social networks such as Alcoholics Anonymous) clearly find benefit to calling themselves an alcoholic or an addict even if it might reflect some internalized stigma. Other patients have strong negative associations to being labeled a drug addict or alcoholic that do not aid in their treatment engagement. Furthermore, patient acceptance of such labels has not been shown to be necessary to achieve good clinical outcomes. The purpose of this chapter is not to police language used or to call out those who use a term with good intentions. It takes time for language to change in society and even in clinical practice. Doing so now in clinical and scientific speaking and writing is the beginning of that process and will ultimately lead to wider use of accurate nonstigmatizing terms (29). Thus, this chapter has made recommendations regarding terms that should be preferred versus those that should be avoided. In general, stigmatizing terms should be avoided, as should disease first constructions. Terms to be avoided by clinicians and scientists because they may be potentially stigmatizing or clinically unclear are outlined in Table 2-1; however, this table is not exhaustive. Scientific and medical terms that are clearly defined and nonstigmatizing are preferred over vague inaccurate terms, terms that are difficult to define, and terms that are used to mean many different things. Better use of terminology can improve clear communication of addiction science and improve quality of care for patients.

TABLE 2-1 Recommendations for Nonstigmatizing, More Clinically Accurate Language

aCurrently marijuana (the plant leaf, stems, and seeds) is not typically sold as medicinal grade or conclusively researched as having more benefits than risks, nor is it FDA approved. Moreover, cannabis is the term more internationally used and is more descriptive relating to compounds being researched to explore medical value—such as cannabidiol. bCould be used if clearly defined and most useful for prescription drug (misuse) when the nature or severity of the condition is unknown. Avoid calling the person a problem or their use a problem. cCan be useful for public health messaging but needs to be clearly defined as it is sometimes used to mean a heavy drinking episode but also used to mean several days of long episode of heavy drinking or other drug use (eg, cocaine). dThis term will likely continue to be used, but it should not imply a binary process (abstinent vs. relapse) that does not reflect real typical clinical course (that can include lapses or in-between states). eA similar term is not typically used for other drugs with addiction liability. This term seems to place tobacco in a category different than other drugs, which may not be helpful considering its high addiction risk and high morbidity and mortality. More favored terms for “smoking” include “tobacco” (or “nicotine”). Further, “cessation” (or abstinence) while highly desired should not be the only goal. Smoking reduction may have limited health benefits related to smoking and may also reduce relapse rates with other substances used by the patient. However, the evidence for smoking reduction having health benefits related to smoking is low, and these results are small compared to complete abstinence.

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4. Broyles LM, Binswanger IA, Jenkins JA, et al. Confronting inadvertent stigma and pejorative language in addiction scholarship: a recognition and response. Subst Abus. 2014;35:217-221. 5. Saitz R. International statement recommending against the use of terminology that can stigmatize people. J Addict Med. 2016;10(1):1-2. 6. Terminology related to the spectrum of unhealthy substance use. 2013. http://www.asam.org/advocacy/find-a-policy-statement/view-policy-statement/public-policystatements/2014/08/01/terminology-related-to-the-spectrum-of-unhealthy-substance-use. Accessed November 18, 2016. 7. Public policy statement: definition of addiction. 2011. http://www.asam.org/qualitypractice/definition-of-addiction. Accessed November 18, 2016. 8. Office of National Drug Control Policy. Changing the language of addiction. https://www.whitehouse.gov/ondcp/changing-the-language-draft. Accessed October 6, 2016. 9. Kelly JF, Dow SJ, Westerhoff C. Does our choice of substance-related terms influence perceptions of treatment need? An empirical investigation with two commonly used terms. J Drug Issues. 2010;40:805-818. 10. Kelly JF, Westerhoff C. Does it matter how we refer to individuals with substance-related problems? A randomized study with two commonly used terms. Int J Drug Policy. 2010;21:202-207. 11. Van Boekel LC, Brouwers EP, van Weeghal J, Garretsen HF. Stigma among health professionals towards patients with substance use disorders and its consequences for healthcare delivery: a systematic review. Drug Alcohol Depend. 2013;131:23-35. 12. Saitz R. Unhealthy alcohol use. N Engl J Med. 2005;352:596-607. 13. Saunders JB, Lee NK. Hazardous alcohol use: its delineation as a subthreshold disorder, and approaches to its diagnosis and management. Compr Psychiatry. 2000;41(2 suppl 1):95-103. 14. Saunders JB, Room R. Enhancing the ICD system in recording alcohol’s involvement in disease and injury. Alcohol. 2012;47(3):216-218. 15. The ICD-10 Classification of Mental and Behavioural Disorders: Clinical Descriptions and Diagnostic Guidelines. World Health Organization, 1992. 16. Babor T, Campbell R, Room R, et al. Lexicon of Alcohol and Drug Terms. Geneva, Switzerland: World Health Organization, 1994. http://whqlibdoc.who.int/publications/9241544686.pdf. Accessed November 19, 2016. 17. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.). Washington, DC: APA, 2000. 18. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders: DSM-5. Washington, DC: APA, 2013. 19. 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. 20. Hasin DS, Obrien CP, Auriacombe M, et al. DSM-5 criteria for substance use disorders: recommendations and rationale. Am J Psychiatry. 2013;170(8):834-851. 21. O’Brien CP. Addiction and dependence in DSM-V. Addiction. 2011; 106(5):1-3. 22. Schwartz RP. When added to opioid agonist treatment, psychosocial interventions do not further reduce the use of illicit opioids: a comment on Dugosh et al. J Addict Med. 2016;10(4):283-285. doi:10.1097/ADM.0000000000000236 23. Friedmann PD, Schwartz RP. Just call it “treatment”. Addict Sci Clin Pract. 2012;7:10. 24. Samet JH, Fiellin DA. Opioid substitution therapy-time to replace the term. Lancet. 2015;385(9977):1508-1509. 25. Wakeman SE. Medications for addiction treatment: changing language to improve care. J Addict Med. 2017;11(1):1-2. 26. Amato L, Minozzi S, Davoli M, Vecchi S. Psychosocial combined with agonist maintenance treatments versus agonist maintenance treatments alone for treatment of opioid dependence. Cochrane Database Syst Rev. 2011;(10):CD004147. 27. Guidelines for the Psychosocially Assisted Pharmacological Treatment of Opioid Dependence. Geneva, Switzerland: World Health Organization, 2009.

28. Kelly JF, Wakeman SE, Saitz R. Stop talking ‘dirty’: clinicians, language, and quality of care for the leading cause of preventable death in the United States. Am J Med. 2015;128:8-9. 29. U.S. Department of Health and Human Services (HHS), Office of the Surgeon General. Facing Addiction in America: The Surgeon General’s Report on Alcohol, Drugs, and Health. Washington, DC: HHS, November 2016. 30. Miller WR. Retire the concept of relapse. Subst Use Misuse. 2015;50 (8-9):976-977. doi:10.3109/10826084.2015.1042333 31. Wolff F, Hughes JR, Woods SS. New terminology for the treatment of tobacco dependence: a proposal for debate. J Smok Cessat. 2013;8:71-75.

CHAPTER 3

The Epidemiology of Substance Use Disorders Rosa M. Crum

CHAPTER OUTLINE Introduction Some EpidemiologicAL Principles Alcohol Use Disorders Drug Use Disorders Recent Trends of Alcohol, Tobacco, and Illicit Drug Use Remission from Substance Use Disorders Correlates and Suspected Risk Factors Comorbidity of Alcohol and Drug Use Disorders Conclusions

INTRODUCTION This chapter is organized to cover several areas. First, a few epidemiological terms and types of epidemiological studies are discussed. Second, some of the literature regarding prevalence, incidence, and trends of alcohol and drug use disorders is reviewed. The remainder of the chapter is devoted to discussing some of the correlates and risk factors associated with substance use disorders.

SOME EPIDEMIOLOGICAL PRINCIPLES Epidemiology has been defined in several different ways but may be considered the study of how diseases are distributed in populations as well as the study of the determinants of disease and health (1–3). Some basic terms used in epidemiology deserve attention in this chapter, because they are helpful in understanding the literature and some of the studies reported here. Prevalence generally is taken to represent the ratio of the total number of cases of a particular disease divided by the total number of individuals in a particular population at a specific time. Incidence refers to the occurrence of new cases of a disease divided by the total number at risk for the disorder during a specified period (4). Prevalence takes into account both the incidence and duration of a disease, because it depends not only on the rate of newly developed cases over time but also on the length of time the disease exists in the population. In turn, the duration of the disorder is affected by the degree of recovery and death from the disease. Incidence generally is taken to represent the risk of disease, whereas

prevalence is an indicator of the public health burden the disease imposes on the community (4). The strength of association between a particular characteristic and the development of disease generally is represented by the relative risk. The relative risk measures the incidence of disease among those with a particular characteristic (such as family history of alcohol addiction), divided by the incidence of disease among those without exposure to that characteristic. If there is no difference in the incidence among those with and without the characteristic, the ratio is equal to 1. The odds ratio is also a measure of the strength of association between a characteristic and disease or other outcomes. A relative risk or odds ratio >1 indicates a positive association of disease with a given characteristic. A relative risk or odds ratio 10 days of opioid use in a 28-day period, was lower in the extended-release naltrexone group (43% vs. 64%, p = 0.001) (9). Moreover, there were no overdose events in the extendedrelease naltrexone group, while seven overdose events were recorded in the TAU group (p = 0.02).

Comparative Effectiveness Studies Comparative effectiveness studies are a subset of effectiveness studies and have been defined as “the generation of and synthesis of evidence that compares the benefits and harms of alternative methods to prevent, diagnose, treat, and

monitor a clinical condition or to improve the delivery of care (10).” The purpose and setting are nearly identical to the purpose and setting of effectiveness studies although the comparator may be a different modality of treatment, for example, medical versus surgical management of coronary artery disease. Rawson et al. (11) compared the effects of 16 weeks of contingency management (CM), cognitive behavioral therapy (CBT), and the combination of the two therapies (CM + CBT) in 171 individuals with DSM-IV–defined stimulant dependence. Retention was superior in the CM and CM + CBT groups compared to the CBT group, p < 0.02. The percentage of study participants achieving 3 weeks of continuous abstinence was also higher in the CM and CM+ CBT groups compared to the CBT group (60%, 69.5% vs. 40%, respectively, p, 0.0001). None of the treatments were superior to the others at the 26 and 52 week follow-up time points. Similar results were reported in a study of CM and CBT in treating cocaine using methadone-maintained patients (12). A pharmacotherapy example of a comparative effectiveness trial is the comparison of sublingual buprenorphine/naloxone versus extended-release naltrexone in the NIDA CTN (ClinicalTrials.gov # NCT02032433). Design considerations involved in evaluating these two different medications have been examined (13). To date, 772 participants have been enrolled. The primary outcome measure is the estimated time to relapse. Secondary outcome measures include abstinence from opioids over time, alcohol and other drug use, withdrawal complaints, adverse events, cognitive function, economic costs, and cost-effectiveness and cost–benefit.

FEATURES OF CLINICAL TRIALS Randomization As described above, clinical trials often use a randomization scheme to assign participants to different treatment arms. The randomized clinical trial (RCT) is considered to be the “gold standard” trial design in the assessment of efficacy (14). The purpose of randomization is to avoid selection bias. Randomization schemes used in SUD trials have been described (15). Randomization can be as simple as assigning each participant to a treatment arm with equal probability although this can lead to imbalances in treatment assignment. The most common randomization method used is the stratified permuted block, which allows for balancing of covariates across treatment arms (14). Block sizes can be varied to

minimize the possibility of the investigators deducing the randomization scheme. More complex randomization schemes such as urn randomization attempt to reduce differences in baseline characteristics by adjusting the probability of assignment to a treatment arm based on the degree of current treatment imbalance (16, 17). Irrespective of the type of randomization scheme used, differences in baseline characteristics of the groups may occur. The degree of influence of the baseline differences on treatment outcome may be estimated using propensity scoring (18).

Blinding “Blinding” refers to the process of concealment of the treatments or group assignments (19). A single-blind protocol conceals the treatment assignment from the participant but not the investigator. The more common double-blind design masks treatment assignment from both the investigator and the study participant. In placebo-controlled, double-blind studies, the active medication and placebo should appear identical in appearance and taste. Since most medications are bitter, placebo capsules or tablets can match bitterness by adding denatonium benzoate (20). Some studies compare two completely different looking medications under blinded conditions. In this instance, participants receive the active medication of one treatment and a placebo treatment of the comparator drug in a balanced fashion. This type of blinding is called by the term “double dummy.” It is not possible to mask treatment assignment in trials comparing different psychosocial therapies. In these types of trials, a new psychosocial therapy is usually compared to an established therapy.

Sample Size, Power, and Effect Size All clinical trials should have a sufficient sample size to detect treatment differences. The estimation of the sample size required for a clinical trial assessing superiority of a medication versus placebo is based on the characteristics of the population under study, whether there are data from clinical trials in this population suggesting a drug–placebo difference and how variable the difference is across studies and statistical considerations, that is, α, the probability of concluding a difference exists between groups when one does not (false-positive rate also known as type I error), usually set at 5%, whether the trial is one tailed or two tailed; β, the probability of concluding no difference

between the groups when one exists (false-negative rate also known as type II error); and the desired power (1-β) to find a true difference if one exists between the treatments. Power is the ability to detect an effect, if, in fact, an effect actually exists; it is strongly influenced by sample size and projected differences between treatment groups. Sample sizes are usually projected to yield power of 80% or greater so that the false-negative rate is 20% or less. Small pilot trials are not considered useful in determining sample size as the confidence intervals are large (21). A confidence interval, expressed as a percentage of probability such as 90%, 95%, or 99%, is an interval estimate in which a derived value such as a mean or median might lie. Thus, a large confidence interval suggests a less reliable estimate of the statistical parameter in question and may lead to an underestimation of the necessary sample size. Sample size estimates may utilize previously published response rates, when available. Suppose an investigator wanted to propose a trial of bupropion for the treatment of methamphetamine use disorder. Previous trials had reported end-of-treatment placebo response rates of 7% (22), 14% (23), and 19% (24). Of note, Elkashef et al. (22) enrolled both individuals who used methamphetamines less-than-daily and those who used daily, while the higher placebo response rates reported by Heinzerling et al. (23) and Anderson et al. (24) were in those who used methamphetamines lessthan-daily. Thus, use characteristics may be taken into account when selecting appropriate placebo response rates. The sample size can then be estimated using the placebo response rate and the proposed differential response in the treatment group. In the absence of literature denoting a drug–placebo difference or placebo response rates, the investigator must choose a difference thought to be clinically meaningful. The placebo response rate might be estimated from other clinical trials involving the substance-using population of interest. Once this is known, the estimated sample size can be calculated (25). The larger the hypothesized difference between the two groups, the smaller the sample size estimate for the trial response rates in clinical trials can be. Trials in substance-using populations may have a higher dropout rate than trials in other disciplines. For example, dropout rates were >40% in those who used cocaine in 8-week randomized trials (26), 47% in a 12-week trial of those who used methamphetamines (27), at 50% in those who smoked cigarettes in a 13-week pharmacotherapy trial (28), 26% and 54% for patients receiving methadone or buprenorphine in a 24-week trial (29). Trials with high dropout rates have missing data issues that can compromise the integrity of the findings, likely leading to type II errors. One way to reduce this possibility would be to increase sample sizes to correct for the high dropout rates.

Another form of missing data in clinical trials is data that is missing intermittently during a clinical trial. Three types of intermittent missing data have been characterized (30,31). These are data missing completely at random (MCAR) defined as being completely unrelated to any constructs being studied, missing at random (MAR) defined as possibly related to observed values but completely unrelated to unobserved outcomes, and missing not at random (MNAR) defined as related to unobserved outcomes. Multiple imputation and full information maximum likelihood models are valid when used to analyze used to MCAR and MAR data (32,33), whereas MNAR data should be subjected to sensitivity analyses (34,35).

Statistical Analysis Plans Statistical analysis plans should specify the proposed analyses for primary, secondary, and exploratory outcomes. The statistical analysis plan can be modified up to the breaking of the blind in a double-blind trial. The plan should define the intent-to-treat (all randomized participants whether they received the intervention or not and whether they may or may not have had data assessments), the modified intent-to-treat (usually randomized, received the intervention, and had at least one assessment), and the per protocol (usually the adherent population that completed the protocol with minimal or no missing data) populations, state the null hypothesis (no difference between groups) and the alternate hypothesis (there is a difference between groups) for a superiority trial, anticipate missing data and define how the missing data patterns will be analyzed, and describe the methods that could be used for missing data in the determination of efficacy. It should be noted that there is no universal set of recommendations from regulatory agencies as to how to handle missing data (ICH E9 Statistical Principles for Clinical Trials). The statistical analysis plan should describe the monitoring and reporting of adverse events, with particular emphasis on events of significance, that is, deaths, near-deaths, and other SAEs.

Statistical Significance and Effect Sizes A statistically significant drug–placebo difference obtained in a superiority trial (usually p < 0.05) may be due to bias, chance, fraud, or a true effect. Given the possible causes of the statistically significant results, the significance of p < 0.05 is commonly but incorrectly interpreted to mean that there is a 5% probability that the null hypothesis is true. Thus, investigators may overestimate the veracity of the findings. To avoid overstating a statistically significant result, it has been

recommended to report effect sizes in conjunction with p values (36). An effect size is a measure of the magnitude of an effect. For example, Cohen’s d, defined as the difference between two means divided by the pooled standard deviation, is a measure of effect size (37). Cohen’s d effect sizes are defined as small (0.2), medium (0.5), or large (0.8 or greater). The reproducibility of the results and the effect size can be tested though replication studies, one of the foundational principles of the scientific method. Reproduction of study results by different investigators in a different set of patients with the disorder adds credence to the findings. In the case of data needed for drug approvals, the concept of “adequate and well-controlled studies” was entered into law in 1962 with the passage of the Kefauver-Harris amendments of the Federal Food, Drug, and Cosmetic Act. Thus, with rare exceptions that are spelled out in the Food and Drug Modernization Act of 1997, the FDA requires replication of study results for drug approvals (38). NIH has also issued a guidance for investigators to enhance rigor and reproducibility of grant findings (39). Thus, both the FDA and NIH encourage rigor in designs to enhance the possibility of replication of findings.

THE RESEARCH QUESTION DICTATES VARIOUS ASPECTS OF TRIAL DESIGN Superiority Designs Superiority designs: In randomized, efficacy, and effectiveness trials, the outcome of interest is whether one intervention comparator produces a superior outcome versus the comparator. For instance, in a double-blind, placebocontrolled efficacy trial, the “null hypothesis” is that there are no differences between the active and placebo medication groups. If statistically significant differences are found, the null hypothesis is rejected and the alternate hypothesis (medication efficacy) is accepted. In the comparison of buprenorphine 16 mg, buprenorphine/naloxone 16/4 mg, and placebo, the proportion of urine samples negative for opioids in the first month of the trial was 17.8%, 20.7%, and 5.8%, respectively (p < 0.001 for both active medication groups) (4). Missing urines were categorized conservatively as “not negative.” The reduction in opioid use at 4 weeks was considered to demonstrate efficacy of the buprenorphine and buprenorphine/naloxone tablet formulations over placebo.

Another type of superiority design is a comparison of a test medication to an active control group. Johnson, Jaffe, and Fudala (40) randomized 162 individuals using heroin to daily doses of 8 mg of sublingual buprenorphine or 20 mg of oral methadone and 60 mg of oral methadone. A double-blind, double-dummy design was used to maintain the blind; that is, participants randomized to the buprenorphine treatment received placebo oral methadone and those randomized to one of the methadone groups received placebo sublingual buprenorphine. (Of note, the double-dummy design is employed to mask treatment assignment when disparate dosage forms are being compared.) Urine samples were collected three times weekly for the 17-week maintenance phase of the study and analyzed for the presence of opioids and cocaine. The buprenorphine, methadone 20 mg, and methadone 60-mg group participants submitted urines that were 53%, 29%, and 44% negative for opioids, respectively. The reductions of opioid use in the buprenorphine group and 60-mg methadone group were superior to the percentage noted in the 20-mg methadone group (p < 0.001 buprenorphine vs. 20 mg methadone; p = 0.04 methadone 60 mg vs. methadone 20-mg group). Thus, a superior response in comparison to a dose of an active control is considered to demonstrate efficacy. Moreover, assay sensitivity was demonstrated as a higher dose of methadone was superior to a lower dose of methadone. Dose–response studies also fall under superiority designs. Since the field of addiction medicine is mostly dealing with patients with chronic conditions (such as addiction), several doses of a medication should be tested in a parallel, fixed dose group design. A statistically significant positive slope is considered to be evidence of efficacy of a medication (ICH-E4 dose–response information to support drug registration) although the lowest dose should also have evidence of efficacy from other studies. Multiple, ascending doses of sublingual buprenorphine (1, 4, 8, and 16 mg/d) were assessed for their ability to reduce opioid use in opioid-dependent (DSM-III) patients (41). Although the a priori comparison for determination of efficacy was the difference in urines negative for opioids between the 1- and 8-mg dose groups (the 8-mg group had more urines negative for opioids (p < 0.0001), and a higher percentage of patients with 13 consecutive negative urines (p < 0.0001)), the trial could also have been analyzed for a dose–response relationship. For example, there was a doubling and tripling of the percentage of participants in the 8- and 16-mg groups who achieved 13 consecutive negative urines, respectively, compared to the 1-mg dose group. Superiority trials may sometimes add a third arm, an active control group. If the active control demonstrates efficacy versus the placebo group, the trial is said

to demonstrate “assay sensitivity” as it aids in the interpretation of findings seen with the drug in question. For example, varenicline was tested against bupropion and placebo for efficacy in smoking cessation. Bupropion was more effective than placebo, demonstrating assay sensitivity. Varenicline’s efficacy was superior to both bupropion and the placebo groups in this study (42). Conversely, if the active control fails to demonstrate efficacy versus placebo, it can be considered to be a “failed trial” rather than a failure to show efficacy if the effect seen with the drug in question also does not separate from placebo responses. Dose–response relationships can also be studied in behavioral therapy trials. Some CM trials evaluate the “dose” or magnitude of a reinforcer given in response to adherence with the targeted behavior. Petry et al. (43) evaluated two different magnitudes of monetary reinforcement ($250 or $560) in 106 individuals using cocaine. Both groups reduced their cocaine use relative to standard care. The higher magnitude monetary reinforcement group also had the longest duration of abstinence relative to standard care (p < 0.05). The frequency of counseling given in medication-assisted treatment is another example of assessment of “dose–response” relationships. One hundred sixty-six DSM-IV–defined opioid-dependent participants were randomized to standard medical management (SMM) and either once weekly (group 1) or three times weekly medication dispensing (group 2) or enhanced medical management and three times weekly medication dispensing (group 3; Fiellin et al. (44)). The percent negative urine samples for opioids in groups 1, 2, and 3 were 44%, 40%, and 40%, respectively, p = 0.82. Enhanced medical management and three times per week dispensing did not increase the treatment response.

Noninferiority Designs Noninferiority designs: A clinical trial that compares two active treatments with the purpose of determining whether the efficacy or effectiveness of one treatment is not worse than the standard established behavioral or pharmacological therapy is a noninferiority trial. Noninferiority trials, previously called equivalence trials, must be of high quality and rigorously conducted. A poorly conducted noninferiority trial could yield a result consistent with noninferiority when a difference between the two treatments could actually exist. Design considerations include the following: (a) what is the noninferiority margin?; (b) what is the sample size and power to detect differences between the treatments?; (c) how will the blind be maintained?; (d) will the study population be similar to those in which the standard treatment was already established?; (e)

is the population being analyzed the “intent-to-treat” population, a modified “intent-to-treat” population, or a “per protocol” population that was fully compliant with the protocol?; in an ITT population, none of the patients are excluded and the patients are analyzed according to the randomization scheme. In other words, for the purposes of ITT analysis, everyone who is randomized in the trial is considered to be part of the trial regardless of whether he or she is dosed or completes the trial; (f) what statistical analyses are being used?; and (g) will sensitivity analyses be conducted to test the robustness of the results? The noninferiority margin can be determined by the treatment effect noted in drug versus placebo superiority trials. Absent such data, the noninferiority margin can be established by expert consensus as it was in the case described below. Noninferiority margins can be as high as 50%, but smaller margins in the 20% range certainly meet the FDA guidelines for a noninferiority margin choice (45). If a 20% margin is chosen, noninferiority of the new treatment may be concluded if the lower bound of the 95% confidence interval (CI) of the difference between the treatments is within the lower bound of the 95% CI of the intent-to-treat population, that is, all randomized participants. The sample size needs to be justified in the protocol and the power should approach or be >90%. It should be appreciated that small sample sizes would bias toward a failure to find differences between the treatments due to a lack of power. A recent noninferiority trial of buprenorphine implants versus sublingual buprenorphine is an example of a noninferiority trial in a substance-using population (46). The purpose of the study was to determine whether buprenorphine implants were capable of maintaining low opioid use or abstinence compared to daily sublingual buprenorphine therapy in currently stable, DSM-IV–defined opioid-dependent patients currently on a sublingual buprenorphine/naloxone dose of 8/2 mg or less. Stability was defined as being on a stable dose of buprenorphine/naloxone with abstinence from illicit opioid use for at least 90 days. To maintain the blind, participants were randomized in a 1:1 ratio to buprenorphine implants with placebo sublingual buprenorphine/naloxone tablets or sublingual buprenorphine/naloxone tablets with placebo implants. Further, since the buprenorphine implants were distinguishable from the placebo implants, the study employed two sets of physicians at each of the 21 sites: one group implanted study participants and the other group treated the participants during the 6-month study. Participants were assessed at week 1 and thereafter at 4-week intervals. A total of 10 urine samples were collected, at monthly visits and four times at random during the 6 months of treatment. A treatment responder was defined as a participant who had 4 out

of 6 months in which no illicit opioid use was detected, either by urine testing or self-report. Urine was analyzed for multiple opioids (codeine, fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, and oxymorphone) by liquid chromatography–tandem mass spectrometry. A 20% penalty was imputed to missing urines in the buprenorphine implant group, adding to the rigor of the trial. Participants could receive supplemental buprenorphine, if necessary. Drug craving, withdrawal, and adverse events were also measured. Power was estimated to be 87.3%, assuming each group had 75% responders. One hundred seventy-seven patients were admitted to the trial. The trial employed a modified intent-to-treat analysis, defined as those randomized to treatment, received implants and sublingual doses of buprenorphine/naloxone or placebo, and had at least one post-baseline assessment. One hundred sixty-five participants completed the study. The buprenorphine implant and the sublingual buprenorphine groups have 96.4% and 87.6% responders, respectively. The lower bound of the 95% CI was within the lower bound of the study confidence interval, establishing noninferiority. Once noninferiority is established, the group difference can be tested for superiority. The response in the buprenorphine implant group was not only noninferior; it was superior to the response rate in the sublingual group (p = 0.03). Sensitivity analyses were conducted; the cumulative 6-month abstinence rate in the buprenorphine implant group (85.7%) was superior to the abstinence rate in the sublingual buprenorphine/naloxone group (71.9%) (p = 0.03).

Adaptive Designs Clinical trials in which sequential assignments of participants to new treatments are made following predetermined decisions rules are called adaptive designs (47). These designs can more closely replicate the type of care clinicians often provide to patients by allowing those patients to receive sequential treatments contingent upon their clinical response. Adaptive designs take into account the order of treatments and adherence to treatment and response of participants during the trial (48–50). The Sequential Multiple Assignment Randomized trial (SMART) design has been proposed to address the types of issues facing clinicians in treating patients with SUDs in which multiple treatments, both behavioral and pharmacological, are available. In the simplest model, participants are randomized to a treatment group and are assessed for response/nonresponse at a decision point. Those patients who do not respond can

then be assigned an alternate treatment assignment while responders may continue with their treatment. Study participants can also be randomized twice, initially to a treatment group and then following a decision point, to a second randomized assignment. Advantages of the SMART design are that it provides options for nonresponding study participants and it allows an assessment of the potential synergistic effects of a treatment sequence. An example of a SMART design in the substance use field is the treatment of DSM-IV–defined heroin dependence with either optimal methadone treatment or stepped care with buprenorphine (51). The purpose of the study was to determine whether buprenorphine could be started as a first-line therapy with switching to methadone if buprenorphine treatment was less than satisfactory. In this study, heroin-dependent participants were randomized 1:1 to initial maintenance doses of 70 mg methadone or 16/4 mg of buprenorphine/naloxone. Transitions were considered at 2-week intervals. Methadone-assigned participants could receive dose increments of 10 mg up to a 120 mg/d maximum based on the following criteria: missed visits within the transition period, insufficient blockade, withdrawal symptoms, or urines positive for illicit opioids. The buprenorphine/naloxone-treated group could receive 8 mg increases during transition periods up to 32 mg using the same criteria. The buprenorphine group could transition to methadone if the 32-mg dose was considered insufficient. In the methadone group, 38 of 48 participants (79%) completed the study. In the buprenorphine group, 77% completed with 17 participants completing on buprenorphine (mean dose = 29.6 mg/d), 20 switched to methadone (mean dose = 111 mg/d), and 11 dropped out. The proportion of negative urines increased over time in both groups with no statistical difference between the groups (p = 0.87). Retention was essentially equivalent across treatment arms; the buprenorphine arm was noninferior to the methadone group (odds ratio = 1.02, 95% CI, 0.65–1.60). The authors concluded that a significant proportion of patients could be treated with buprenorphine/naloxone therapy in a stepped care model with switching to methadone when needed.

OUTCOME METRICS CLINICAL TRIALS

USED

IN

Abstinence and/or reduction of drug or alcohol use are often primary outcome variables in clinical trials involving substance-using populations. The FDA has a guidance on the development of medications for the treatment of alcohol use

disorder that illustrates the FDA’s current thinking on outcome measures and trial designs (52). The FDA advises that trials of treatments for alcohol use disorder should employ randomized, placebo-controlled, superiority designs of at least 6 months duration with a primary end point based on a responder analysis. A responder is either a participant who is abstinent for a significant period of time at the end of a trial, following a negotiated grace period, or a participant who has not experienced any heavy drinking days (defined as having more than four standard drinks for men or three standard drinks for women per drinking occasion). The requirement for the 6-month trial duration is based on literature that abstinence at 6 months predicts abstinence at 5 years (53), with health benefits accruing to the abstinent individual. The FDA’s acceptance of the validity of the percent heavy drinking days end point as a surrogate for clinical benefit is based on studies examining alcohol consumption using a graduated frequencies measure from the National Alcohol Surveys (54), the National Epidemiological Survey on Alcohol and Related Conditions (55), an analysis of transitioning in and out of problem drinking in a 7-year longitudinal study (56), and a pooled analysis of three clinical trials involving problem drinkers (57). Although an unofficial opinion, an FDA medical reviewer has opined that efficacy trials of medications for treatment of stimulant use should have similar durations and outcome measures (58). The responder definition in these trials would include those participants exhibiting abstinence of a duration that predicts “ongoing abstinence and/or good psychosocial functioning and physical functioning” and those with less than full abstinence if the remaining level of use “can be considered nonharmful.” This is in contrast to the recommendations of a group of research and treatment experts who opined that a 50% reduction in drug use was clinically meaningful (59). An analysis of several continuous variables of cocaine use (percent days abstinent, percent negative urine samples, maximum days of cocaine abstinence) and one dichotomous variable (at least 3 weeks of abstinence), measured in multiple clinical trials, related these improvements to reduced cocaine use and improvement of functioning on the addiction severity index (ASI) (60) during a 12-month follow-up period (61). Cocaine abstinence and reduced use of cocaine were also been shown to correlate with decreased levels of endothelin-1 (ET-1), a marker of endothelial dysfunction (62). Moreover, the number of cocaine use days was correlated to the reduction in ET-1 levels.

Quantification of Substance Use The measurement of drug or alcohol use can be by biological assay, self-report,

or a combination of the two measures (63). Urine is the most tested biological fluid tested for the presence of drugs, likely due in part to the noninvasive nature of collecting urine. Relating the measurement of drugs or alcohol in urine to use is more complex than originally thought. Detection times for drugs and alcohol are reported in Table 6-1. Alcohol and most drugs, with the exception of cannabis and PCP, have detection times in urine of 2-4 days. Thus, urine sampling once a week would not cover the potential days of use, possibly resulting in falsely concluding that a patient was abstinent. Increasing urine sampling to 3 days per week certainly covers the majority of the week but brings up the problem of frequent research visits and carryover, that is, consecutive semiquantitative urine positive samples in the absence of new use. Quantitative analysis of benzoylecgonine has been proposed as a method to correct carryover in assessment of cocaine (71). Urine samples and self-report can be discrepant for identification of use. An algorithm integrating both quantitative urinalysis of benzoylecgonine and self-report of cocaine use has been developed (63). Finally, clinical trials in substance-using populations involve missing data, and urinalysis data are no exception. Missing urines can be imputed as positive, neutral, or negative, leading to different results in terms of percent days abstinent or consecutive days abstinent. The worst-case scenario can produce biased estimates in a treatment effect. Missing data in the COMBINE study were subjected to five imputation methods: complete case analysis, last observation carried forward, missing = heavy drinking, multiple imputation (MI) method, and full information maximum likelihood (FIML). The MI and FIML produced the least biased estimates of the effect of naltrexone (72).

TABLE 6-1 Detection Times for Drugs and Alcohol in Urine Samples

Measuring Withdrawal Syndromes Withdrawal syndromes associated with discontinuation of alcohol, caffeine, cannabis, opioid, sedative–hypnotics, stimulants, and nicotine/tobacco are described in DSM-5 (73). Management of withdrawal symptoms is recognized by the FDA as a potential indication for use of medications in alcohol and opioid withdrawal. Management of nicotine/tobacco withdrawal is considered to be a mechanism affecting efficacy of nicotine replacement therapies (74). Although management of withdrawal could be a separate indication for some conditions, viz., cannabis, sedative–hypnotic, and tobacco/nicotine withdrawal if clinical benefit could be demonstrated, for the most part, it is relegated to being a secondary outcome measure in clinical trials. There are multiple withdrawal scales to measure components of opioid withdrawal: the Short Opiate Withdrawal Scale (75), the Subjective Opiate Withdrawal Scale and the Objective Opiate Withdrawal Scale (76), and the Clinical Opiate Withdrawal Scale (77). Alcohol withdrawal domains can be reliably measured using the Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) (78,79).

Measuring Drug Craving Drug craving: There is no universal definition of craving. It is usually defined as a conscious awareness of a desire to use a drug (80). Craving is included in the

DSM-5 diagnostic criteria to consider for a SUD and in the ASAM definition of addiction. In the ASAM definition of addiction, craving is noted as a component of addiction whereby the individual has increased hunger for drugs or rewarding experiences. Craving has a complex relationship with drug use. A full discussion of craving and the limitations of its measurement are beyond the scope of this chapter. Craving can be measured as a single-item construct, but this has been criticized as lacking the breadth to describe dimensional aspects of the experience (81). Craving can also be measured as a multi-item construct like the questionnaire on smoking urges (81). In clinical trials, craving is usually measured as a secondary outcome variable that often serves a role in the convergent validity of behavioral findings, that is, reduced craving associated with reduced use or abstinence. Craving can be measured in real time using ecological momentary assessment techniques where study participants are queried on craving and its relationship to drug intake or abstinence through mobile devices (82).

Measuring Cognitive Function Cognitive function: Although not routinely measured in clinical trials, cognitive functioning may impact outcomes in trials and treatment. Individuals with cognitive deficits have higher dropout rates in substance use treatment (83,84), and substance-using populations often have deficits in cognitive tests. For a full discussion of cognitive deficits in substance-using populations and their possible remediation, the reader is referred to Vocci (85). A few examples will suffice. Those who use cocaine demonstrated cognitive inflexibility (perseverative responding) in the Wisconsin Card Sorting Test (86, 87). There is some evidence that medications may be able to affect set-shifting, improving cognitive flexibility. A 200-mg dose of modafinil corrected a set-shifting deficit in patients with schizophrenia (88), suggesting that medications can affect perseverative responding. Attentional bias toward drugs may factor into treatment response. Poor performance on a drug-related Stroop test (89) and a conventional Stroop test by cocaine-using patients (90) predicted treatment dropout, although further research is needed to establish causality. A cognitive battery could be used during the screening process to evaluate cognitive deficits and balance groups with respect to cognitive dysfunction. Cognitive tests incorporated into clinical trials would need to show that improvement was not due to practice effects. Additionally, improvements in cognition would need to be accompanied by a clinical benefit to serve as an outcome measure for FDA approval of a medication.

Psychiatric Scales There are multiple psychiatric scales used in clinical trials. The Structured Clinical Interview for DSM-5 (SCID-5) is used to systematically evaluate psychiatric diagnoses during screening. The SCID-5 has multiple versions, including a research version and a clinical trial version (SCID-5-CT) that can be customized to map onto the inclusion and exclusion criteria of a trial. Other psychiatric rating scales that measure mood disorders used in trials involving substance-using populations are the Beck Depression Inventory (91), the Hamilton Depression Rating Scale (92), and the Hamilton Anxiety Rating Scale (93). These scales can be incorporated into screening procedures as ancillary inclusion or exclusion criteria, as stratification criteria, or as outcome measures (94). A wide array of psychiatric scales have been developed for various clinical trials over the decades. For example, scales used in the DSM-5 field studies can be found at www.psychiatry.org/dsm5. A Handbook of Psychiatric Measures has also been published (95).

Addiction-Focused Scales The ASI measures problems associated with addiction in several domains: drug and alcohol use, medical and psychiatric issues, legal problems, family issues, and employment status (60,96). Although originally designed to tailor treatment to address problems of patients entering treatment, it has been used in clinical trials to measure alcohol and drug use and associated functioning (97). A fairly comprehensive and easily accessible resource for instruments used in NIDA studies can be found at https://datashare.nida.nih.gov/assessments. Reduction of HIV Risk ScalesReduction of HIV Risk Scales The Risk Assessment Battery measures behaviors associated with drug use and sexual behavior that are associated with HIV risk. It is one of the scales used in trials with substanceusing populations that measure infectious disease risk. A computerized version exists (98). Drug and sexual risk subscores can be evaluated separately. It is usually measured at the beginning and at the end of a trial. The HIV Risk Behavior Scale is an 11-item questionnaire that is also used to quantify drug and sexual risk behaviors that may put the individual at risk of contracting or transmitting HIV (99).

Quality of Life Measures The Medical Outcome Study (MOS) 36-item short form health survey (SF-36)

assesses eight domains of physical and emotional health (100). It can be used to assess changes in health across time in a clinical trial and could be used to satisfy the FDA’s request to demonstrate that changes in drug use produce medical benefit or improvements in well-being to an individual. Another quality of life scale that has gained wide usage is the EQ-5D (101). This scale measures the domains of mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. It has been translated into more than 60 languages, making it a good choice for measuring quality of life issues in international clinical trials where multiple languages would be used in data collection.

Patient-Reported Outcome Measures The NIH has developed a standardized, validated Patient-Reported Outcome Measures Information System (PROMIS) to fill a gap in research on selfreported health measures (https://commonfund.nih.gov/promis/index). Approximately 70 domains of self-reported health can be evaluated using PROMIS. It has been translated into multiple languages and is available on paper, electronic, mobile, and Web-based platforms.

Pharmacokinetic Measures The plasma pharmacokinetics of a medication can yield important information on dosing intervals and pharmacokinetic–pharmacodynamic correlations. For example, daily dosing of 8 mg sublingual and alternate daily dosing of 16 mg sublingual buprenorphine yielded trough plasma levels of 0.80 ng/mL and 0.77 ng/mL, respectively (102). There were no differences in withdrawal scores, suggesting plasma concentrations above 0.7 ng/mL would suppress withdrawal symptoms. Higher doses of buprenorphine yielding higher plasma concentration and higher mu receptor occupancy were associated with greater blockade of hydromorphone’s effects (103). Blockade of hydromorphone agonist effects required buprenorphine plasma concentrations ≥3 ng/mL (104). In vaccine trials, the antibody titer may be correlated to efficacy. Vaccines will produce a variable immune response, resulting in an array of antibody titers. In a cocaine vaccine trial, 21 participants with IgG levels ≥42 μg/mL had more cocaine-negative urines than placebo-dosed participants (p < 0.03) (105). The correlation to antibody titers can guide future vaccine development.

Healthcare Service Utilization Measures

Healthcare service utilization can be measured from the standpoint of the patient or the provider/healthcare system (106). Indicators of healthcare quality include accessibility to treatment, continuity of treatment, the range of services offered, and the integration of care (107). These indicators appear to be more geared to evaluating an existing treatment system but could be incorporated into a clinical trial evaluating one or more of these indicators. For example, treatment accessibility has been studied in a trial where patients seeking methadone maintenance treatment were randomized to an interim methadone group that received methadone for up to 120 days or to a waiting list control (108). To evaluate continuity of treatment and range of services, the Treatment Services Review (TSR) surveys treatment services addressing the seven domains of the ASI provided to patients receiving alcohol or substance use counseling (109,110). Again, it is geared more toward addressing issues in the extant treatment system, but it could be used to evaluate the amount of services accessed by participants during a clinical trial.

Cost Analysis–Related Measures Although rarely a primary outcome measure, economic data obtained during effectiveness trials can assess the economic value of an intervention (111). An economist should be involved in the design of the trial if an economic analysis is contemplated. The main types of analyses are cost-effectiveness analysis measuring benefits in terms of quantity or quality of life as a unitary construct, cost–utility analysis measuring quantity and quality of life across several aspects of health and well-being (eg, quality-adjusted life years or healthy years equivalent are estimates of the benefit of a healthcare intervention), and cost– benefit analysis addresses whether the benefits associated with an intervention exceed its costs. For example, a cost and cost-effectiveness analysis of the nine treatment groups comprising the COMBINE study was conducted in terms percent days abstinent, the incremental cost per patient to avoid heavy drinking, and the incremental cost per patient of achieving a good clinical outcome (112). Three intervention groups were noted to be cost-effective relative to the other treatment groups: medical management (MM) with placebo, MM with naltrexone, and MM with naltrexone and acamprosate. A benefit–cost analysis comparison of interim versus standard methadone treatment failed to reveal any significant monetary differences between the interventions although there was a net monetary benefit noted in the combined study sample (113).

Treatment Adherence Measures Adherence to therapy is an important variable to measure in both behavioral and medication trials. Behavioral therapy sessions can be recorded and assessed for fidelity to the therapy and the therapist’s competence in delivering the therapy (114). Adherence to medication regimens is an issue in clinical trials for all pharmacotherapy trials except those in which the administration of the therapeutic agent is directly observed. Medication adherence can be measured through multiple means: addition of riboflavin into oral medications for measurement in urine samples (115), pill count and medication diaries (116), medication event monitoring systems (MEMS) in which opening of a bottle containing medication is captured electronically (117), self-report (118), direct measurement of the medication in urine (23,24), capsule photographs taken with cellular telephones (119), and pharmacy fill–refill. The reliability and comparability of the various forms of adherence are another consideration in designing clinical trials. In a study in people who used cannabis, riboflavin (vitamin B2) and serum 6-OH buspirone levels showed a declining adherence to medication, whereas pill counts and diaries overreported adherence (116), calling into question the reliability of self-report. The effect of medication adherence can be illustrated in clinical studies attempting to replicate the initial finding of the efficacy of bupropion to reduce methamphetamine use (22). A NIDA-funded replication study of bupropion in individuals who used methamphetamines less than daily methamphetamine reported no difference in reduction of methamphetamine use at the end of the trial between the bupropion and placebo groups (p = 0.32) (24). Adherence, measured by urinary bupropion levels, was reported in 47% of the bupropiontreated group. Thus, this could be considered a failed trial rather than a failure to replicate. A second trial of bupropion in individuals who used methamphetamines less than daily found no significant difference in abstinence between the bupropion (29%) versus placebo (14%) groups in the intent-to-treat analysis (p = 0.08) (23). Medication adherence, measured by bupropion plasma levels, was low (32%). A post hoc analysis of medication-adherent (13/41) versus nonadherent bupropion participants (28/41) reported end-of-treatment abstinence in 54% and 18%, respectively (p = 0.018). These positive and negative findings show the impact of adherence in the replication of bupropion’s efficacy.

MONITORING CONTROL

AND

QUALITY

Data gathered in clinical trials are entered into a confidential database during the trial. The Public Health Service Act (301 (d), 42 U.S.C. 241 (d)) authorizes investigators performing trials involving substance-using populations to withhold information from civil, criminal, administrative, or legislative bodies unless the information is considered a reportable issues, that is, child abuse, elder abuse, or threats of violence toward others (120). The privacy of research participants is ensured by the obtaining a Certificate of Confidentiality from the NIH or the FDA. Participants’ data are coded to establish confidentiality. Confidentiality at the research site is maintained by keeping the linking file separate from the database, password protecting the database, and restricting access to individuals who need to input or review data. The informed consent document explains that certain outside entities may review case report forms and the database, that is, the FDA, industry monitors if the trial is industry sponsored, or NIH personnel if the trial is NIH funded. Industry-sponsored trial monitors visit a clinical site at least three times: before participants are enrolled, during the study, and at the end of the study. The privacy of the research participant is maintained since only coded data are reviewed. Safety is monitored at the clinical site by the investigators and by the IRB, the DSMBs, the FDA, the pharmaceutical industry (if industry sponsored), and the NIH (if the study is NIH funded). The protocol contains the definition of serious adverse events (SAEs) and how, when, and to whom SAEs will be reported. The investigators have the primary role for participant safety and can discontinue a participant if they think it is in the participant’s best interest to do so. The IRB reviews the protocol prior to study commencement and then periodically reviews enrollment and adverse events. Sometimes, a medical monitor (who is usually blinded with respect to treatment assignment) will review safety issues and advise investigators. In other cases, a DSMB, a collection of clinical trial experts and medical experts that advise the investigators on trial design features, study enrollment, and safety and efficacy issues, will be chartered. The DSMB, when appropriate, can recommend changes in the protocol, up to and including termination of the study. It is the investigator’s responsibility to report DSMB recommendations to the IRB and other regulatory entities. The NIH requires DSMBs for multicenter trials funded by NIH (121) and encourages consideration of setting up a DSMB for trials

involving randomized, blinded data (1). The public reporting and monitoring of national and international clinical trials are done through the ClinicalTrials.gov website. Section 801 of the FDA’s Amendment Act mandates that applicable clinical trials, including NIH-funded trials, be reported on ClinicalTrials.gov. Although phase I studies are exempt from posting on the site, many phase I studies are posted.

REPORTING RESULTS IN A JOURNAL ARTICLE There are over 65 journals in the addiction medicine field. An important consideration by investigators is what journal to send their results to. There is a website specifically designed to assist investigators with this decision process (www.parint.org). This website offers guidance and a tutorial on the process of journal selection and manuscript preparation. Once a journal has been selected, the authors should visit that journal’s website to determine the formatting, word count, and other specific requirements, for example, reporting oversight/institutional review and informed consent procedures. The CONSORT website offers an information checklist of issues to consider when reporting randomized trial results (www.consortstatement.org). The outcome measures and statistical methods used in a trial should be described in the methods section of the paper. The statistical methods used for imputation of missing data should be stated. Planned versus post hoc analyses should be clearly described as the former carries more weight with reviewers, editors, and the journal readership. It is recommended that effect sizes accompany the p values so that readers can judge the strength of the effects reported. The conclusions and recommendations to changes in practice should not go beyond what is supported by the results.

CONCLUSIONS Clinical trials in substance-using populations must comply with all the requirements of performing investigations in human subjects. Additionally, there are unique challenges to performing and interpreting clinical trials in substanceusing populations. The determination of abstinence is not straightforward as carryover may be observed in urine samples, necessitating a correction algorithm. Moreover, there is no consensus as to what constitutes an adequate

duration of abstinence or what level of improvement in psychosocial functioning or well-being would be acceptable in those who do not achieve full abstinence. More research is needed to engage the FDA in determining the issue of what constitutes an adequate response to a pharmacotherapy for cannabis, opioid, and stimulant disorders. The NIAAA has worked with the FDA in determining the level of drinking reduction that is associated with a therapeutic response to a pharmacotherapy (52). Additionally, high dropout rates and other missing data in clinical trials in substance-using populations may lead to type II errors and require sophisticated analyses to account for the missing data. Adherence to taking medication, although not unique to patients with SUDs, is low to moderate in this patient population, another variable that could lead to a type II error. Clinical trial designs need to consider these issues in the design and analysis of future trials in patients with SUDs with the goals of preventing missing data, improving medication adherence, and increasing the reproducibility of results.

Acronyms Explained Certificate of Confidentiality (CoC) A Certificate of Confidentiality is a document obtained from either the NIH or the FDA that allows a researcher to refuse to disclose names or other identifying information about participants in a clinical trial in response to local, state, or federal subpoenas.

Data and Safety Monitoring Board (DSMB) A DSMB is composed of medical and clinical trial experts who are charged with making recommendations regarding study design, enrollment, efficacy issues up to and including trial termination due to overwhelming efficacy, and protocol changes due to safety issues up to and including trial termination for safety reasons. DSMB functions and oversight are distinct from the requirement of study review and approval by an institutional review board. A DSMB is required for all NIH-funded multicenter trials and is encouraged in other situations.

Institutional Review Board (IRB) An institutional review board is composed of a group of at least five individuals possessing professional competence to review research activities and able to

ascertain the acceptability of proposed research in terms of institutional commitments and regulations, applicable laws, and standards of professional conduct and practice.

Investigational New Drug (IND) Application A commercial IND is an exemption to the law that a pharmaceutical company must have an approved drug in order to ship across state lines. The investigational drug can then be shipped to investigators across the United States and internationally if the FDA approves the IND. Another type of IND is an investigator IND, obtained by clinical investigators to study already marketed drugs for indications other than those approved in the labeling.

New Drug Application (NDA) An NDA is a compilation of relevant information regarding the chemistry, manufacturing control data, pharmacology, pharmacokinetics, toxicology, and clinical and statistical analyses of data on a drug product that a pharmaceutical company submits to the FDA in pursuit of marketing approval.

Clinical Trial Phases Phase I studies are the initial studies of a drug in human subjects. Most phase I drug research is conducted in healthy volunteers in inpatient settings. The usual number of participants is 20-80 and the emphasis is on safety and pharmacokinetics of the drug. In the development of medications for substance use disorders, the FDA often requests an interaction study of a putative medication with a known drug of abuse, for example, cocaine, in cocaineexperienced nontreatment seeking volunteers before allowing outpatient studies to commence in persons with cocaine use disorder. Phase II studies, usually conducted in 100-200 study participants, are the initial determination of a drug’s efficacy and safety in the intended patient population. Phase III studies are intended to replicate the efficacy of a drug in an expanded population and to explore the efficacy and safety of the proposed dose range, fixed versus flexible dosing strategies, duration of therapy, and interactions with concomitant medications. It is not uncommon to have 10003000 study participants in phase III studies in order to capture serious adverse

events that occur at low incidence rates. Phase IV studies, also known as postmarketing studies, are often performed to gather further safety data on specific clinical issues, for example, concerns about hepatotoxicity, under “real-world” conditions. Comparative effectiveness trials, also conducted in phase IV, compare different treatments using flexible protocols that allow clinician judgment with regard to dose changes, for example. The comparison group is often a “treatment-as-usual” group.

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CHAPTER 7

The Addiction Medicine Physician as a Change Agent for Prevention and Public Health Kevin Kunz

CHAPTER OUTLINE We Are Responsible Protecting and Promoting The Public Health The Role of the Addiction Medicine Physician Transformational Change A Proven Approach to Effecting Change in Health Care Summary

WE ARE RESPONSIBLE There is an urgent need to translate addiction science into everyday clinical practice, while also translating it into institutional and public policies that constructively impact health. This text presents a vast array of effective evidence-based interventions, which can be applied in clinical and community settings. However, these lifesaving and life-enhancing practices are neither fully appreciated nor adequately applied. Unhealthy substance use is one of the world’s largest and most costly health issues. Unhealthy substance use is prevalent on every continent and in virtually every culture, accounting for the top causes of preventable death and disability on a global scale. In the United States, unhealthy substance use and addiction cause 23% of all deaths (1). In the United States, the unrelenting and accelerating opioid use and overdose crisis of the last two decades has now brought the attention of medicine and health care to a sharper focus on all unhealthy substance use. Despite the availability of a large and growing body of science to guide effective care, American medicine is primarily focused on treating the complications of substance use rather than on the prevention and treatment of substance use disorders (SUDs). It is the ethical responsibility of every physician to provide competent medical care and to incorporate current scientific knowledge into his or her medical practice. Yet SUD have historically been the unattended orphan of the medical profession. A growing workforce of addiction medicine physicians is now positioned to join those of addiction psychiatry to drive system-level changes to improve the quality of patient care and advance population health. They can do this by serving as expert clinicians, teachers and faculty, and

community or governmental-level change agents. Addiction medicine itself has entered a new era. The recent recognition of the subspecialty of addiction medicine by the American Board of Medical Specialties (ABMS) and the Accreditation Council for Graduate Medical Education (ACGME) has brought SUD into mainstream American medicine and has increased the opportunity for all physicians to more effectively address these disorders. There are also ongoing expansions of governmental and health system initiatives to create and fund substance use disorder prevention, treatment, and recovery programs. Thus, medicine and health care at-large are entering the preparation and action phases for addressing this long neglected global malady. The goal of this chapter is to offer an introduction to the role of addiction medicine physician leadership in integrating science and evidence-based practice into systems of care and public health initiatives, large and small.

PROTECTING AND PROMOTING THE PUBLIC HEALTH American medicine and health care may reasonably take pride in the technical application of science and discovery, yet we rank near the bottom on a global rating of health—36 of 37 among developed nations (2). This is nowhere more obvious than in disease and social dysfunction caused or exacerbated by unhealthy substance use. Unhealthy substance use and addiction is America’s number one health problem (3,4). Though death is a crude measure of health, it is informative that nearly a quarter of annual deaths in the United States are attributable to harmful substance use and addiction (1,5–8). These deaths are almost always preceded by medical, social, public health, and economic sequelae of substance use. The good news is that SUD are not only treatable conditions (9,10) but they are also responsive to well-coordinated prevention and public health initiatives, which can be informed by leaders in our field. This is true also for other conditions often referred to as “process” or “behavioral” addictions, such as gambling disorder, sexual “addiction,” problematic Internet use, etc. The current US epidemic of opioid use disorders (11), in which physicians and medicine are complicit, has propelled attention to the role of individual physicians, as well as medicine and healthcare systems generally, in the field of addiction medicine. Physicians and the American public have been sensitized by the opioid crisis rocking our national health and our collective consciousness.

Concern and calls to action to combat the opioid crisis stand in stark contrast to the passivity expressed in relation to the high prevalence of nicotine addiction over the past 50 years and in relation to decades of unhealthy use of other substances. Missing from the current approach of medicine today is the front end of the continuum of healthcare practice: attention to issues of public health and illness prevention. In this space, every physician and especially every addiction medicine physician can incorporate new competencies into their professional practice. Prevention is a woefully neglected aspect of routine medical care when it comes to substance use: unhealthy substance use is a preventable condition and addiction is a preventable disease, which when unaddressed become chronic and more difficult and costly to treat. Progress in the prevention effort in medicine generally and for substance use specifically has been restricted in part by our national healthcare systems, which developed from and are sustained by an acute care disease model (12). There is sparse implementation of available evidence-based prevention and treatment strategies, while there are easily accessible advanced and costly treatment options for late-stage complications of addiction: trauma, organ damage, cancer, metabolic disorders, psychiatric complications, etc. As well, late-stage “interventions” for social sequelae of substance use, such as incarceration, disability, and unemployment assistance, are usually more readily available than less costly and more effective prevention and public health initiatives. This entire situation is now being considered “upside down.” The acute care focus of American medicine has historically rewarded the short-term care of back-end medical complications of substance use, while providing minimal reward for front-end and often more cost-effective prevention. Feinberg (13) suggests that there are other reasons why it is difficult to gain broad institutional support for prevention: success is invisible, lack of drama makes prevention less interesting, statistical lives have little emotional effect, there is usually a long delay before rewards appear, benefits often do not accrue to the payer for prevention, persistent behavioral change may be required, bias against errors of commission may deter action, avoidable harm is accepted as normal, there is a double financial standard in the evaluation of prevention as compared to treatment, commercial interests may conflict with disease prevention, advice is inconsistent or changes, and advice may conflict with personal or religious or cultural beliefs. In a physician’s interaction with a patient, he or she is expected to engage

and apply specific core competencies learned in medical school, residency, and community practice. As physicians, this is what we do. It is our passion. Yet for all the years and money spent on medical education and training, and spent annually in medical practices and healthcare systems, the profession of medicine in America has not adopted or implemented adequate competencies and strategies to systematically improve the population health of our nation’s citizens. All physicians must endeavor to weave into their practice a “red thread” of public health, disease prevention, and governmental policy advocacy, striving to prevent illnesses from occurring or recurring through educating patients and the public, providing effective prevention and early intervention services, and when possible recommending effective public policies and conducting research. Public health services also include efforts to limit health disparities and promote healthcare equity, quality, and accessibility (14). A public health approach and particularly a focus on prevention are essential to effectively address the health issue of unhealthy substance use, as well as preventing its costly medical and social consequences. To address these and other concerns, the landscape of health care in this country must change. Thibault (15) has noted that this requires addressing the full continuum of care from prevention and early intervention to chronic disease management, breaking down the silos of health professional education and practice, and assuring competency rather than curricular completion.

THE ROLE OF THE MEDICINE PHYSICIAN

ADDICTION

The newly recognized field of addiction medicine is embracing these needed changes in medicine as it prepares a physician workforce to assure that all patients receive prevention and early intervention services and effective treatment and disease management for addiction and its many co-occurring disorders. Addiction medicine physicians play four essential roles in this process: providing clinical expertise in direct patient care and in consultation with other providers in multispecialty and interdisciplinary settings; serving as faculty and teachers to educate and train others; performing clinical and health policy research; and functioning as change agents to speed the evolution of needed reforms.

Within addiction medicine and focusing on the role of physicians as change agents, the ABMS and ACGME competencies of systems-based practice and professionalism are especially salient. Systems-based practice is the physician’s ability to “demonstrate awareness of and responsibility to the larger context and systems of health care” and to “be able to call on system resources to provide optimal care” (16). Since unhealthy substance use and addiction are influenced by societal and public policy forces, and impact upon most other areas and disciplines within medicine, a systems-based approach is necessary. The core ABMS and ACGME competency of professionalism includes accountability to society. Addiction medicine physicians can effectively employ this competency by bringing attention and quality care to SUD at a level consistent with the attention medicine gives to other medical conditions. Physicians dedicated to the health of individual patients and families are also ethically obligated stakeholders in health promotion for communities and larger populations. Some physicians eschew these aspects of medical competencies as “politics,” believing that they do not apply to their own practice of medicine. However, it has been wisely stated that “medicine is a social science, and politics is nothing more than medicine on a larger scale” (17). The field of social medicine, not to be confused with socialized medicine, posits that social and economic conditions profoundly impact health, disease, and the practice of medicine; that the health of the population is a matter of social concern; and that society should promote health through both individual and social means (18). Conversely, a disease state such as addiction also profoundly and adversely impacts society. One aim of social medicine includes physician promotion of “social justice” through the reduction of health disparities or inequities deriving from “social determinants of health”—the social, environmental, cultural, and physical factors that different populations are born into and which impact childhood development and adult maturation (19). These factors are often key determinants in the use of addictive substances, in the medical and social consequences of their use, and in the opportunities for medical and social interventions available for prevention, treatment, and recovery. Some practices an addiction medicine physician can employ to fulfill his or her role in this regard are reviewed later in this chapter.

TRANSFORMATIONAL CHANGE

The old adage that a “Band-Aid approach won’t fix this problem” clearly applies to the unsuccessful efforts of medicine and health care to attenuate the morbidity and mortality associated with unhealthy substance use and addiction. Medicine, healthcare systems, and key stakeholders are now being challenged to produce a thorough and dramatic change in the form, character, and appearance of the antiquated interventions, or complete lack thereof, necessary to address unhealthy substance use and addiction. As the 21st century gets under way, we are entering an era ripe for transformational change in the prevention and treatment of SUD. Transformational change (20) derives from a radical divergence from the underlying consciousness, strategy, and processes that an organization or system has been using. It can be identified by a shift in the culture of an organization, field, or population that results in new expectations and new practices. Examples include the near-total restriction of tobacco smoking in public places as well as more private venues, the removal of all tobacco products from major health and drug stores, and the acceptance of routine vaccinations. The United States is now witnessing the emergence of another transformative shift of consciousness: that addiction is a disease and not a character, moral, or criminal problem. Addiction medicine physicians are challenged to lead, contribute to, and actualize strategies and processes driving system changes to reflect this new public and medical reality. Physicians are the ultimate purveyors of messaging and action in this arena because SUD are medical disorders impacted by genetics and environment, and these same medical disorders significantly impact human environment and society. America’s current acute care health system resulted from transformative change triggered by the 1910 Flexner report (21). This report was the basis for a sweeping reform and renewal of American medical education and practice. Physician training was increased to a minimum of 6-8 years post secondary education, medical research adhered to the protocols of the scientific method, physician training itself was restructured in a scientific manner, literally half of all medical schools were closed, and the state regulation of physician education and practice was instituted. These changes—substantial improvements at the time—were fundamental and have remained dominant and are accepted as unalterable. The need for a new shift from an acute care model to one that attends to the full continuum of care from prevention and early intervention to chronic disease management now demands a transformation of similar magnitude to that

initiated by Flexner over a century ago (22). Nowhere is this more obvious than with the prevention and treatment of unhealthy substance use described throughout this text. Transformational change involves breakthroughs and challenges. In the last 20 years, the science of addiction and the evidence base for prevention and treatment have increased significantly. Both the need and the challenges for disseminating and implementing the science and evidence base are starkly apparent to health professionals and others. Physicians can and must take a lead in the campaign for modernization of care for these disorders. A key prerequisite for transformational change is its dependence on leadership that integrates and models the change being sought. If physicians were still using tobacco in large numbers, how would that have impacted the public health campaign for reducing the prevalence of tobacco use and related disease? If physicians seek to work across traditional boundaries with other stakeholders, here too by working collaboratively, they can both model a winning strategy and improve the health of patients and our nation. In this, they can lead. In fact, the skills physicians use so well in the clinical care of patients to positively accentuate and promote the benefits of personal change are needed now to achieve advancement in structure and cooperation between interdependent elements in healthcare systems. Finally and most importantly, transformational change engages the heart. Science, economics, analysis, and critical thinking are necessary yet insufficient to produce lasting changes in behaviors and the collective consciousness. And just as they are in the care of the patient, these are all key drivers of positive changes in systems. Systems are driven by individuals who interact, cooperate, and collaborate with one another. We are not computers or robots. We are driven by our aspirations, by issues, and activities we deeply care about that give meaning to our lives. To actualize system change, addiction medicine physicians armed with the science of addiction and knowledge of best practices for reform have much to offer. The Institute of Healthcare Improvement has promoted and validated the well-known Plan-Do-Study-Act cycle, which breaks the change process into straightforward steps (23). The detail of these steps is incorporated into the content below and illustrated with the case of Dr. Smart.

A PROVEN APPROACH TO EFFECTING

CHANGE IN HEALTH CARE 1. Take a systems approach. 2. Put together a diverse, multidisciplinary team. 3. Develop a shared purpose and plan of action. 4. Act. 5. Evaluate, improve, repeat. 1. Take a Systems Approach. A system is a set of interdependent elements interacting to achieve a common goal (24). Physicians know or can learn the elements and processes in the systems in which they are matriculating and can engage in interactions for improvement. Cooperation (interaction) across traditional boundaries is not as daunting a barrier as often perceived for physicians seeking system change. Medical specialties, other health professions, and system managers often operate in “silos of excellence.” Administrators, financial stakeholders, policy makers, the public, and other interest groups also have their own “world views,” goals, and preferred practices. Although a physician entering this larger system may initially feel intimidation or hesitation, most newcomers will find this a welcoming environment. In this milieu, physicians have a unique capacity to be accepted as participants and critical leaders in improving healthcare systems and advancing the quality of care for their own patients and many others. Physician leaders holding the precept “do what is best for the patient” can bring quality of care into discussions where other outcomes may dominate. Physicians, and particularly addiction medicine physicians, have been absent or scarce in deliberations at nearly every system level due to a limited workforce, overwhelming patient care considerations, or the assumption that “someone is working on this.” Key decisions on the care of patients thus have often excluded effective input from addiction medicine physicians and defaulted to stakeholders with more parochial interests. An effective physician leader first examines the existing situation, then imagines possibilities, and seeks a process and a plan for improvement. He or she can participate in changing the system shortcomings or in creating a new system. There are several realities physician leaders can recognize early: leadership is an action, not a position; leadership is not victimhood—you cannot be a leader and a victim simultaneously; leaders define reality—with data; leaders develop and test changes; leaders take risk and have courage, because

complacent or threatened persons or organizations may react loudly and negatively to a proposed change; leaders must cross boundaries, stepping outside and letting go of defending their silo; and physician leaders seek and achieve new interactions with a diversity of stakeholders (25).

Dr. Smart’s Emergence as a Change Agent A family medicine physician we will call Dr. Smart works in a large hospital and clinic system and was frustrated because she could not receive referrals and assistance in a timely manner for her patients in need of acute substance use disorder services, including consultations, and accepted level of care placements. Depending on the immediate patient need, her frustration might come from the hospital’s medical–surgical charge nurse (we have a lot of very sick patients right now, we are too busy to take care of a person with an alcohol use disorder or person with drug addiction), the system’s pharmacy (our protocol is for our medical director to review the patient’s history, current diagnosis, and a psychiatry consult before we dispense the medication you requested), the billing and utilization office (your patient in withdrawal is no longer suicidal, you will have to discharge him today), from one of her system physician colleagues (why do you go overboard for these patients when they are not interested in helping themselves), or from a patient’s family (my 17-year-old daughter has seen you twice asking for help, why isn’t her drug problem being addressed?). In fact, these are not uncommon situations, usually deriving from stigma, ignorance, and outmoded and inefficient care systems. The family physician could address one individual or service at a time—and ultimately all the staff in those departments —to educate them about the disease of addiction and the modern treatment of SUD. Yet that might not be productive. Taking a systems approach would involve all of the key stakeholders and be a better use of her time and energy toward long-term, integrated, and mutually appreciated solutions. As a physician, she can go to system’s medical director or as far up the chain of administration as possible, state her concern clearly, acknowledge that it is an imperfect world yet that improved patient care and reduced system cost are everyone’s goal, and within reach if addressed department or system wide. This physician becomes a change agent and a physician leader the day she speaks with an authority or “lever puller” within the system. Along the way, she must be an effective communicator and teacher because from the lower echelons to the highest in health systems, education of the stakeholders in essential. Now Dr. Smart needs to be both an advocate for her patients and an advocate for

system change. To do that, she must become an enduring champion for change. A single phone call or visit with the medical director or head nurse will not suffice. Instead of complaining to the pharmacist, pleading with the charge nurse or cursing utilization review, her approach to system change mimics her approach to patients: they deserve care for their ailments, optimization of their functioning, and attention to their ongoing well-being. Dr. Smart’s job is to let system stakeholders know change is possible, to assist them, and to collaborate with them, and it will take time. Now that she has the attention of system “lever pullers,” what is next? Read on. 2. Put Together a Diverse, Multispecialty, Interdisciplinary Team. Transformational change needs a broad set of participating stakeholders, from both the internal and external organizational environments, who can collaborate with each other. It requires inclusion and collaboration by diverse and multiple stakeholders: from medicine and all disciplines, including nursing and other health disciplines; from financial, governmental, and policy players; from patients and the public. Health care affects all Americans. It is one of our highest national values and impacts all aspects of public and social health. It is central to the successes and failures of American society and culture. We all own it, and we must all participate in improving it. Every addiction medicine physician has a contribution he or she can make. Multispecialty (physicians from different medical specialties), interdisciplinary teams provide for a group of healthcare professionals from diverse and complimentary fields who work together toward a common goal; ideally accelerating a cooperative environment. Physicians can assume the role of champion, but they do not always have to be the team leader; they can assume a mentoring role by modeling listening skills, openness to change, willingness to make suggestions and continued participation on the team. Physicians should expect and encourage a diversity of styles—most healthcare professions have their own cultures and values, and the reality is physicians do not own the single standard. Stakeholders who are involved in the process of change are more likely to be cooperative if they sense openness instead of resistance when offering a view, which varies from physicians’ traditionally authoritarian stance of having the ultimate answer. When meeting with nonphysicians, the pool for ideas and suggestions can be expanded when the physician or group leader asks each person for his or her concerns and opinions. Inclusion of freely expressed and diverse ideas from a group of interdisciplinary stakeholders accelerates a cooperative environment.

Dr. Smart Plots a Course Dr. Smart was not discouraged by the reception she received from her superiors in the health system. They listened patiently, agreed that things could be improved, and in a pleasant tone suggested she speak with individual department chiefs and persons she perceived as obstacles to better care for her patients. Having already had nonproductive individual conversations with the subject departments and staff, she decided to bring all the players together. For 6 weeks, she “socialized” the idea of an intradepartment meeting and sought out sympathetic or at least open-minded staff to participate in an opening dialogue. She designed a 60-minute lunch time meeting titled “Introduction to Standards of Care for Patients with Unhealthy Substance Use and Addiction.” Key leaders and staff from all departments were invited, as well as clinic and hospital staff physicians (medical, surgical, behavioral health services, ED, and critical care units). She also invited external stakeholders including community treatment programs, the county health officer, and substance use professionals. For an agenda, she first gave a 10 slide overview of SUD, levels of care, and state of the art prevention and treatment modalities. Next, she facilitated very brief statements from willing and prepared representatives from nursing, pharmacy, social services, behavioral health, and 2 other physician champions from the obstetrical and internal medicine staff. The session was well attended. At the close, she asked how many attendees thought that additional sessions and discussions would be useful. She signed up 16 panelists and attendees to meet again in a month. Dr. Smart now had the beginnings of a multispecialty, interdisciplinary team. 3. Develop a Shared Purpose and Plan of Action. Human systems derive their identity from a shared, common purpose. The dialogue of change thus begins with the question, “What are we trying to accomplish?” And to engage the passion of the participants asks, “Why is this important to you?” It is crucial to develop and gain consensus on the purpose and aim of the desired improvement, enlisting and aligning as many stakeholders as necessary or possible to consider alternatives to the status quo. State clearly the testable objective of the plan. The “aim” of the desired improvement should be time specific, measurable, and define the patients, populations, and system(s) to be involved. The Institute of Medicine has suggested that there are six broad categories for most desired improvements: safety, effectiveness, patient centeredness, timeliness, efficiency, and equity.

Detail the components of the plan, remembering you may be starting small, and develop quantitative measures, which can be used to monitor and calculate the outcome. With the outcome data, it can be determined whether the plan resulted in an improvement. As a physician leader, your own commitment and endurance are essential. Physicians who desire and work for change that will result in a system’s improvement become knowledgeable and gain experience in making small improvements and always cooperate with others. They start with small goals and objectives and seek collaboration. Defined rules are a critical attribute of a cooperative environment. This is a group process, since persons both within and outside of the departments or organization have varying experience on the system elements involved and can suggest change concepts from which a proposed single change is chosen. No change effort will succeed without cooperation. Cooperative interactions may be ethical and altruistic, yet they are a prerequisite and pragmatic strategy for engineering change in interdependent systems. Effective leaders learn, model, and teach expertise in basic dialogue and group communication. Basic negotiation attitudes and skills are requisite for success and can be acquired from reading or courses. Success is more likely when the decision process focuses on issues and not individuals and empowers ownership in the change process and results. The frequently expressed complaint that nothing will change until “that person moves on” is counterproductive. There are always issues that can be win–win for all parties. Change is dependent on new solutions, not lamenting current shortcomings.

Dr. Smart and the SUD Standards of Care Team At the first meeting of the self-identified team, also over lunch, there was a broad and often divergent range of concerns expressed. Dr. Smart facilitated the meeting and made sure everyone was able to state their issues regarding the care of patients with SUD. As attendees spoke, she used a whiteboard to categorize and list the issues presented. She titled the sections: safety, effectiveness, patient centeredness, timeliness, and efficiency. The group then began meeting weekly. By the 6th week, the self-named SUD Standards of Care Team had produced a list of five system changes that all agreed would be beneficial and could be accomplished: routine application of screening; brief intervention and referral to treatment (SBIRT) in the system’s adult primary care; urgent care and

emergency departments; routine use of the Screening to Brief Intervention (SB2I) tool (26) for patients ages 12-21; an available counselor to assist with BIRT when indicated; a warm hand-off to a social worker to assure a confirmed “bridge” to the indicated level of SUD treatment for patients needing more than a brief intervention; and immediate availability of medications from the pharmacy when requested by physicians and other providers identified as members of the SUD Standards of Care Team. A document with the targeted changes and a detailed plan for implementing them and evaluating the results was vetted by the group over several meetings. Team representatives then brought their proposal to the health system leader with whom Dr. Smart had met with 3 months earlier. She was impressed that personnel from various departments had worked together on the proposal and agreed to set a meeting with the team representatives and system department–level leaders who would need to endorse and oversee implementation of the proposal. This was accomplished 4 weeks later with a consensus that the objectives of the team were reasonable and the plan could be implemented and tested. 4. Act. With a detailed plan in place and the assurance that the people, procedures, and processes needed to execute it are in place, and after all stakeholders—including patients if they are involved—are onboard, begin on a planned start date.

Dr. Smart’s Initiative Gets Traction Dr. Smart set another system-wide informational meeting where the team and the critically involved system leadership and administrators outlined the rationale and objectives for the plan of improvement, with a detailed timeline, responsibilities, and evaluative methodology. The implementation start date was announced at the meeting and subsequently through multiple health system communication paths. The meeting was attended by 75 internal and external stakeholders and interested staff. 5. Set Up a Strategy for Evaluation and Improvement. Monitor key aspects and measures for the plan, document problems and unexpected observations, and begin preliminary analysis of the data. Recall the saying “what get measured gets done,” and remember that there is no innovation without data. Take the time and engage the people and system elements that the cycle will involve or impact. At appropriate and strategic intervals, analyze the emerging data. Compare

them with your predictions and discuss with the team, reflecting on what was learned. Determine what modifications should be made and prepare a plan for next steps.

The SUD Standards of Care Team Follows Through Implementing the four overlapping objectives of the plan had some early bumps and unexpected consequences. Modifications were made. At the 3-month evaluation mark, the predetermined evaluative indices were reported: repeat visits and readmissions through the ED decreased, intensity of laboratory and other diagnostic and care services for substance using patients decreased, and the number of clinic patients entering community-based outpatient treatment and the use of appropriate medications increased. A survey of involved system staff indicated that they believed the changes had improved patient care, communication, and morale. The various departments and the care providers who were directly caring for the patients indicated that they were both satisfied with the results of the changes. The administration presented data showing that there was no increased cost associated with the changes and likely a savings in several departments and expense categories. A predesigned patient survey indicated that those who received services under the new changes were highly satisfied.

The SUD Standards of Care Team Becomes Institutionalized The SUD Standards of Care Team continued to meet regularly and address other system-based modifications to improve quality care and reduce costs. Eighteen months after Dr. Smart’s first meeting with the system leadership, she was approached by the health system’s Medical Director, its CEO, and the Chair of the Family Medicine Residency and asked to consider establishing an ACGME accredited addiction medicine fellowship, for which the health system would provide funding and other support.

SUMMARY Unhealthy substance use impacts people we work with, live with, and those with

whom we share community; persons we care about; and those we love. On some level, it is personal for all of us. Foremost, health care is much more than a calculated business venture; it is compassion and caring for all with whom we are connected. Every addiction medicine physician is needed to bring prevention, high-quality treatment, and systems improvement into reality. Addiction medicine can lead and contribute to the well-being of communities and nations as well as to our patients and their families. Whether physician contributions are made in assessing, planning, and acting on improvements in a small clinic, a large healthcare system, or at the level of governmental policy impacting public health, this is all within the mission and character of the field of addiction medicine. Addiction medicine physicians are clinical experts, faculty and teachers, researchers, and change agents. This is our work and we can succeed.

REFERENCES 1. Addiction Medicine: Closing the Gap between Science and Practice. New York: The National Center on Addiction and Substance Abuse, 2012. 2. U.S. Health in International Perspective: Shorter Lives, Poorer Health. Washington, DC: Institute of Medicine of the National Academies, 2013. 3. Substance Abuse: The Nation’s Number One Health Problem. Princeton, NJ: The Robert Wood Johnson Foundation, 2013. http://www.rwjf.org/content/dam/farm/reports/reports/2001/rwjf13550 4. Mokdad AH, Marks JS, Stroup DF, Gerberding JL. Actual causes of death in the United States, 2000. JAMA. 2004;291(10):1238-1245. 5. Kochanek KD, Murphy SL, Xu J. Deaths: Final Data for 2014. Natl Vital Stat Rep. 2016;65(4):1-122. http://www.cdc.gov/nchs/data/nvsr/nvsr65/nvsr65_04.pdf#page=89 6. 2014 SGR—The Health Consequences of Smoking—50 Years of Progress. A Report of the Surgeon General. Full Report/Supplement_CDC 2014 Data found at TobacooFreeKids.org. https://www.tobaccofreekids.org/research/factsheets/pdf/0176.pdf 7. CDC 2006–2010. Average Annual Number of Deaths and Alcohol-Attributable Deaths (AAD). http://www.cdc.gov/pcd/issues/2014/pdf/13_0293.pdf#page=8 8. Stahre M, Roeber J, Kanny D, et al. Contribution of excessive alcohol consumption to deaths and years of potential life lost in the United States. Prev Chronic Dis. 2014;11:E109. doi:10.5888/pcd11.130293. 9. Richter L, Kunz K, Foster SE. A public health approach to addiction: the health professional’s role. In: Herron AJ, Brennan TK, eds. Essentials of Addiction Medicine. 2nd ed. New York, NY: American Society of Addiction Medicine/Wolters Kluwer, 2015. 10. US Department of Health and Human Services, Office of the Surgeon General. Facing Addiction in America: The Surgeon General’s Report on Alcohol, Drugs, and Health. Washington, DC: US Department of Health and Human Services, 2016. https://addiction.surgeongeneral.gov/surgeongenerals-report.pdf. Accessed February 15, 2017. 11. Rudd RA, Seth P, David F, Scholl L. Increases in Drug and Opioid-Involved Overdose Deaths— United States, 2010–2015. MMWR Morb Mortal Wkly Rep. 2016;65:1445-1452. doi:http://dx.doi.org/10.15585/mmwr.mm655051e1. 12. Marvasti FF, Stafford RS. From sick care to health care—reengineering prevention into the U.S. System. NEJM. 2002;367(10):889-891. 13. Feinberg HV. The paradox of disease prevention: celebrated in principle, resisted in practice. JAMA.

2013;310(1):85-90. 14. What is Public Health? CD Foundation http://www.cdcfoundation.org/content/what-public-health 15. Thibault GE. Reforming health professions education will require culture change and closer ties between classroom and practice. Health Aff (Millwood). 2013;32(11):1928-1932. 16. A trusted credential. Downloaded on May 5, 2017 from http://www.abms.org/board-certification/atrusted-credential/based-on-core-competencies/ 17. Virchow R. Der Armenarzt. Medicinische Reform 1848:125–127. 18. Mackenbach JP. Politics is nothing but medicine on a larger scale: reflections on public health’s biggest idea. J Epidemiol Community Health. 2009;63:181-184. 19. Social Determinants of Health. https://www.healthypeople.gov/2020/topics-objectives/topic/socialdeterminants-of-health 20. Gass R. What is Transformational Change?. Center for Transformative Change. htpp://transform.transformativechange.org/2010/06/robertgass 21. Flexner A. Medical Education in the United States and Canada: A Report to the Carnegie Foundation for the Advancement of Teaching, Bulletin No. 4. New York, NY: The Carnegie Foundation for the Advancement of Teaching, 1910:346, OCLC 9795002. Retrieved June 8, 2015. 22. Duffy TP. The Flexner Report—100 Years Later. Yale J Biol Med. 2011; 84(3):269-276. 23. Institute for Healthcare Improvement. http://www.ihi.org 24. Nolan TW. Understanding medical systems. Ann Intern Med. 1998;128(4): 293-298. 25. Reinertsen JL. Physicians as leaders in the improvement of health care systems. Ann Intern Med. 1998;128(10):834-838. 26. Levy S, Weiss R, Sherritt L, et al. An electronic screen for triaging adolescent substance use by risk levels. JAMA Pediatr. 2014;168(9): 822-828. doi:10.1001/jamapediatrics.2014.774.

SECTION 2

Pharmacology

CHAPTER 8

Pharmacokinetic, Pharmacodynamic, and Pharmacogenomic Principles Lori D. Karan and Anne Zajicek

CHAPTER OUTLINE Introduction Basic Pharmacology Concepts Summary

INTRODUCTION Pharmacotherapy in the clinical practice of addiction medicine is based on the application of pharmacological principles to ease the suffering from addiction to various addictive substances and behaviors. Pharmacological principles in this chapter will focus on the pharmacokinetics of drug delivery to the brain and placenta; pharmacogenomics, the genetic differences in metabolism, transport, and receptors that effect interindividual differences in drug disposition and response; and pharmacodynamics effects including tolerance and withdrawal.

BASIC PHARMACOLOGY CONCEPTS Pharmacokinetics Pharmacokinetics describes the time course of drug concentrations in blood and tissues (eg, , brain). Drug concentrations in blood and other sites are determined by absorption, distribution, metabolism, and elimination. The magnitude of a drug’s pharmacological effect depends on the free (unbound) drug concentration at its site of action.

Absorption Absorption is the process of drug movement from the site of drug delivery to the site of action. Psychoactive drugs can be taken orally (ethanol, amphetamines, barbiturates, opioids), intranasally (glue, solvents, amyl nitrate, cocaine, heroin), via smoking (combusted versus vaporized and then aerosolized sources of nicotine, marijuana, freebase cocaine), intravenously (heroin, cocaine, methamphetamine), transdermally (fentanyl and nicotine patches), and by subcutaneous injection. Figure 8-1 illustrates the differences in drug

concentrations over time for the various routes of administration. The more rapidly a psychoactive drug is delivered to its site of action in the central nervous system, the greater are its reinforcing effects. The more rapidly achieved and higher peak concentrations from intravenous and pulmonary (smoking) routes illustrate this point.

Figure 8-1 Venous drug concentrations after different routes of administration. Bioavailability is defined as the fraction of unchanged drug that reaches the systemic circulation after administration by any route. The bioavailability factor (F) takes into account the portion of the administered dose that is able to enter the circulation unchanged. For intravenously administered drugs, F = 1.0 (100%). Bioavailability depends on a given drug’s site-specific membrane permeability, activity of drug transporters, and its first-pass metabolism. Firstpass metabolism is the metabolism that occurs before a drug reaches the systemic circulation. It occurs most extensively for lipid-soluble drugs such as morphine, methylphenidate, and desipramine and can significantly reduce bioavailability. Morphine, for example, requires nearly twice the dose when administered orally as compared to intravenously. First-pass metabolism is relatively unimportant for drugs administered through the intravenous, sublingual, intramuscular, subcutaneous, and transdermal routes, since drugs administered by these routes enter the general circulation directly. For orally administered drugs, the rate of absorption is affected by (i) the

pharmaceutical properties of the oral dosage form, for example, immediate versus extended release formulation; (ii) the pH of gastric contents (drugs can be destroyed by extreme acid or basic conditions); (iii) gastric emptying time (faster gastric emptying time results in more rapid delivery to the small intestine, the site of absorption, except with dumping where the delivery to the small intestine is too fast to be optimally absorbed); (iv) intestinal transit time (for drugs absorbed in the small intestine, there is an decreased rate of absorption with a faster intestinal transit time); (v) integrity of intestinal epithelium; and (vi) the presence of food (which decreases the interaction time between the drug and the intestinal villi) (1). Efforts have been made to reformulate potentially addictive prescription drugs to reduce the rates of absorption in order to reduce the peak concentrations and reduce this reinforcing effect (2). Intranasal drug administration holds promise not only for medications with a local effect on the nasal mucosa but also for potent medications with systemic activity such as peptide hormones and antimigraine medications. The nasal cavity is covered by a thin mucosa, which is well vascularized. Local anesthetics such as cocaine are vasoconstrictive and limit their own absorption. Once transferred across the single epithelial layer of the nasal mucosa, drug molecules directly enter the systemic blood circulation without undergoing first-pass metabolism. In addition, the central nervous system activity of intranasal naloxone may be enhanced via absorption through the cribriform plate high in the nasal cavity as well as via the olfactory and trigeminal nerves (3). Smoked and inhaled drugs bypass the venous system and thus have the most rapid rate of delivery. Absorption of inhaled drug depends on the physical characteristics of the drug, including its volatility, particle size, and lipid solubility (4). Drugs that reach the alveoli of the lungs have rapid access to the bloodstream through closely applied capillary alveolar surfaces on the large pulmonary surface areas. Because a large portion of the cardiac output passes through the pulmonary circulation, both smoked nicotine (including its freebase form) in cigarettes and freebased cocaine are examples of highly reinforcing drugs that are rapidly delivered to the brain. Drugs must pass through biological membranes to be absorbed. With passive diffusion, biological membranes are more permeable to lipid-soluble and uncharged molecules. Some drugs have diminished absorption because of a reverse transporter associated with P-glycoprotein. This reverse transporter actively pumps drug out of the gut wall cells back into the gut lumen. When P-

glycoprotein is inhibited, increased drug absorption results. Some food and drug interactions alter first-pass metabolism and absorption from the intestinal wall. For example, components of grapefruit juice and other foods that either inhibit (eg, grapefruit juice) or induce intestinal wall CYP3A4 or P-glycoprotein can lead to altered bioavailability of drugs that are substrates for this cytochrome (5,6). Also, the nonselective monoamine oxidase inhibitors (MAOIs) such as phenelzine and tranylcypromine—and, to a much lesser extent, the MAO B inhibitor selegiline and the reversible MAOI moclobemide—inhibit MAO A in the intestinal wall and liver. This inhibition diminishes the first-pass metabolism of tyramine, which is present in cheeses and various foods such as cured meats and yogurt in which protein breakdown is used to increase flavor (7). When tyramine, an indirect-acting sympathomimetic amine, reaches the systemic circulation, it can produce increased release of norepinephrine from the sympathetic postganglionic neurons; this, in turn, can result in a severe pressor response and hypertensive crisis. Hastening gastric emptying can help to achieve a more rapid drug effect without altering bioavailability. Taking a drug on an empty stomach with at least 200 mL of water and remaining in an upright position can speed gastric emptying. Food, recumbency, heavy exercise, and drugs that slow gastric emptying (such as narcotics and anticholinergic drugs) can result in later and lower peak concentrations of the index drug. Upon absorption, when drug concentrations are graphed against time, a peak drug concentration (Cmax) is reached at Tmax. The trough concentration is Cmin. The area under the concentration–time curve (AUC) is a measure of drug exposure that can be calculated and quantified.

Distribution Once absorbed, a drug is distributed to the various organs and tissues of the body. Distribution is influenced by organ perfusion, organ size, binding of the drug within the blood and tissues, and the permeability of tissue membranes (8). Most psychoactive drugs enter the brain because they are highly lipid soluble. The blood–brain barrier hinders the ability of non–lipid-soluble drugs to reach the brain tissue by diffusion (9). Unlike the fenestrated capillaries found throughout the body, which allow movement of molecules 90% bound are considered highly protein bound, and reduced protein binding for these highly protein bound drugs can lead to large increases in drug effect. The rate of blood flow delivered to specific organs and tissues affects drug distribution. Well-perfused tissues can receive large quantities of drug, provided that the drug can cross the membranes or other barriers present between the plasma and tissue. In contrast, poorly perfused tissues, such as fat, receive and release drug at a slow rate. This action explains why the concentration of drug in fat can be maintained long after the concentration in plasma has begun to decrease; anesthetics are examples of this phenomenon. For example, since women tend to have more body fat than men, the FDA recommended in 2013 and again in 2016 that women be prescribed half the dose of zolpidem. This recommendation was because women were having increased car accidents the morning after taking zolpidem.

Clearance Elimination refers to disappearance of the parent and/or active molecule from the bloodstream or body, which can occur by metabolism and/or excretion. Excretion is the process of removing a compound from the body without chemically changing that compound. Drugs can be excreted through the urine or feces, exhaled through the lungs, or secreted through sweat or salivary glands. The term clearance (Cl) represents the theoretical volume of blood or plasma that is completely cleared of drug in a given period of time. The factors that determine hepatic clearance are hepatic blood flow, the fraction of drug that is unbound, and the drug’s intrinsic clearance. If the intrinsic clearance of an unbound drug is very large, blood flow to the liver becomes rate limiting. If the intrinsic clearance of an unbound drug is very small, then this metabolic capacity (ie, intrinsic clearance) of the liver, rather than hepatic blood flow, becomes the major determinant of hepatic clearance. In this case, activity of hepatic enzymes determines drug clearance. Metabolic capacity determines drug clearance in most cases. Most drugs display first-order elimination kinetics: the fraction or percentage of the total amount of drug present in the body removed at any one time is constant and independent of dose. Following administration of a drug with first-order kinetics, concentrations show an exponential decline of drug concentrations. The slope of this decay line is the elimination rate constant, kel, which is the percent of drug cleared per unit time (eg, percent/hour). The half-

life (t1/2) of a drug is the amount of time it takes for a drug concentration to decrease by half. One half-life represents a 50% change, and 2, 3, 4, and 5 halflives represent 75%, 87.5%, 93.7%, and 96.8% changes, respectively. The time to reach steady state depends upon the duration of the half-life, whereas the amount of drug in the body at steady state will depend upon the frequency of drug administration and its dose. With drugs with dose-independent (first-order) disposition and elimination characteristics, five half-lives is a reasonable estimate of the time to reach steady state. For example, if the concentration at 2 hours postdose is 100 μg/mL, and the concentration at 4 hours postdose is 50 μg/mL, the t1/2 is 2 hours. One means of calculating t1/2 is

Using a more physiological approach, t1/2 is directly related to the volume of distribution (Vd) and inversely related to the clearance (Cl). This relationship can be written as follows:

The constant 0.693 in this equation is derived from the natural logarithm of two [ln(2)]. Because drug elimination can be described by an exponential process, the time taken for a twofold decrease can be shown to be proportional to ln(2). Although it is reasonable to assume that t1/2 and clearance are inversely related (clearance increases, so t1/2 decreases), effects of Vd on t1/2 do occur, which can offset the change in Cl (Vd decreases by the same proportion as clearance decreases, resulting in no change in t1/2). In contrast, for drugs with zero-order elimination kinetics, the amount of drug removed (rather than the fraction of drug removed) at any one time is constant and dependent on dose. The maximal rate of metabolism and/or elimination is generally due to saturation of a key enzyme. This zero-order process is described by the Michaelis-Menten equation:

where v is the velocity of the reaction, Vmax is the maximum velocity of the reaction, Km is the concentration of the metabolic substrate when the velocity is ½Vmax, and Cpss is the steady-state concentration of drug. In the case of linear kinetics, Km is >>> Cpss, and v = Vmax × Cpss/(Km), or the v is proportional to the drug concentration: the higher the drug concentration, the faster the velocity. When Km Ser. Drug Metab Dispos. 2009;37(6):1312-1318. 62. Jones JD, Mogali S, Comer SD. Polydrug abuse: a review of opioid and benzodiazepine combination use. Drug Alcohol Depend. 2012;125(1-2):8-18.

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CHAPTER 11

The Pharmacology of Opioids Daryl Shorter and Thomas R. Kosten

CHAPTER OUTLINE Definition of Drugs in the Class Substances Included in the Class Epidemiology of Opioid Use Disorder Pharmacokinetics of Specific Drugs Pharmacodynamics Drug–Drug Interactions Tolerance Development Toxicity States and their Medical Management Medical Complications of Opioids Conclusions and Future Research Directions

DEFINITION OF DRUGS IN THE CLASS Three distinct types of opioid receptors are found in the nervous system: mu, kappa, and delta. These opioid receptors are G-protein–coupled, 7transmembrane receptors. The endogenous opioid neuropeptide agonists include the endorphins, enkephalins, and dynorphins as well as the more recently characterized endomorphins (1,2). The endorphins are cleavage products of the protein, pro-opiomelanocortin (POMC), which is produced primarily in the anterior pituitary of humans by the POMC gene. The major endorphin agonist produced from POMC is beta-endorphin, while the shorter products, alphaendorphin and gamma-endorphin, are less biologically active peptides (3). Betaendorphin stimulates mu opioid receptors (MOP-r) in mediating both the analgesic and rewarding effects of opioids. The enkephalins and dynorphins are opioid peptides with affinity for MOP-r as well, but enkephalins are primarily active at delta opioid receptors, while dynorphins exert their activity primarily through kappa opioid receptors (1). The endomorphins, endomorphin-1 and endomorphin-2, are opioid tetrapeptides with high affinity and selectivity for MOP-r. Although the parent gene and precursor protein of the endomorphins are still yet to be characterized, these agents may represent an important advance in development of opioid medications due to their potent antinociception and reduced adverse effects in rodent models (4). Opium is a naturally occurring mixture directly derived from the juice of the opium poppy (Papaver somniferum). Opioid analgesic medications are agonists

at MOP-r. Morphine (the prototypical MOP-r agonist) is the main active alkaloid in opium and constitutes roughly 10% (by weight), while codeine and thebaine are also present, but in much lower concentrations. Codeine is used medicinally as an analgesic and antitussive, whereas thebaine can be used as a starting point for producing semisynthetic MOP-r ligands. Several exogenous opioids are significant for opioid use disorder: heroin, morphine, oxycodone, codeine, meperidine, pentazocine, hydromorphone, and hydrocodone, as well as methadone, levo-alpha-acetylmethadol (LAAM), and buprenorphine.

SUBSTANCES INCLUDED IN THE CLASS Naturally Occurring Agents Morphine Morphine is a natural product of the poppy plant, Papaver somniferum. Its use dates back to the early 19th century, following the publication of a method for its isolation in 1817 (5). Today, morphine treats moderate to severe pain and is used orally, intravenously, intramuscularly, or intrathecally. Mammalian cells can also endogenously synthesize morphine (6).

Codeine Codeine is methylmorphine, and crosses the blood–brain barrier faster and has less first-pass metabolism in the liver for greater oral bioavailability than morphine. It also is metabolized to morphine via cytochrome 2D6 (4) and to hydrocodone by an unknown mechanism (7).

Thebaine and Synthetic Compounds Thebaine is not used clinically or recreationally, but is a potent convulsant and the chemical basis for several semisynthetic opioids. Modifications of thebaine results in hydrocodone (Vicodin), oxycodone (OxyContin), hydromorphone (Dilaudid), and heroin. Synthetic modifications also include antagonists such as naloxone (Narcan), naltrexone (Trexan or ReVia or Vivitrol), and nalmefene (Revex), as well as partial agonists such as buprenorphine alone (Subutex) or, when combined with naloxone, (Suboxone, Zubsolv) (4).

Synthetic Agents Heroin Heroin is derived from morphine, and its rapid onset of action and short half-life make it preferred over morphine among people who engage in unhealthy opioid use. Heroin is in Schedule I (ie, not available for any therapeutic use in the United States), although a few select countries (eg, Switzerland, the Netherlands, Spain, Germany, Canada, and the United Kingdom) use it as a medication for treatment of intravenous heroin use disorder. In these countries heroin is used only in patients who have not responded to methadone or buprenorphine maintenance treatment or residential rehabilitation (8–10). A prodrug that is not itself active, heroin is rapidly deacetylated to 6-monoacetyl morphine (6-MAM) and morphine, both of which are active at the MOP-r. It is most effective intravenously but increasingly is used intranasally and, sometimes, smoked (11), which is possible with high-purity heroin. Nasal and smoked use also reduces the risk of human immunodeficiency virus (HIV-1) transmission and overdose (12).

Oxycodone Although oxycodone is structurally similar to codeine, it is pharmacodynamically comparable to morphine with a 1:2 equivalence to morphine (13). It is combined with aspirin or acetaminophen for treating moderate pain and is available orally without a coanalgesic for severe pain (14). By the mid-2000s, oxycodone had become one of the most widely misused and diverted opioids in the United States, particularly in the controlled-release (CR) formulation, since it could be easily crushed and self-administered (intranasally or IV) for a potentially toxic, rapid “high” (15,16). Subsequently, in 2010, the medication was reformulated and released in a tamper-resistant, unhealthy usedeterrent form characterized by reduced euphoria, nasal irritation with insufflation, and difficulty with extraction of the active compound (17). Following reformulation, oxycodone misuse dropped, but heroin use rose.

Meperidine Meperidine is a phenylpiperidine with limited potency and a short duration of action. Clinically, meperidine is used primarily for the management of acute, postoperative pain in the central nervous system (CNS) and gastrointestinal and

genitourinary systems, and prophylactic use of meperidine has been shown to reduce postoperative shivering, particularly for patients undergoing spinal anesthesia (18). Meperidine is no longer used for treatment of chronic pain owing largely to concerns regarding toxicity of its major metabolite, normeperidine, which can produce seizures and CNS excitation, for example, disorientation, drowsiness, vertigo, or urinary retention (19). While meperidine is metabolized primarily by the liver, normeperidine is renally excreted, has a substantially longer half-life (15-30 hours), and carries a risk of accumulation in those with renal disease and the elderly (20). Meperidine should not be used for >48 hours or at doses >600 mg/d. Because it has serotonergic activity, it can produce a serotonin syndrome (ie, clonus, hyperreflexia, hyperthermia, and agitation) when combined with monoamine oxidase inhibitors (21). Additionally, meperidine use has been associated with electrocardiogram (ECG) changes, such as QTc prolongation, which can lead to torsade de pointes, a potentially fatal arrhythmia (22).

Pentazocine Pentazocine treats moderate to severe pain but is a weak antagonist or partial agonist (ie, it has a “ceiling effect,” plateau in maximal effect, contrasted with a full agonist) at the mu receptor. It is also a kappa receptor partial agonist and displays activity at the delta opioid receptor as well as the sigma receptor. Pentazocine shows differences in CNS effect and degree of analgesia depending upon the medication dose. In addition, pentazocine has two enantiomers with different pharmacological profiles, and the prescribed formulation, (±)pentazocine, provides pain reduction and is rewarding. In rats, (−)-pentazocine is rewarding through mu and delta opioid receptors, while (+)-pentazocine is not rewarding through agonism of the selective sigma-1 receptor, which also underlies its hallucinogenic and psychotomimetic properties (23). In 1983, as a deterrent to unhealthy use, pentazocine was manufactured in combination with naloxone (Talwin NX). Thus, if injected, this formulation would actually precipitate withdrawal in those with physiological dependence. After this change, unhealthy use of pentazocine in the United States has declined.

Hydromorphone First synthesized in the 1920s, hydromorphone is a more potent opioid analgesic than morphine. It is used for the treatment of moderate to severe pain and is excreted, along with its metabolites, by the kidney. It can be given intravenously,

by infusion, orally, and per rectum, with low oral bioavailability. On a milligram basis, it is five times more potent than morphine when given orally and 8.5 times as potent when given intravenously (24). A minor pathway for the metabolism of morphine to hydromorphone has been identified (25).

Hydrocodone Hydrocodone is a prescription medication for relatively minor pain, such as oral/dental or osteoarthritis. Hydrocodone undergoes hepatic metabolism entirely by the CYP2D6 system to its active metabolite, hydromorphone, which is then further converted by phase 2 glucuronidation (26). When used in combination with acetaminophen, there can be an increased risk of hepatotoxicity when used in unhealthy ways (14). The amount of hydrocodone used in the United States has increased substantially. In 1990, the world’s population consumed 4 tons (3628 kg) of hydrocodone, and by 2009, annual worldwide consumption of hydrocodone had risen to 39 tons (35 380 kg), with 99% of that amount being consumed by Americans. Of note, a substantial portion of this is consumed for nonmedical use (27). As a result, in October 2014, the Drug Enforcement Agency (DEA) rescheduled hydrocodone from Schedule III to Schedule II, in large part due to its high potential for unhealthy use. Subsequently, in the year following the change, hydrocodone prescriptions decreased by 22%, from ~120 to 93.5 million.

Methadone Methadone is a synthetic long-acting full mu opioid agonist, active by parenteral and oral routes. It was first synthesized as a potential analgesic in Germany in the late 1930s and first studied for human use in the 1950s in the United States. It has been used primarily as a maintenance treatment for heroin use disorder since the first research done in 1964 (28), and it was approved by the U.S. Food and Drug Administration (FDA) in 1972. Methadone is also effective in the treatment of chronic pain; however, it should be used with caution in opioidnaïve patients due to the risk of accumulation and respiratory depression. Methadone has a diphenylheptylamine chemical structure and consists of a racemic mixture of D(S)- and L(R)-methadone (29). The L(R)-methadone enantiomer has up to 50 times more analgesic activity and also the potential to produce more respiratory depression than the D(S)-enantiomer. Both enantiomers have modest N-methyl-D-aspartate (NMDA) receptor antagonism, which is

thought to be the underlying neurobiological mechanism for the limited development of tolerance observed with this medication (30,31).

Levo-alpha-acetylmethadol LAAM is a synthetic, longer-acting (48-hour) congener of methadone that is also orally administered. LAAM was first studied in the 1970s for the treatment of heroin use disorder (32) and approved in 1993 by the FDA (33) after a large multicenter safety trial. A black box warning was added to the product label due to postmarketing reports of prolonged QTc interval on ECG that were associated with treatment with LAAM (34,35). Although LAAM remains approved for human use in the United States, no pharmaceutical company is manufacturing the medication at this time. As the new drug application for LAAM has not been withdrawn, LAAM could once again be made available in the United States (36).

Buprenorphine Buprenorphine alone, and in combination with opioid antagonist, naloxone, was approved in 2002 by the FDA as an office-based treatment for heroin and opioid use disorder (37,38); at the same time, buprenorphine was reclassified by the Drug Enforcement Administration from a Schedule V to a Schedule III drug (39). Buprenorphine is primarily a MOP-r–directed partial agonist, but also acts as a kappa partial agonist. The structure of buprenorphine is that of an oripavine with a C7 side chain, which contains a tert-butyl group. Norbuprenorphine is a major metabolite of buprenorphine in humans, with activity at the MOP-r as well (40). The SAMHSA DATA 2000 (Drug Addiction Treatment Act 2000) established eligibility requirements for physicians to use buprenorphine in the office-based treatment of opioid use disorders. Prescribers must complete an 8hour continuing medical education course and notify the government of their intent to use buprenorphine for treatment of patients with opioid use disorder by obtaining a waiver from the DEA. Additionally, prescribers must have both the capacity to provide or refer patients for ancillary services. When originally proposed, the number of patients who could be provided treatment from a single prescriber at any one time in an individual or group practice was no more than 30; as of 2016, the limit on the number of patients was raised to 275 (41,42). As well, Nurse Practitioners and Physician Assistants are now able to prescribe this medication.

The formulations of specific drugs are shown in Table 11-1.

TABLE 11-1 Formulations and Their Methods of Use/Unhealthy Use

Formulations to Deter Unhealthy Use Formulations are being developed for many opioids to deter unhealthy use. The addition of an opioid antagonist, such as naloxone or naltrexone, to the parent opioid compound is a common pharmacological strategy, employed with medications including pentazocine/naloxone (Talwin NX) and buprenorphine/naloxone. Other formulations are designed with physical deterrents to intranasal or parenteral use and include adding capsaicin or a gelling polymer to make dissolved pills unpleasant to use due to nasal irritation or difficult to crush or dissolve due to structurally resistant, tamper-proof outside coatings (43).

Clinical Uses Clinically used opioids (ie, MOP-r agonists) are indicated primarily for treatment of acute and chronic pain conditions. For minor pain, such as postdental procedures, opioids such as hydrocodone are used. For moderate to severe, postsurgical, or chronic pain, opioids such as morphine may be prescribed. Neuropathic or regional pain syndromes can sometimes be relieved by opioids, though their prolonged use in these conditions remains an area of continued investigation. Opioids have been well established as cough suppressants; however, only codeine is typically used for this indication. Although the mechanism of action is not entirely clear and more research into this indication is needed (44), low-dose opioids have also been found to improve refractory breathlessness in terminal illnesses, such as end-stage chronic obstructive pulmonary disease (COPD). The opioid agonists, methadone and buprenorphine, are employed as treatment for opioid use disorder; with the latter two used for either withdrawal management to reduce withdrawal symptoms or maintenance therapy (to reduce craving and re-establish physiological homeostasis). All opioid medications carry the risk for development of substance use disorder and diversion, and as a result, they must be dispensed cautiously. This caution, however, must be carefully balanced against the risk of undermedicating pain for each individual patient. Depot naltrexone (Vivitrol) was approved in 2010 as a monthly IM injection for prevention of relapse following withdrawal management from opioid use disorder. An implantable version of buprenorphine is also recently approved with at least two other depot forms of buprenorphine pending FDA approval for monthly use (45).

Nonmedical Use of Prescription Medications (NUPM) Recreational or illicit use of opioids may initiate from a desire to experience the euphorigenic effects of these agents. There are also those who favor use of prescription medications because they are not associated with the societal stigma of heroin or the negative consequences of IV drug use. Additionally, some patients are prescribed opioids for pain treatment and go on to develop unhealthy opioid use. Heroin, as mentioned, is not available for medical indications in the United States. Methadone and buprenorphine are sometimes diverted by those for whom it is prescribed, generally not for euphoria-inducing effects, but rather to prevent the onset of opioid withdrawal symptoms (46).

Historical Features Sumerian clay tablets (3000 BC) refer to the poppy; Sumerians named opium “gil” (“happiness”). The ancient Egyptians also cultivated poppies. “Thebaine” is derived from the name for the Egyptian city “Thebes.” “Opium” may be a Greek-derived word (“opion” = poppy juice). Opium figures prominently in Greek mythology and was also mentioned in Hippocrates’ writings (460-377 BC). The ancient Roman author Pliny warned of the dangers of compulsive use of opium. In 1804, a young German pharmacist, Friedrich Sertürner, isolated morphine (which he named after Morpheus, the Greek god of dreams) (47). A major development in the delivery of opioids, the hypodermic needle was perfected in 1853, which allowed for rapid analgesia, but also greater morbidity and mortality when misused. Diacetylmorphine was first synthesized as a semisynthetic analog in the 1870s by the Bayer company and marketed under the name “heroin.”

EPIDEMIOLOGY DISORDER

OF

OPIOID

USE

The pharmacology of opioids is of particular relevance to the treatment of substance use disorder, given recent increases in the use of illicit opioids, as well as nonmedical use of prescribed opioid medications (48). According to the 2014 National Survey on Drug Use and Health (NSDUH), there were an estimated 4.3 million people currently (ie, past month) nonmedically using prescription opioids and 914,000 people who used heroin in the past year. By extension, an estimated 1.9 million persons (aged 12 or older) met the Diagnostic and

Statistical Manual of Mental Disorders, 5th edition (DSM-5) criteria for diagnosis of opioid use disorder related to prescription opioids, and ~586,000 met criteria for heroin use disorder. Regarding adolescent use, in 2014, an estimated 467,000 persons aged 12-17 years old were currently using nonmedical pain relievers, and 168,000 adolescents met criteria for opioid use disorder related to prescription opioids. Importantly, these estimates for adolescent use represent a near-continuous decline over the last several years and are supported by other epidemiological studies, including Monitoring the Future, which found that use of “narcotics other than heroin” in 12th graders peaked at 4.3% of respondents in 2004, but had declined to a rate of 1.7% in 2016 (49). Less than 1% of students in 8th, 10th, and 12th grades reported current use of heroin in 2014. Interesting differences occur in the nonmedical use of prescription opioids on the basis of racial/ethnic group identification. For example, a study of 18- to 23-year-old adults who used opioids nonmedically but who had not yet met criteria for opioid use disorder/dependence found that a higher proportion of white adults who used opioids for euphoria, used opioids orally or by snorting. In contrast, non-white adultstended to use oral opioids to self-medicate health problems (50). Additionally, in a separate study in college students, researchers found recreational use was more prevalent among white people who use opioids, while self-treatment of pain was more prevalent among African Americans (51). Recent studies examining racial bias in pain assessment and treatment further suggest that the undermedication of pain among certain groups is related to false beliefs and misperceptions about physiological differences between whites and people of color regarding pain tolerance (52). Altogether, these factors may contribute to the differing manifestations of nonmedical use of prescription opioids among diverse populations and represents an important area of future study, particularly as it is related to potential opportunities for targeted intervention. The medical implications of unhealthy opioid use and diversion are quite significant. Family members and friends are the most common source of nonmedically used opioids; however, family members and friends most commonly receive those medications directly from physicians. Prescribing practices related to opioids are not the sole clinical concern. Benzodiazepines and opioid pain medications are commonly used in combination, and recent guidelines from the CDC clarify the dangers of concomitant use and caution against it, given the elevated risk of respiratory depression, coma, and death (53). Additionally, opioid-related overdoses have become an area of significant

concern, particularly since counterfeit medications have flooded the illicit market and may be adulterated with agents that contribute significantly to toxicity. According to the National Center for Health Statistics, the number of drug poisoning deaths involving natural and semisynthetic opioids increased each year from 2749 deaths in 1999 to 11 693 deaths in 2007, while the number of deaths involving synthetic opioids other than methadone (ie, fentanyl, meperidine, and propoxyphene) increased from 730 deaths in 1999 to 2666 deaths in 2011 (54). Interestingly, the number of methadone-related deaths increased from 784 deaths in 1999 to 5518 deaths in 2005, but since that time, methadone-related deaths have declined, accounting for 4418 deaths in 2011. Of note, benzodiazepines were also involved in 31% of opioid analgesic deaths in 2011. Also, the number of opioid-related deaths among non-Hispanic blacks more than doubled between 1999 and 2011, while the number of deaths among non-Hispanic whites more than quadrupled. According to the Substance Abuse and Mental Health Services Administration (SAMHSA) Treatment Episode Data Set (TEDS), annual admissions to substance use disorder treatment for primary heroin use disorder increased from 228,000 in 1995 to ~256,000 in 2010, with the percentage of primary heroin admissions remaining steady at about 14%-15% of all treatment admissions (55). At that time, 30.1% of persons with heroin use disorder sought treatment with methadone or buprenorphine maintenance, whereas only 19.9% of those with prescription opioid use disorder sought such pharmacotherapy. However, as the rates of prescription opioid use disorder has increased, there has been a subsequent increase in treatment seeking. According to TEDS, the annual number of admissions for other opiates/synthetics increased from 28 316 in 2000 to 157 171 in 2010, growing from 1.6% of all admissions in 2000 to 8.6% of all admissions in 2010. Likewise, studies historically found that heroin was the most frequently reported drug of choice in new treatment admissions. However, a multistate survey of methadone maintenance treatment programs (MMTP) conducted in 2005 revealed that oral prescription opioids accounted for the majority of cases, with oxycodone (79%), hydrocodone (67%), methadone (40%), and morphine (29%) as the most common, outpacing admissions for heroin (56). One-third of those persons using oral medications also reported a history of intravenously using their primary drug of choice, suggesting that even among those with physical dependence on oral agents there is a risk for progression to IV use. Although concerns regarding access to treatment persist, some improvement is evident. Currently, according to SAMHSA, there are ~36 100 US physicians

eligible to prescribe buprenorphine as office-based treatment to patients for treatment of opioid use disorder, an increase of 33% since 2014 (57). Approximately 67% of those prescribers are certified to treat up to 30 patients, and 25% are certified to treat up to 100 patients.

Neurobiology, Mechanisms of Action, and Relationship to Addiction Liability Opioids have primarily agonist effects at the MOP-r (encoded by the MOP-r gene [OPRM1]) (58). MOP-r are members of the G-protein–coupled 7transmembrane domain superfamily; they are coupled to Gi and Go proteins. Thus, MOP-r agonists typically acutely result in the downstream inhibition of adenylyl cyclase with a consequent reduction in the production of cyclic AMP (cAMP), the opening of potassium channels, the inhibition of calcium channels, and the activation of mitogen-activated protein kinase (MAPK) (59,60).

Distribution in CNS and Mediation of Different Functions MOP-r are widely distributed in both the CNS and peripheral nervous system (PNS), with the constellation of their psychological and analgesic effects being mediated primarily in the CNS (61–63). Therapeutically desirable analgesic effects can be mediated in areas including dorsal spinal cord and thalamus, whereas undesirable effects are thought to be mediated elsewhere. Respiratory depression, for example, is thought to be mediated primarily by activity in the brain stem (64), while gastrointestinal effects, such as constipation (experienced by as much as 40% of those prescribed opioids), are thought to be mediated through CNS activity as well as activation of MOP-r in the gastrointestinal tract, submucosa, ileal mucosa, stomach, and proximal colon (65). The classic rewarding effects of MOP-r agonists are likely mediated to a substantial degree in ventral and dorsal striatal areas and can depend (although not exclusively) (66) on downstream activation of the dopaminergic mesocorticolimbic and nigrostriatal systems (67,68). Symptoms of physiological dependence and withdrawal from MOP-r agonists, such as autonomic instability (eg, blood pressure and heart rate elevation), diaphoresis, and anxiety, are thought to stem from increased noradrenergic activity within the locus coeruleus and related centers (69,70).

MOP-r Signaling Properties and Addiction Liability A major underlying concept in the addiction liability of MOP-r agonists is their pharmacodynamic efficacy (ie, their relative ability to stimulate downstream second messenger systems). In general, compounds with progressively greater efficacy (eg, morphine or fentanyl-like compounds) have greater analgesic effects but also have greater potential for unhealthy use including addiction than partial agonists such as buprenorphine (59,71). Furthermore, other downstream effects of MOP-r agonist exposure are now postulated to be of relevance to the relative balance of therapeutic and undesirable effects of MOP-r agonists, including propensity to cause tolerance or potential for unhealthy use. Major mechanisms of current interest are the relative propensity of compounds to cause MOP-r desensitization and internalization, potentially related to their ability to stimulate the β-arrestin signaling pathways (72,73). For example, the main active heroin metabolite, morphine, results in lesser desensitization and internalization of receptors, compared to the endogenous neuropeptide ligands, or methadone (74). Thus, methadone maintenance can be used effectively for extended periods without the development of further tolerance (or progressively greater methadone dose requirements) (75). By contrast, heroin (through its primary metabolite, morphine), or prescription opioids, may result in progressive cycles of physical dependence and tolerance, secondary to a lesser recruitment of endogenous MOP-r desensitization/internalization mechanisms (76).

PHARMACOKINETICS OF SPECIFIC DRUGS It is beyond the scope of this chapter to provide a comprehensive table of dosing equivalents. There are a number of excellent reviews on this topic (4,14,77).

Morphine Pharmacokinetics Morphine is largely selective for MOP-r and most physicians consider it the drug of choice for the treatment of moderate to severe cancer pain (78). The pharmacokinetics of morphine and its metabolites vary, depending on the route of administration. Its favorable safety profile is due in large part to its pharmacokinetic profile. The oral bioavailability varies, from 35% to 75%, with

a plasma half-life ranging from 2 to 3.5 hours. The half-life is less than the time course of analgesia, which is 4-6 hours, thus reducing accumulation. Morphine is biotransformed mainly by hepatic glucuronidation to the major but inactive metabolite morphine-3-glucuronide (M3G) and the biologically active M6G compound (79), with prolonged clearance because of enterohepatic cycling with oral dosing (80). In the setting of chronic liver disease, morphine oxidation is more affected than is glucuronidation. Use of lower doses or longer dosing intervals is recommended to minimize the risk of accumulation of morphine when chronic liver disease is present, particularly with repeated dosing. At 24 hours, more than 90% of morphine has been excreted in urine. M6G elimination seems to be closely tied to renal function, so accumulation of metabolites can occur. With renal compromise, 90%) with oral administration and long apparent half-life with long-term administration in humans (96). The medical safety of long-term methadone maintenance treatment has been well studied (97). Oral methadone has a rapid absorption but delayed onset of action, with peak plasma levels achieved by 2-4 hours and sustained over a 24-hour dosing period (61,96,98,99). Moreover, the mean plasma apparent terminal half-life of racemic D,L-methadone in human subjects is around 24 hours (96). The l-enantiomer has a half-life of 36 hours (95,100,101). Biotransformation of methadone is accelerated in the third trimester; therefore, methadone dose may need to be increased in the final stages of pregnancy (102). When taken on a chronic basis, methadone is stored and accumulated mostly in the liver (98,103). Methadone plasma levels are relatively constant because of slow release of unmetabolized methadone into the blood, which extends the apparent terminal half-life. Methadone is more than 90% plasma protein bound both to albumin and globulins (102,104). These properties help explain why methadone maintenance treatment is effective as a once-daily, orally administered pharmacotherapy for opioid use disorder (28). Methadone is biotransformed in the liver by the cytochrome P450–related enzymes (primarily by the CYP3A4 and, to a lesser extent, the CYP2B6, CYP2D6, and CYP1A2 systems) to two N-demethylated biologically inactive metabolites, which undergo additional oxidative metabolism (29,95). Methadone and its metabolites are excreted in nearly equal amounts in urine and in feces (105–109). In patients with renal disease, methadone can be cleared almost entirely by the GI tract, reducing potential toxicity by preventing accumulation (107–109). Methadone disposition is relatively normal in patients with mild to moderate liver

impairment (105,110,111). Patients with severe long-standing liver disease have decreased methadone metabolism and thus slower metabolic clearance of methadone, yet lower than expected plasma methadone levels as a result of lower hepatic reservoirs of methadone because of reduced liver size. Interestingly, due to genetic differences, select patients may require higher doses of methadone due to “rapid metabolism” of the medication.

Levo-alpha-acetylmethadol Pharmacokinetics

(LAAM)

LAAM, a congener of methadone, shares with methadone the properties of long duration of effect (48 vs. 24 hours for methadone, in part owing to its active metabolites norLAAM and dinorLAAM, as well as its steady-state perfusion of MOP-rs), oral effectiveness (32), and function as a pure opioid agonist, active mostly at the MOP-r. NorLAAM and dinorLAAM accumulate with chronic administration. In addition, LAAM and its metabolites bind to tissue proteins (32). The clearance of norLAAM and LAAM is similar, whereas the clearance of dinorLAAM is more prolonged than that of its parent compound (32). The peak pharmacological effect of LAAM as measured by amount of pupillary constriction occurred at 8 hours and then diminished at a rate similar to that of norLAAM metabolism (32). Because of the metabolism of LAAM by the cytochrome P450 3A4 system– related microsomal enzymes to norLAAM and dinorLAAM, drug interactions can occur (eg, rifampin and long-term unhealthy alcohol use tend to induce this enzyme system). In their presence, increased biotransformation of LAAM could accelerate the production of norLAAM and dinorLAAM. LAAM metabolism theoretically could be retarded if hepatic drug metabolism is diminished, as occurs in the presence of very large quantities of either ethanol, perhaps with large doses of benzodiazepines, or with intake of cimetidine (32).

Buprenorphine Pharmacokinetics Buprenorphine undergoes extensive first pass in the liver; thus, it is administered sublingually with 50%-60% bioavailability. Buprenorphine is metabolized to norbuprenorphine, due to dealkylation in the cytochrome P450–related enzyme 3A4 system, of which buprenorphine itself is a weak inhibitor (112). Despite the

ceiling effect of buprenorphine as previously described, there have been a number of reported cases of deaths in Europe with concurrent unhealthy benzodiazepine use (113). There have been many reports of the intravenous use of the sublingual preparation of buprenorphine in many countries, which is the main reason that naloxone is added for deterrence against unhealthy use. A second formulation of sublingual buprenorphine (combined with naloxone) was developed in 1984 and is now increasingly used in the United States and worldwide (97). In this formulation, naloxone will not precipitate withdrawal when taken sublingually because of its limited oral bioavailability; however, it may block the initial euphoric effects of buprenorphine if used by the intravenous route and can also precipitate acute opioid withdrawal (114,115). Because of the partial agonist ceiling effect, with acute buprenorphine intoxication, there may be mild mental status changes, mild to minimal respiratory effects, small but not pinpoint pupils, and essentially stable vital signs. In some situations, naloxone apparently can improve the respiratory depression but with limited effect on the other symptoms (115). Patients should be observed for 24-48 hours. Initially developed as an analgesic, buprenorphine has been shown in most studies to be as effective as morphine in many situations. In addition to its activity in the MOP-r system, buprenorphine has some modest kappa opioid receptor (KOP-r) antagonist activity as well (116). Owing to its ceiling effect, increasing buprenorphine doses in humans beyond 32 mg sublingually using the film version has no greater MOP-r agonist effect and at 16 mg appears to occupy all the available mu opiate receptors (61,117–119). Buprenorphine has a long duration of action (24-48 hours) when administered on a chronic basis, not because of its pharmacokinetic profile, but because of its very slow dissociation from MOP-r. Two important properties of buprenorphine are (a) its apparent lower severity of withdrawal signs and symptoms on cessation, compared with heroin and other opioids, and (b) its reduced potential to produce lethal overdose when used alone in opioid-naïve or nontolerant persons, because of its partial agonist properties. Given intravenously, buprenorphine has an apparent betaterminal plasma half-life of about 3-5 hours. When given orally, it is relatively ineffective because of its first-pass metabolism (32), that is, rapid biotransformation, probably by the intestinal mucosa and, especially, by the liver. Sublingual preparations of buprenorphine can be film or tablet, both of which require about 120 minutes for time to peak. However, peak plasma concentrations of the sublingual tablet and film and mean area under the plasma concentration time curve are lower than that of the liquid at equivalent doses

(117,120–122).

PHARMACODYNAMICS The pharmacodynamics of the clinically important MOP-r agonists are wide ranging, with the most pronounced effects produced in the CNS and GI tract. The mechanism of action for all of the clinically relevant opioids described here is at the MOP-r, in which they act preferentially as agonists, except for pentazocine and buprenorphine, which are partial mu opioid agonists (119) and low efficacy ligands (antagonists) at kappa receptors (116). The euphorigenic effects of any opioid agonists are mediated in part by the ventral tegmentum, where opioid agonist–mediated inhibition of GABAergic neurons results in disinhibition and thus activation of dopamine neurons extending to the nucleus accumbens. Norepinephrine-secreting cells in the locus ceruleus appear to play an important role in opioid withdrawal, whereas both serotonin and dopamine exert effects on addiction and craving (123,124). Opioids in general affect heat regulation mechanisms in the hypothalamus. Body temperature decreases slightly, except with chronic high doses where temperature may be increased (4). Opioids also act in the hypothalamus to inhibit the release of gonadotropin-releasing hormone (GNRH) and corticotropin-releasing hormone (CRH), producing a reduction in luteinizing hormone (LH), follicle-stimulating hormone (FSH), adrenocorticotropin hormone (ACTH), and beta-endorphin (125). With decrease in these hormones, plasma concentrations of testosterone and cortisol are lowered. Mu agonists increase the amount of prolactin in plasma by decreasing dopaminergic inhibition. Given chronically, there is tolerance to the effects of morphine on the neuroendocrine system. Mu opioid agonists also tend to have antidiuretic effects (123,124,126,127) and can cause constriction of the pupil (4). Additionally, opioids can cause seizures at doses much higher than those used clinically, and these overdoses can be managed with opioid antagonist medications, such as naloxone. Of note, naloxone is less potent in antagonizing seizures due to meperidine in comparison to other opioids such as morphine or methadone, likely due to its proconvulsant metabolite, normeperidine. Because of the increased risk of seizure with long-term use of meperidine, it is no longer used for chronic pain; when used for treatment of acute pain, meperidine should not be used for >48 hours or at doses >600 mg/d (21). All opioids must be used cautiously in patients with impaired respiratory

function. Also, opioids have the potential to elevate intracranial pressure (128) (eg, in the setting of head injury, they can produce an exaggerated respiratory depression, as well as mental status changes that can confuse the clinical picture). Typical side effects of all opioids include drowsiness, nausea, and constipation, while vomiting, pruritus, and dizziness are less common; however, all of these tend to lessen in intensity over time. Codeine is commonly used to suppress cough at doses lower than those used for analgesia (starting with 10-20 mg given orally) and can increase to higher doses for chronic (lower airway) cough. Codeine reduces cough via a central mechanism by stimulation of mu receptors on different neuron than those involved in analgesia or addiction, with doses >65 mg not indicated, owing to little increased therapeutic effect with increasing side effects (4). Pentazocine as a mixed agonist–antagonist drug has a “ceiling effect,” like buprenorphine, which limits the degree of analgesia. Pentazocine can lead to the development of psychotomimetic side effects, not reversible with naloxone, suggesting these may not be mediated through MOP-r. Pentazocine also has affinity for kappa opioid receptors (129). Finally, pentazocine can precipitate withdrawal in opioid-tolerant patients currently taking opioids, due to its weak antagonist effects. Methadone, like all mu opioid agonists, affects multiple organ systems, with tolerance developing at different rates to each effect. In the treatment of either opioid use disorder or chronic pain, proper dosing (titrated to the tolerance of the individual patient) is essential to avoid CNS depression. The precise neuronal and molecular mechanisms of physical tolerance have not been fully elucidated (123). However, it has been shown in studies of the d(R)-enantiomer of methadone (which is relatively inactive at the MOP-r) that this isomer has modest NMDA antagonist activity, which attenuates the development of morphine tolerance in rodents, but does not affect physical dependence (30). Chronic administration of opioids can lead to the gradual development of tolerance to the effects on hypothalamic-releasing factors, with return to normal levels and activity of anterior pituitary-derived ACTH and beta-endorphin and normal ACTH stimulation in ~3 months and resumption of normal menses and return of plasma levels of testosterone to normal within 1 year (97,125). In humans, prolactin release is under tonic inhibition by tuberoinfundibular dopaminergic tone. With the use of short-acting opioids, there is a prompt increase in the release of prolactin resulting from abrupt lowering of dopamine levels in the tuberoinfundibular dopaminergic system (130). With heroin use,

thyroid levels may be elevated because of raised thyroid-binding globulin; thus, there are increased measures without abnormal function (97,125). The hypothalamic and pituitary effects of opioids can produce antidiuretic effects by the release of vasopressin (4,125). Short-acting opioids can cause many effects in the cardiovascular system, including peripheral vasodilatation, decreased peripheral resistance, reduced baroreceptor reflexes, histamine release, and decreased reflex vasoconstriction caused by raised PCO2 (4). In the stomach, hydrochloric acid secretion may be inhibited, and somatostatin release from the pancreas may be elevated (4). Acetylcholine release from the GI tract is inhibited, resulting in slowed motility and reductions in the absorption of many drugs. The presence of increased appetite has also been noted. Biliary, pancreatic, and intestinal secretions may be reduced and digestion in the small intestine slowed. In the large intestine, there is reduced propulsion and higher tone (4,97,125,126). Tolerance to each of these effects develops with chronic administration.

DRUG–DRUG INTERACTIONS Other drugs can interact with opioids because of their effects on hepatic enzymes in the cytochrome P450–related enzyme system (74) (see chart). The drug–drug interactions with opioids are complex and must be considered on a case-by-case basis in individual patients. The major categories of drugs potentially interacting with opioids include both inducers and inhibitors of CYP3A4, as well as inhibitors of CYP2D6, such as paroxetine (111). CYP3A4 inducers typically have minimal clinical effects but include rifampin (131), rifabutin (132), carbamazepine (133), phenytoin (134), and phenobarbital (92); all the same, given the ability of these medications to increase the rate of metabolism of opioids, there is a chance that use of these medications in combination with opioids may induce withdrawal symptoms (135). CYP3A4 inhibitors, which include fluconazole (136), fluvoxamine (137), fluoxetine (138), paroxetine (111), and possibly erythromycin and ketoconazole, have shown few clinically significant drug interactions (29,95,104). A number of studies have examined specific antiretroviral medications used in the treatment of HIV-1 and their interaction with methadone. The reported pharmacokinetic interactions, usually through the CYP3A4 system, affect either methadone or the antiretroviral medication, which sometimes have clinical manifestations (139,140). Among the opioids, methadone levels are significantly affected by the regular consumption

of more than four alcoholic drinks per day (141), which can increase levels of methadone (142).

TOLERANCE DEVELOPMENT Tolerance may be defined as a loss of any effect after repeated use, leading to the need for higher doses to get the desired equivalent effect (123,143). All opioid medications lead to tolerance and physical dependence, but rates of development vary by medication, different effects, and individuals. Development of tolerance to opioids does not involve drug disposition and metabolism, but is an interplay at the single-cell and neuronal system levels (123). Methadone also has modest NMDA antagonism that may attenuate tolerance (30,79,123). Importantly, the GI and neuroendocrine side effects of short-acting opioids tend to persist (96).

TOXICITY STATES AND MEDICAL MANAGEMENT

THEIR

Acute opioid overdose is characterized by the triad of altered mental status (ie, stupor, coma), respiratory depression, and “pinpoint” pupils. On physical examination, evidence of opioid use, such as marks signaling past or recent injection in the antecubital fossae, may be noted. Individualized dosing and reliance on regular clinical assessments are important, as diminished respiration occurs with opioids until tolerance develops. When any opioid is used beyond the degree of tolerance that is developed, reduced response to carbon dioxide centers in the pons and medulla can lead to CO2 retention. Initially, there is depressed cough (which is mediated by the medulla) as well as nausea and vomiting, which may be mediated by the area postrema of the medulla and which disappear rapidly with the development of tolerance. Constriction of the pupil is the result of parasympathetic nerve excitation. In opioid overdose, convulsions have been reported, probably because of inhibition of the release of GABA in the CNS (4). Mydriasis or normal pupils may be observed in patients with an overdose of meperidine, propoxyphene, dextromethorphan, pentazocine, and diphenoxylate with atropine (ie, Lomotil) (4,144,145). A full opioid overdose can be effectively treated with an opioid antagonist. However, repeated naloxone administration is usually needed, or the overdose may be only transiently reversed, and the patient may lapse back into coma (141).

MEDICAL OPIOIDS

COMPLICATIONS

OF

The two main effects of opioid overdose on the CNS are depression of the mental status and depression of respiratory activity. A suppressed gag reflex predisposes the patient to aspiration of gastric contents into the lungs. A few opioids may cause generalized seizures (eg, high-dose meperidine). Respiratory depression is the most frequent cause of death (4). Overdose of opioids may cause noncardiogenic pulmonary edema (NCPE) and bronchospasm and occurs in 48%-80% of heroin overdoses (4). Overdose may also cause a release of histamine leading to vasodilatation and orthostatic hypotension; of note, this effect can be used therapeutically in the treatment of pulmonary edema and myocardial infarction. Nausea and vomiting from opioids may stimulate vasovagal tone and cause bradycardia. Prolongation of QTc interval and torsades de pointes can occur (146), and since a QTc interval >500 ms is considered to be a potential risk factor for sudden death, a recent study of methadone patients showing a mean QTc value of 428 ms clearly illustrates this risk with methadone (147,148). Opioid-induced spasm of the sphincter of Oddi can produce biliary colic. Intravenous opioid use can lead to bacterial endocarditis; venous thrombosis; septic pulmonary emboli; emboli of cornstarch and talc (additives) to the retina, lungs, kidney, and liver; pseudoaneurysms; and mycotic aneurysms (145). Heroin, morphine, and pentazocine may cause rhabdomyolysis and nephropathy when used intravenously, leading to glomerulonephritis (145). Centrally mediated muscle rigidity of the chest and abdominal wall can occur, and intravenously used opioids may also cause osteomyelitis, septic arthritis, polymyositis, and fibrous myopathy (4). Injection routes (intravenous, subcutaneous) of opioids can transmit HIV-1 infection, hepatitis B, hepatitis C, and bacteria causing cellulitis, skin and neck abscesses, endocarditis, and botulism (145).

CONCLUSIONS AND RESEARCH DIRECTIONS

FUTURE

The neuronal and molecular basis of opioid tolerance and physical dependence

appears to differ between different end points (eg, analgesia vs. respiratory depression vs. mediation of reward) and offers much for future research. Two specific areas for investigation are the genetics of MOP-r function and relating stress responsivity to opioid function. Understanding the genetics of MOP-r function is still quite early with a focus on only five single nucleotide polymorphisms (SNPs) in the coding region of the human OPRM1 gene (149). Three of these 5 SNPs lead to amino acid changes, and one (the A118G and the C17T variants) has a high allelic frequency of more than 40% in some ethnic groups. The C17T variant may have some association with opioid use disorder (149) and contribute to intersubject variability in response to opioid ligands or especially the opioid antagonists (149–151). Patients with opioid use disorder show atypical responses to stress and stressors, as demonstrated by changes in HPA axis function. During cycles of physical dependence, abstinence, and relapse, there is a flattened circadian rhythm of glucocorticoid levels, with increased levels during opioid withdrawal. Additionally, the effects of MOP-r partial agonists such as buprenorphine on specific indices of neuroendocrine function have not been extensively studied. Overall, the molecular mechanisms for partial opioid agonism, with low doses producing agonist and high doses producing antagonist responses, need a comprehensive theory as well as data to support that theory, as new opioids are developed. These contributions may also significantly improve our therapeutic options for analgesia and treatment of addiction.

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Neuropsychopharmacology. 2005;30:417-422.

CHAPTER 12

The Pharmacology of Stimulants David A. Gorelick and Michael H. Baumann

CHAPTER OUTLINE Definition Substances Included Formulations and Methods of Use Historical Features Epidemiology Pharmacokinetics Drug–Drug Interactions Pharmacodynamic Actions Neurobiology Future Research Directions

DEFINITION Stimulants are a class of drugs that enhance activity in the central and sympathetic peripheral nervous systems, chiefly by augmenting neurotransmission at norepinephrine and dopamine (ie, catecholaminergic) synapses. Most stimulants exert their effects by binding to presynaptic plasma membrane monoamine transporters that are responsible for moving previously released neurotransmitter molecules from the synaptic space back into the presynaptic neuronal cytoplasm, a process known as uptake. By disrupting the function of norepinephrine and dopamine transporters, stimulant drugs inhibit the uptake process and increase extracellular concentrations of norepinephrine and dopamine, thereby amplifying associated receptor signaling and neuron-toneuron transmission.

SUBSTANCES INCLUDED Stimulants include both naturally occurring plant alkaloids, such as cocaine (Fig. 12-1), ephedra, and khat, and more than a dozen synthetic compounds, such as the amphetamines and methylphenidate. Most of these are variants of the basic phenethylamine chemical structure, which is shared by the endogenous catecholamine neurotransmitters norepinephrine and dopamine (Fig. 12-2). The wakefulness-promoting agents modafinil and its (R)-isomer, armodafinil, have a mechanism of action similar to that of stimulants, but a different chemical

structure and reduced propensity for addiction (1). They are not considered in this chapter.

Figure 12-1 Chemical structures of cocaine, mazindol, and methylphenidate.

Figure 12-2 Chemical structures of endogenous catecholamine neurotransmitters (dopamine, norepinephrine) and phenethylamine stimulant drugs. All stimulants share the same range of psychological and physiologic effects, while differing in potency and pharmacokinetic characteristics. Caffeine, the most widely used stimulant, is considered separately in Chapter 13. 3,4Methylenedioxymethamphetamine (MDMA, “Ecstasy”), a structural analogue of methamphetamine with both stimulant and hallucinogenic characteristics, is considered separately in Chapter 16.

FORMULATIONS AND METHODS OF USE Plant-Derived Stimulants Several stimulant-containing plants are available for traditional oral use in many areas of the world. These include coca (containing cocaine) in South America, ephedra (containing ephedrine) in North America and East Asia, and khat (containing cathinone) in East Africa and Arabia. Oral use often is culturally sanctioned and may not be associated with addiction. Use of more potent formulations (eg, the extracted active chemical) or more rapidly acting routes of administration has significant addiction potential and is illegal even where oral formulations are allowed.

Cocaine Cocaine is an alkaloid with a tropane ester chemical structure (see Fig. 12-1) similar to that of scopolamine and other plant alkaloids. It occurs in leaves of several Erythroxylum species (coca bush), especially Erythroxylum coca and Erythroxylum novogranatense, which grow at altitudes of 1500-6000 feet in the Andean region of South America (2,3). The leaf contains cocaine (0.2%-1%) and more than a dozen other tropane alkaloids (such as benzoylecgonine, methylecgonine, ecgonine, and cinnamoylcocaine), most of which are of unknown pharmacologic activity. About two dozen other Erythroxylum species contain little or no cocaine (4). Cocaine exists as two stereoisomers: naturally

occurring (−)-cocaine and (+)-cocaine, which has less affinity for the dopamine transporter and is relatively inactive in vivo because of its very rapid metabolism by butyrylcholinesterase (5). The coca bush is cultivated primarily in Bolivia, Colombia, and Peru. Domestic use of oral cocaine is legal in these countries, usually as coca tea or by chewing the leaves (6,7). Coca leaves typically are chewed in conjunction with lime or plant ash, which alkalinizes the saliva and thus enhances absorption of the cocaine. Cocaine is legally available (schedule II of the Controlled Substances Act [CSA]) in the United States only as a 4% or 10% injectable solution (or powder for reconstitution) or viscous liquid for use as a local or topical anesthetic. Legal cocaine preparations rarely are diverted for misuse. Illicit cocaine is smuggled into the United States specifically for recreational (ie, nonmedical) purposes from its countries of origin. The average purity of seized cocaine in the United States is about 50% (8). Preparation of illicit cocaine begins with crushing the coca leaves and heating them in an organic solvent (often kerosene) to extract and partially purify the cocaine (9). After several more extraction and filtering steps, the coca paste (now 80%-90% pure) is heated in an organic solvent (often ether or acetone) with concentrated acid to convert it to salt form. The salt is readily converted back to the base by heating it in an organic solvent at basic pH. This process is known as “freebasing” and was practiced by cocaine users during the 1980s, before cocaine base (or “freebase”) was widely available on the retail street market. “Crack” as a street name for base cocaine reportedly derives from the crackling sound made during this heating process. Cocaine is available for street use in two forms: base and salt (10,11). These forms have different physical properties, which favor different routes of administration. The base has a relatively low melting point (98°C) and vaporizes before substantial pyrolytic destruction has occurred. This allows cocaine base to be smoked, though the majority of the cocaine may be in the form of small particles (200 mg and include anxiety, nervousness, jitteriness, negative mood, upset stomach, sleeplessness, and “bad effects” (66). Individual differences in use, sensitivity, and tolerance seem to play an important role in the likelihood and severity of negative subjective effects (67). Individuals with anxiety disorders may be more sensitive to the anxiogenic effects of caffeine (68), and higher acute doses of caffeine can also elicit panic attacks (69). The DSM-5 recognizes Caffeine-Induced Anxiety Disorder, which is defined as anxiety symptoms or an anxiety disorder (eg, Generalized Anxiety Disorder) caused by caffeine use (70).

PERFORMANCE EFFECTS Cognitive Performance Moderate acute doses of caffeine, usually up to 300 mg, tend to increase human performance on cognitive tasks assessing reaction time, vigilance, as well as simple and complex attention, with greater effects of caffeine for fatigued individuals (71). Higher doses of caffeine (eg, >400 mg) may impair performance in non–sleep-deprived nonusers of caffeine (71). The effects of caffeine on various memory tasks, higher-order executive functioning, and decision-making have also been investigated, but results are mixed (71).

Physical Performance Caffeine is reliably ergogenic across a variety of exercise situations, and in particular during prolonged exercise, with activity potentially mediated via multiple mechanisms, including effects on muscle contractility, reduced perception of effort, and lowered sensations of pain (71).

Withdrawal Reversal A problem in interpreting the effects of caffeine on performance is that most studies have compared the effects of caffeine and placebo on the performance of people who use caffeine habitually who have been required to abstain from caffeine, usually overnight. Thus, improvements in performance after caffeine

relative to placebo may simply reflect a reversal of withdrawal effects or restoration to baseline performance (72). However, some studies have shown caffeine-related performance enhancements among light nondependent caffeine consumers and nonconsumers (73), nonwithdrawn caffeine consumers (74), as well as caffeine consumers after a protracted period of abstinence (75). Based on the preclinical literature, which clearly documents the behavioral stimulant effects of caffeine, it seems quite likely that caffeine enhances human performance on some types of tasks (eg, vigilance), especially among nontolerant individuals. Among high-dose habitual caffeine consumers, performance enhancements above and beyond withdrawal reversal effects are perhaps modest at best (72).

REINFORCING EFFECTS Given that caffeine is the most widely self-administered mood-altering drug in the world, the circumstantial evidence for caffeine functioning as a reinforcer is compelling. Several carefully controlled research studies over the past 30 years provide unequivocal evidence for the reinforcing effects of caffeine (66). Caffeine reinforcement has been demonstrated with various participant populations, using a variety of methodological approaches (eg, choice procedures, ad libitum self-administration), and across different caffeine vehicles (eg, coffee, soft drinks, capsules). The average incidence of caffeine reinforcement across studies in people who use caffeine normally is ~40%, with higher rates observed (ie, 82%-100%) among certain subsamples such as heavy caffeine consumers, those with histories of substance use disorders, in studies involving repeated exposure to caffeine and placebo test conditions before reinforcement testing, and in the context of having to perform a vigilance task after drug administration (76). Doses as low as 25 mg per cup of coffee and 33 mg per serving of soft drink function as reinforcers (77–79). Doses >50 or 100 mg tend to decrease choice or self-administration, with relatively high doses of caffeine (eg, 400 or 600 mg) sometimes producing significant caffeine avoidance (80). Positive subjective effects of caffeine predict the subsequent choice of caffeine relative to placebo, and negative subjective effects predict the subsequent choice of placebo relative to caffeine (81). There is good evidence to suggest avoidance of caffeine withdrawal symptoms increases the reinforcing effects of caffeine among regular caffeine consumers. For instance, people who use caffeine who report negative effects of placebo (ie, withdrawal symptoms) tend to choose caffeine over placebo, and when physical dependence is

manipulated, subjects chose caffeine more than twice as often when they were physically dependent than when they were not physically dependent (76).

CAFFEINE TOLERANCE The degree of tolerance development to caffeine depends on the caffeine dose, the dose frequency, the number of doses, and the individual’s elimination rate (82). Complete tolerance does not occur at low daily dietary doses. Very high doses of caffeine (750-1200 mg/d spread throughout the day) administered daily, produce “complete” tolerance (ie, caffeine effects are no longer different from baseline or placebo) to some but not all effects (76). Tolerance develops to the effects of caffeine on subjective drug effect ratings, sleep disruption, diuresis, parotid gland salivation, increased metabolic rate (oxygen consumption), increased plasma norepinephrine and epinephrine, and increased plasma renin activity. Tolerance to caffeine-caused increases in blood pressure occurs but is incomplete (76).

CAFFEINE INTOXICATION Caffeine intoxication is a diagnosis in DSM-5 (70) and in the ICD-10 (83). Caffeine intoxication is defined by the DSM-5 as the emergence of five or more of the following symptoms after excess ingestion of caffeine: restlessness, nervousness, excitement, insomnia, flushed face, diuresis, gastrointestinal disturbance, muscle twitching, rambling flow of thought and speech, tachycardia or cardiac arrhythmia, inexhaustibility, and psychomotor agitation (70). Among adults, negative effects are not usually observed at acute doses 500 mg). Individual differences in sensitivity (eg, metabolic differences) and tolerance likely influence dose effects. Caffeine intoxication typically resolves within a day (consistent with caffeine’s half-life of 4-6 hours) and often with no long-lasting consequences. However, medical treatment and monitoring are necessary when significant caffeine overdose occurs. Caffeine can be lethal after ingestion of very high doses (ie, about 5-10 g), and there is documentation of accidental death and suicide by caffeine ingestion (84). It has been suggested that the lack of regulation and availability of highly caffeinated energy drinks/shots in recent years may be increasing the incidence

of caffeine intoxication, especially among young people. A report by the Drug Abuse Warning Network found that the number of emergency department visits involving energy drinks doubled from 2007 to 2011 with most of the 20,783 energy drink–related visits involving males and individuals between the ages of 18 and 25 (5). A report from the national poison data system for 2014 revealed that the large majority of energy drink cases involved young children and adolescents (85). Claims that energy drinks have contributed to sudden deaths have led to public scrutiny and an ongoing FDA investigation on the safety of energy drinks.

CAFFEINE WITHDRAWAL The caffeine withdrawal syndrome is well characterized. A 2004 comprehensive review of carefully controlled caffeine withdrawal research provided a strong empirical basis for 13 symptoms (Table 13-2). The symptoms were conceptually grouped into the following five categories and later validated by a factor analysis (86,87): (a) headache; (b) fatigue or drowsiness; (c) dysphoric mood, depressed mood, or irritability; (d) difficulty concentrating; and (e) flu-like somatic symptoms—nausea, vomiting, and muscle pain/stiffness. The caffeine withdrawal syndrome is defined by the DSM-5 as the presence of at least three symptoms within 24 hours of abrupt caffeine reduction or cessation. Symptoms must cause clinically significant distress or impairment in social, occupational, or other important areas of functioning (eg, unable to care for children, unable to work). Headache is a hallmark feature of caffeine withdrawal with ~50% of people who use caffeine regularly reporting headache by the end of the 1st day of abstinence (86). Caffeine withdrawal headaches have been described as gradual in development, diffuse, throbbing, and sensitive to movement. Caffeine abstinence produces rebound cerebral vasodilatation and increased cerebral blood flow, and such vascular changes are the likely mechanism underlying caffeine withdrawal headache (88,89).

TABLE 13-2 Empirically Validated Signs and Symptoms Resulting from Caffeine Abstinence

From Juliano LM, Griffiths RR. A critical review of caffeine withdrawal: empirical validation of symptoms and signs, incidence, severity, and associated features. Psychopharmacology (Berl). 2004;176:129.

Caffeine withdrawal usually begins 12-24 hours after terminating daily caffeine intake, although onset as early as 6 hours and as late as 43 hours has been documented. Peak withdrawal intensity generally occurs 20-51 hours after abstinence. The duration of withdrawal ranges from 2 to 9 days, with headache possibly persisting for 3 weeks (87). Although there is wide variability across individuals, the incidence and severity of caffeine withdrawal appears to be positively correlated with daily caffeine dose (90). Nevertheless, caffeine withdrawal has been observed after repeated dosing as low as 100 mg/d (90,91), and after relatively short-term exposure to daily caffeine (eg, 3 consecutive days of 300 mg/d), with greater severity after 7 and 14 consecutive days (90). Low doses of caffeine can suppress caffeine withdrawal. Among individuals maintained on 300 mg caffeine/day and tested with a range of lower doses, a substantial reduction in

caffeine dose (to 80 on the Internet addiction test) (40), there was greater activity in the anterior and posterior cingulate cortices, consistent with impaired inhibitory control and decreased cognitive efficiency of response inhibition processes (39). In addition, among Internet gamers with IAD, diffusion tensor imaging demonstrated abnormalities in the posterior cingulate cortex and thalamus with higher fractional anisotropy in the thalamus associated with greater severity of Internet addiction (41). More recently, a study of 41 men with IGD examined neural processes underlying impaired decisionmaking related to gains and losses and found that the IGD group, compared to healthy controls, showed weaker modulation for experienced risk within the bilateral dorsolateral prefrontal cortex and inferior parietal lobule for potential losses (42). In addition, during outcome processing, the IGD group presented greater responses for the experienced reward within the ventral striatum, ventromedial prefrontal cortex, and OFC for potential gains (42). Recent functional neuroimaging studies have demonstrated that adolescents with IGD exhibit aberrant activations in the frontostriatal network, the supplemental motor area, the cingulate cortex, the insula, and the parietal lobes (43,44). Additionally, there is a suggestion of dysfunction in functional connectivity in the resting state between multiple brain regions (45,46) and that this dysfunction is associated with greater impulsivity (47). Other structural imaging suggests decreased gray matter volumes and altered white matter integrity in areas involved in inhibition and emotional regulation (48–50). In considering whether Internet addiction is a real disorder, an approach different from the DSM-5 polythetic approach may be useful in creating a narrow construct within which to categorize Internet addiction. In a monothetic approach, all criteria must be endorsed in order to give a diagnosis, and it should have high sensitivity for diagnosing true positives. If a monothetic approach can be constructed that has good construct and predictive validity, then expanding out from that may allow a criterion set that has reasonable clinical utility in reducing false negatives. Griffiths (51), in considering the necessary components of addiction that would subtend diagnostically both substance and behavioral addiction, identified six necessary domains based on the work of Brown (52,53) in modeling problem gambling behavior: salience, mood modification, tolerance, withdrawal symptoms, conflict, and relapse. This method is interesting, and clinicians who treat patients with substance use disorders will recognize the symptom set in their patients and thus the economy in the approach:

Salience: The drug or behavior has gained primacy in a person’s life, which can be a cognitive change, dominating the person’s mental life or, behaviorally, dominating a person’s activity in a compulsive fashion. Mood modification: The substance or behavior subjectively gives one a rewarding high or alleviates a negative mood state. Tolerance: The person must increase the amount or intensity of the substance or behavior in order to achieve the desired effect. Withdrawal symptoms: After stopping or reducing the substance or behavior, the person demonstrates either physical symptoms after or dysphoria characterized by irritability, mood lability, depressive symptoms, and so on. Conflict: The person has conflicts regarding the use of the substance or the behavior that manifests as either interpersonal (eg, marital strife) or intrapsychic (eg, guilt). Relapse: After a period of abstinence, the use or behavior is reinstated with the same intensity. Proponents of a polythetic approach to Internet addiction modeled after DSM-5 substance use disorder might point out that one of the hallmarks of the modern concept of addiction is the idea of loss of control despite negative consequences, which is embodied in several of the DSM-5 criteria and not included as one of the six necessary domains of the monothetic approach. However, compulsive behavior in the salience category accounts for the symptom of loss of control. It may be argued that problematic Internet use better fits criteria for DSM-5 disorder groups other than the substance-related disorders (ie, Internet addiction). This is what was behind the differing nomenclature, such as Pathological Internet Use, which is modeled after pathological gambling, which was an impulse control disorder (ICD) diagnosis in DSM-IV but which as gambling disorder has been moved to the substance-related and addiction disorders in DSM-5 (1). For example, PIU has been proposed as an obsessive– compulsive disorder (OCD) spectrum disorder. However, in compulsive disorders such as OCD, the intrusive thoughts or compulsive behaviors are typically ego-dystonic, whereas in PIU, the preoccupation is ego-syntonic and pleasurable. While most patients with OCD are anxious and full of doubt and tend to avoid risk, others dispel their obsessions and resultant anxieties through compulsive Internet use (CIU). Patients with unhealthy Internet use tend to underestimate risk. Shapira et al. (54), using the Structured Clinical Interview for DSM-IV (SCID), Internet use history, and a Yale-Brown Obsessive Compulsive

Scale modified for Internet use, examined 20 recruited volunteers or referred patients with problematic Internet use characterized as uncontrollable, markedly distressing, time-consuming, or resulting in social, occupational, or financial difficulties and not solely present during hypomanic or manic symptoms. In general, the subjects had, in contrast to patients with compulsive disorders, low levels of distress and resistance to excessive Internet use. Their problematic Internet use symptoms were highly impulsive, with all subjects meeting DSM-IV criteria for an ICD not otherwise specified, whereas only 15% subjects met DSM-IV criteria for OCD based on their problematic Internet use. However, this uncontrolled study had a small sample size and a clear selection bias, so generalizing from the results may be problematic. Nonetheless, like pathological gambling, PIU could be conceived as an ICD, and several authors have proposed this (5,55–57). In fact, a cross-sectional association analysis of n = 81 subjects equally grouped into IAD, pathological gambling, and normal controls revealed that those with IAD have increased trait impulsivity comparable to those with pathological gambling and a positive correlation of trait impulsivity to IAD severity (58). Similarly, Meerkerk et al. (59) explored personality correlates predictive of CIU, an IAD proxy, and demonstrated in a survey among n = 304 respondents who met the criteria (score > 28) on the Compulsive Internet Use Scale (CIUS) (60) that dysfunctional impulsivity (ie, rash spontaneous, including constructs of novelty seeking, sensation seeking, behavioral undercontrol, and disinhibition) was the strongest predictor of CIU compared to reward or punishment sensitivity (59). Hallmarks of ICD are repeated failure to resist impulses that are harmful to self or others and tension or arousal before and pleasure or relief during the act, followed by guilt or self-reproach. However, this may not necessarily be the case in patients with problematic Internet use and will need to be explored with larger epidemiological studies and more refined research of potential diagnostic criteria. In addition to symptoms that overlap with impulse control disorders (eg, intense preoccupation with Internet use, CIU, loss of control over online time), however, Internet addiction also shares symptoms with behavioral addiction, such as development of euphoria, craving, and tolerance (61). The DSM-5 workgroup had at one point been contemplating problematic Internet use as a compulsive–impulsive disorder in the group of ICDs (57). As such, it may be that the placement of what may be considered Internet addiction among the DSM-IV impulse disorders was an artifact of the failure to expand the category of substance-related disorders to broader diagnostic category that includes non– substance-related “behavioral addiction.” The monothetic approach to addiction

described above supplies one potential model for building that category (51). The utility of a monothetic approach is that in requiring all symptoms to be present, if any subgroup of those with problematic Internet use fits the criteria, then the high specificity should make it easier to validate as a disorder. In order to provide construct validity of the monothetic model, it remains to objectively demonstrate tolerance and perhaps physiological or neuroimaging concomitants of withdrawal that are more than reported withdrawal-related dysphoria (although dysphoria may be sufficient for a polythetic approach, as it is in pathological gambling) (62). Assuming high construct validity, if anyone has Internet addiction, it is someone who meets monothetic criteria. As is, in DSM-5, IGD has been pulled from the more inclusive concept of Internet addiction and placed in Section 3 with the other “Conditions for Further Study,” and the placement of gambling disorder in the substance-related disorders raises the possibility of other behavioral addiction ultimately being validated as belonging to that group, modeled on “use disorders”(1). Recent work by Brand et al. (19) and others further supports this notion, and the American Society of Addiction Medicine has formally included non–substance-related behavioral patterns of pursuing reward or relief in its definition of addiction (63). Another approach to developing stable and valid criteria for Internet addiction has been to build a bottom-up construct of most frequent symptoms from factor analysis of a group. Pratarelli and Browne (64) conducted a 94-item anonymous survey in college students (n = 524) and demonstrated the nonindependent factors: Internet addiction (preoccupation, external complaints, less sleep, food, exercise, and punctuality) (salience), sexual (downloading graphic sexual material), and an Internet use factor (excessive use for professional, educational, gaming, shopping activities, etc.). When the data were best fit to a structural equation model, the addiction factor was primary and causal to sex and use factors rather than vice versa. Charlton (65) performed a factor analysis on 47 variables derived from the six-factor monothetic model of addiction described above (51–53), with added items that evaluated engagement (computer apathy/engagement and computer anxiety/comfort) from data collected from a survey of 404 college and graduate students. The addiction factor loaded upon all items of the monothetic model behavioral addiction criteria supporting the construct validity of this model of computer addiction (65). However, the engagement factor also loaded upon tolerance, euphoria, and cognitive salience, demonstrating that these factors are not unique to addiction. This suggests that high computer engagement is part of the structure of “computer (includes Internet) addiction” but is not necessarily pathological in

and of itself. One can be highly engaged in Internet use without negative consequences. Beard and Wolf (66) describe a woman who is preoccupied by thoughts; desires increased time spent in activity; is unsuccessful or unable to control or cut back interactions; is restless, anxious, or moody when not interacting; and interacts for longer periods than intended. Without a defined substrate, the symptoms seem ominous in the example above, but the high engagement of this woman for her baby is not pathological, and the authors suggest that additional requirement of impairment in a person’s daily functioning (ie, jeopardized loss of relationship or work/educational opportunity, lied to significant others to conceal extent of Internet involvement, or used the Internet so as to escape problems or relieve dysphoria), over and above symptoms of high engagement, is necessary for a diagnosis of Internet addiction (66). This finding is paralleled in the work of Ko et al. (67), who in establishing a criterion set for adolescent Internet addiction that had high diagnostic accuracy and specificity, as well as good sensitivity, determined three main criteria: characteristic symptoms of Internet addiction not dissimilar from DSM-IV substance dependence symptoms, an exclusion criterion, and functional impairment due to Internet use. Since the Internet is here to stay, future work will need to differentiate the substrates of behavioral addiction from an overall diagnosis of IAD, much as SUDs are classified according to substance used, for example, alcohol, stimulants, and sedative–hypnotics. The most likely domains are static and live sexual content (frequently in the context of co-occurring stimulant and other use disorders), video gaming, and gambling/day trading and perhaps social networking/live interfacing (including chat, texting, video), shopping/auctions, netsurfing, and music/video downloading/torrenting. An interesting need for differentiating purported behavioral addiction such as “sex addiction” and those that are solely microprocessor-based will occur at some point and represents a similar problem to that of the more inclusive IAD diagnostic range and the narrower, substrate-based concepts, such as IGD. At present, only IGD is included as a proposed diagnostic category in Section 3 of DSM-5. Much as social networking is a recently invented phenomenon, there may be future Internet applications that end up as new substrates for Internet addiction. Inquisitive individuals are at risk for “falling down the Wiki rabbit hole” because the hypertext content links can bring one to interesting new content pages in an infinite regress, but evidence of this at a disorder level has not yet been reported. Recent evaluations of social network sites demonstrate that they are used for social purposes, mostly related to maintenance of already established offline

networks, and there has been scant documentation of pathological use (68). Kuss and Griffiths (68) identified interesting correlates of social networking related to increased use, such as social enhancement in extraverts with high self-esteem and social compensation in introverts with low self-esteem, as well as high narcissism and low conscientiousness. In addition, they found correlates that might signal addiction vulnerability, such as decreases in academic achievement, non-Internet community participation, and relationship problems. Substance addictions occur at high rates with other mental disorders in the population, so it would not be surprising to see a related pattern in those with behavioral addiction (69). Carli et al. (70) conducted a systematic review of 20 studies of the correlation of PIU, as assessed by the IAT and other scales, with other psychopathology and found, among the mostly Asian cross-sectional studies, consistent and strong correlation of PIU with attention deficit hyperactivity disorder (ADHD) and depression. Among online gamers (n = 722) who filled out a survey questionnaire, weekly online gaming time was averaged 28.2 ± 19.7 hours and was significantly and linearly associated with severity of depression, social phobia, as well as Internet addiction scores (71).

ASSESSMENT Talking to patients, one can discuss the intensity and impact of their use of microprocessor-containing devices and assign general risk categories based upon the information provided. A simple screening cutoff can begin to establish whether use is “normal” or unhealthy. From there, it becomes more difficult to establish what one is dealing with, owing to the lack of scientific consensus as to whether certain types of unhealthy microprocessor use rise to the level of disorders, what type of disorders they may be, and what the criteria are for those disorders. As discussed above, functional impairment is a good marker for a clinically relevant use of microprocessors (72). Below is an attempt to broadly define various severity levels of microprocessor use. Use: A reasonable time spent accomplishing specific goals using microprocessors, such as a Google search on “pathological computer use” (2,230,000 results in 2017—more than nine times that cited in the 2014 edition of 243,000) or getting back your dog that strayed because the staff at the pound found the chip under his skin with your name and telephone number. Remember that high engagement does not necessarily mean pathology. Problem use: One can conceptualize this as use with trouble in that the use is

causing clinically significant impairment. The issue here is the repeated taking on of undue risk, getting oneself into legal problems, the interference with fulfilling major role obligations, or continuing the microprocessor use in spite of recurring social or interpersonal problems. These parallel the prior substance abuse category for the DSM-IV substance-related disorders and might present as subthreshold for DSM-5 IGD, for example, when the syndrome causes impairment but 5 h of daily Internet use or online gaming is associated with suicidal ideation and planning, and Internet interactions may inhibit revealing suicidal thoughts or plans or seeking professional help and may provide normalizing feedback about self-harm (102).

Morbidity Morbidity occurs at several levels. The amount of time spent with microprocessors results in necessary tasks going undone. Real-life social relationships get less time, and what may be thought to be more satisfying relationships are developed on the Internet. Impairment can be difficult to tease out but, as described above, becomes a crucial component of a diagnosis over and above high engagement. The patient is not necessarily a recluse but can

document that those hours spent in his room involve communicating with “friends” around the world to play “World of Warcraft.” Objective observers may rate these relationships less favorably, often reminiscent of a patient with alcohol use disorder’s drinking buddies. Managing multiple identities can be taxing, and identity fragmentation occurs if one’s Internet persona is markedly different from one’s real-life persona. Clinicians have to assess cyber relationships in detail. Some patients present as having lost touch with what is the “true” reality. Impairment may also result from physical activity of prolonged sitting in front of screens, with increased obesity and less exercise. Decreasing use of national parks, 4 million fewer golfers, and a decline in outdoor activities may be related to increasing use of microprocessors. However, inactivity is preferable to accidents that occur while multitasking. The American College of Emergency Physicians (2008, http://www.emergencycareforyou.org/YourHealth/InjuryPrevention/Default.aspx? id=1240) responded to increasing reports of injuries related to being hit or falling while texting by issuing an alert against “text walking.” It may seem to be common sense that people should watch where they are walking, but the number of vehicle hits, falls, and running into trees, lamp posts, and other people has become noticeable in emergency rooms across the country.

PRETREATMENT ISSUES Motivation—Rationale Treatment

for

Choice

of

As with most addiction, motivation prior to engagement in treatment may be scant or absent. Problems are minimalized, rationalized, or denied. A nonconfrontational discussion of impairment often helps the patient to gain perspective. This can be done using the principles of motivational interviewing, where the facts about the impact of microprocessor overuse are carefully elicited and then fed back to the patient in a nonjudgmental manner (103). This helps the patient to use his or her native analytic capacity and values in determining that the overuse is actually problematic or impairing and helps to tip the decisional balance toward seeking help to reduce the problem. An important way station between Internet addiction and returning to the real world is more therapeutic use of the Internet and microprocessors. This is

somewhat of a departure from the abstinence-oriented approach of classic addiction treatment. A mother was successful in restricting her daughter’s IM from 3000 per day to 500 and then 200. Online support groups are thought to help, but a review of 38 controlled studies of illness (not just Internet addiction) support groups found no robust evidence of effects, in part because most were measuring complex interventions (104).

Selection and Preparation of Patients/Suitability Unlike the subpopulations that comprise the sufferers of many substance addiction, those with unhealthy microprocessor use are technically competent, often innovative, and well educated (105), which makes them more suitable as a group for clinical interventions. However, the subpopulation has been demonstrated to have high rates of current and lifetime co-occurring mental disorders, which tend to have a negative impact upon recovery (54). Retreat into cyberspace may mask co-occurring social phobia and/or other anxiety disorders.

Therapist Characteristics Familiarity with the Internet and uses of microprocessors and technology is important for understanding patients, expressing empathy, and earning respect and credibility with patients, all of which are associated with better treatment outcomes (106).

Treatment and Technique Choice and Timing of Interventions When parents or significant others are in control, taking away or restricting access to the microprocessor may increase motivation or result in destructive anger, so clinicians must expect to hear about and perhaps participate in whatever decision is made. However, similar to binge eating and other disorders of compulsive food intake, complete abstinence is usually not a feasible longterm treatment goal, as use of microprocessors is unavoidable in today’s world and nonuse is associated with significant vocational and social disadvantage.

General and Stage-Specific Interventions The general plan is reintroduction into the real world, which must be done in

stages to ease transitions. It is a desensitization process, with small steps to be taken that will bring about a sense of success and increased self-esteem. Where identity issues predominate, the successful elements of the Internet identity should be characterized, and there should be an open discussion of integrating these into the real-world persona. Therapy should be seen as a rewarding process that helps the patient get in real life what has been available only on the Internet. This is consistent with community reinforcement principles in replacing the rewards of the used substance with more natural and socially appropriate reinforcers (107). With compulsive patients, the therapist can take responsibility for the compulsive behavior and relieve the patient’s anxiety. Medication treatment for co-occurring OCD and/or anxiety can be helpful. Clearly, treating co-occurring mood, anxiety, psychotic, and SUDs is likely to be helpful in supporting recovery from involvement of significant others and is key to supporting recovery and reintegration into the real world. Social skills training may also be helpful.

RELEVANT TREATMENT RESEARCH Compared to research on psychosocial treatments of SUD, there is far less relevant treatment research because funding agencies have not yet recognized the problem as deserving much attention (ie, significant clinical impact, public outcry, or political will). A survey of clinicaltrials.gov for Internet addiction reveals one German study of CBT-based treatment for computer gaming addiction and one nonactive CBT study of IGD and sleep disorders. The development and use of the Internet are seen as an enormous technological advance. More and more material is being made available on the Internet, and its legitimate use is increasing exponentially. There is strong commercial support for Internet use, as the Internet generates huge advertising revenues and is used to sell many products. Complaints about Internet addiction can be seen as spoiling the party. The American Medical Association called in 2007 the National Institutes of Health and the Centers for Disease Control to start research programs in Internet addiction, but as of 2017, no federal grant programs have as yet been announced. As such, much of the available epidemiological and treatment outcome research devoted to Internet addiction has been based upon case studies and survey data, of which Internet-based surveys can be driven by the motivation of the responders and thus subject to selection bias. Given the increased international attention to IGD, King et al. (108) conducted a systematic review of 30 studies mostly from China and South Korea of

psychosocial interventions for IGD carried out between 2007 and 2016. The authors found, using the 25-item CONSORT statement (109), that overall research quality was impaired due to the disparities in the definition, diagnosis, and measurement of IGD, the lack of randomized controlled studies with proper blinding of data acquisition and analysis, and unavailability of recruitment dates, sample size justification, follow-up reports on changes in gaming or Internet use, and effect sizes (108). These trends in the design and execution of international research studies continued despite the 2013 publication of DSM-5 IGD criteria and a preliminary international consensus for IGD assessment published by Petry et al. in 2014 (110). There are more than 20 instruments that have been developed to assess IGD but typically only assessed for 9 of the DSM-5 criteria, most frequently failing to assess if the patient jeopardized or lost a relationship, job, or educational or career opportunity (110), but more recent constructs are fitted to the IGD criterion set (111). Clearly, the research in this area is in need of standards in assessment and diagnosis with better study design and execution.

Psychologically Based Treatments Winkler and colleagues conducted a meta-analysis of the extant treatment research for IAD, including studies with various Internet-related problems, and found evidence in pre–post analyses for effective treatment of IAD, time spent online, depression, and anxiety (112). Yeun and Han (113) conducted a metaanalysis of 37 studies to determine the effect size of prevention-oriented psychosocial interventions for Internet addiction in mostly South Korean schoolaged children and demonstrated, in spite of considerable variation in diagnostic approaches and predominantly nonrandomized designs, a large protective effect on the development of Internet addiction as well as a large effect on self-esteem and improved self-control. Elements that weighed strongly as variables were duration of treatment exposure > 10 sessions, CBT, parental involvement in therapy (for children), and self-control training (113). Yellowlees and Marks (114) suggest that given that cognitive process maintains IAD, appropriate psychotherapeutic strategies would include cognitive restructuring focused on the applications of choice, behavioral exercises, and graded exposure therapy with increasing duration of offline activity. As such, an early uncontrolled trial of CBT specifically focused upon Internet addiction demonstrated efficacy in reducing pathological Internet usage and improving online time management among 114 patients who were screened with the IAT (105). Young (115) conducted a more recent noncontrolled study with 128 treatment-seeking patients screened for IAD with the IAT who were then treated with 12 weekly

sessions of CBT for Internet addiction (CBT-IA), a CBT-based intervention that initially uses behavior therapy to examine computer and noncomputer behavior to promote abstinence from problematic sites or applications, moves into cognitive work to identify maladaptive cognitions that serve as rationalizations and triggers, and finally works on harm reduction strategies for maintenance of gains and relapse prevention. Most participants were able to manage their IAD symptoms effectively by the 12th session and 70% maintained this at 6 months (115). Similarly, Wölfling et al. (116) treated N = 42 mostly single adult men with Internet addiction (4/5 with IGD-type problems) with an integrated threephase program with 15 group and 8 individual sessions based on CBT and demonstrated significant reductions in problem severity and negative consequences of Internet use in this uncontrolled sample (116). In a Chinese sample, Liu and colleagues conducted a study of manualized 6-session (2 hours) multifamily group therapy (MFGT) focused on strengthening adolescent–parent communication and shifting needs fulfillment away from the Internet to real-life interpersonal interactions, compared to a waiting list control group in N = 42 adolescents and N = 42 parents, demonstrating in the intervention group a significant reduction in scores on the Adolescent PIU Scale and time spent on the Internet both at the end of treatment and at 3-month follow-up (117). As yet, there are no high-quality randomized controlled trials reported for psychosocial treatment of IAD as a stand-alone construct. Focusing more specifically on treatment of specific “Internet use disorders,” there is some evidence from controlled trials suggesting the efficacy of psychosocial interventions for IGD and Internet-related gambling. Zhang and colleagues (73) conducted a 6-week study of 40 young Chinese adults with IGD, comparing a convenience sample of those that received a weekly craving behavioral intervention (CBI) based on the cognitive behavioral model of Dong and Potenza (28), and targeting Internet gaming cue-reactive craving (N = 23), to a matched group that did not (N = 17) and found significant reductions in the CBI group on visual analogue scale (VAS) measures of cue-induced craving, durations of weekly gaming, and overall Internet addiction severity (73). Deng et al. (74) likewise targeted craving behavior in N = 63 Chinese college students with IGD in a quasiexperimental trial of a 6-session weekly cognitive– behavioral intervention (including identification of craving triggers and emotion regulation training, n = 44) compared to a convenience sample (n = 19) waiting list control group and found significant reductions in severity of IGD, as well as in VAS measures of current craving for online gaming at postintervention and at 3- and 6-month follow-up (74). The change in self-reported craving accounted

for a significant portion of the effect of the intervention on IGD severity at all three assessment points, and further analyses revealed that the reduction in craving was mainly attributable to amelioration in depression symptoms and shifting fulfillment of psychological needs from the Internet to real-life interpersonal interactions, suggesting that craving is an important treatment target in psychosocial treatment of IGD and perhaps other Internet-related disorders (74). A study combining medications and behavioral intervention shows promise for CBT for IGD in the context of comorbid mood disorders. Kim et al. (118) tested 8-session CBT versus no behavioral intervention in Korean adolescent males (N = 72) with major depression and IGD-type Internet addiction (based on DSM-IV substance abuse criteria) who were treated with bupropion and demonstrated significant reductions in online gaming time and Internet addiction severity in the CBT group at study end and at 4-week followup, as well as a significant reduction in depression severity compared to controls. Cognitive–behavioral-based interventions may also have applicability in treating Internet gambling disorder. With Internet-based behavioral addiction, it is unclear as to whether a focus on reducing pathological Internet use or more specific targeting of the substrate will have more clinical efficacy. Petry and Gonzalez-Ibanez (120) conducted a secondary analysis of results from a primary study of brief interventions for problem gambling (119) where for this analysis the data from the three active intervention groups (10-15’ brief advice, 50’ motivational enhancement therapy (MET), and MET + 3 additional CBT sessions) were combined and compared to the control group (assessment only) in mostly male (>80%) college students with (N = 57) or without (N = 60) recent Internet gambling (120). Although at baseline the recent Internet gamblers gambled more frequently and with higher stakes and had significantly more anxiety and interpersonal and school impairment than did the non-Internet gamblers, the impact of the three active interventions compared to controls in significantly reducing gambling behavior over time was not different between groups, suggesting that Internet-based gambling disorders are responsive to brief therapies focused on gambling behavior rather than Internet behavior per se (120). In contrast, Luquiens et al. (121) screened with a survey and recruited non–treatment-seeking problem Internet gamblers on a poker website for a 6week randomized clinical trial of three brief interventions targeting gambling behavior, emailed automated personalized feedback from individual survey scores, an emailed self-help book with an unguided CBT program, and a CBT program emailed weekly with professional guidance, versus a waiting list control group, and found that in all groups, the dropout rate was high, but study

completers had significantly reduced gambling severity scores. However, the group that received the professionally guided CBT had the highest dropout rate, suggesting that CBT-type interventions may not be appropriate in Internet gamblers who are not treatment seeking (121).

Pharmacotherapy and Psychologically Based Treatments Regarding pharmacotherapy for IAD, one study reported therapeutic success with escitalopram, a selective serotonin reuptake inhibitor antidepressant (122); however, the active treatment phase was open label. Han et al. (123) treated males (n = 11) addicted to Internet video gaming with sustained-release bupropion titrated to 300 mg/d over a 6-week period and compared them to healthy controls who had the same video game preference as the experimental group, but not pathologically. Not only were the total amount of time spent playing, related maladaptive behaviors, and video game craving reduced at 6 weeks and significantly correlated with the drop in time spent playing, but video cue-induced brain activity in the dorsolateral prefrontal cortex, as assessed by fMRI, was also reduced from baseline (123). An 8-week trial of methylphenidate for ADHD (mean dose 30.5 mg/d) in Korean children (n = 62) examined the impact on measures of Internet addiction and Internet usage as well as ADHD symptoms and visual continuous performance test function and demonstrated reduced inattention and impulsivity–hyperactivity scores, as expected, as well as significantly reduced scores on hours of Internet use and the Internet Addiction Scale, which was significantly correlated with the decrease in ADHD symptoms (124). Additionally, a single case study reported, after failure of multiple antidepressant trials as well as psychosocial and self-help approaches, successful treatment of Internet-based sex addiction with up to 150 mg/d of oral naltrexone when added to a baseline of sertraline 100 mg/d, which supported normalized social, occupational, and personal function (125). Finally, Han and Renshaw (126) conducted an 8-week randomized trial of bupropion SR 300 mg/d plus weekly education for problematic Internet use compared to weekly education alone in male patients (N = 50, 13-45 years old) with DSM-IV major depression and severe problem Internet gaming and demonstrated that in addition to significantly reduced depression severity in the medication group there was significantly reduced severity of Internet addiction as well as mean online game playing time. Interestingly, in the prospective case series of recruited and treatment-seeking pathological Internet subjects described above, there were

high rates of current comorbid bipolar depression that responded to anticonvulsant treatment (with or without adjunctive antipsychotic or antidepressant agents) with both normalization of mood and moderate to marked remittance of pathological Internet use (54). However, it is important to note that if IAD follows suit with chemical addiction, then effective treatment of cooccurring other mental disorders will generally have effect sizes insufficient to treat the IAD (127).

SUMMARY AND CONCLUSIONS Use of microprocessors continues to increase rapidly as these are placed in a wide variety of communication and amusement devices. These devices are always available, cost little to use, and provide many rewards. About 1% of the US population has unhealthy microprocessor use. These problems are likely to increase as microprocessor use and power continue to increase. While sharing many commonalities with other addiction, unhealthy microprocessor use differs in that no exogenous substance is involved and patients are technologically savvy and computer literate and are able to manipulate their identities in cyberspace. Even without resorting to a pathology model, current societal adaptation to the use of microprocessors can, at its most extreme, be likened to the London gin epidemic, where citizens previously comfortable with a culture that drank beer and ale, frequently to intoxication, had to adapt poorly to a new more potent alcoholic liquid, with disastrous results in a population that was already ripe for social unrest (128). Eventually, the culture moderated its use more globally, leaving the bulk of maladaptive and damaging alcohol-related trajectories to those with alcohol use disorders. It may be that our culture is on a similar path and in the wake of our corporate learning curve will be those for whom microprocessors provide a “substance” fulfilling its role as a substrate for a pathological use disorder (3,54,80,125,129–131).

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CHAPTER 48

Behavioral Syndromes to Consider as Forms of “Addiction” Abigail J. Herron, Paul J. Rinaldi and Petros Levounis

CHAPTER OUTLINE Introduction Compulsive Buying Disorder Excessive Tanning Kleptomania Shared Features of Behavioral and Substance Addictions Co-Occurrence of substance use and Behavioral Addictions Diagnostic Challenges Treatment Models Conclusion

INTRODUCTION Three primary components have been described as the core elements of addiction: craving or compulsion, loss of control, and continued behavior despite associated negative consequences (1). While the term addiction has been often used to exclusively describe impaired control over substance use (2,3), these core elements can be seen in certain behaviors associated with short-term rewards that lead to persistent behavior despite adverse consequences. This shared feature of diminished control has given rise to the concept of behavioral addictions, syndromes similar to substance addiction (generally referred to as substance use disorders), but with a behavior as the core of the disorder rather than a substance (4,5). Traditionally, these behaviors have been classified as impulse-control disorders (ICDs). The Diagnostic and Statistical Diagnostic Manual of Mental Disorders, 5th ed. (DSM-5) expanded this category to “Disruptive, ImpulseControl, and Conduct Disorders,” which include oppositional defiant disorder, intermittent explosive disorder, conduct disorder, antisocial personality disorder, pyromania, kleptomania, and other specified and unspecified disruptive, impulse-control, and conduct disorders (6). Several other disorders have been proposed for formal recognition as ICDs, including compulsive shopping, problematic Internet/computer use, compulsive sexual behavior, compulsive skin picking, and compulsive tanning (7,8). Defining characteristics of these disorders include repetitive or compulsive engagement in a specific behavior despite adverse consequences, diminished control over the problematic behavior,

and tension or an appetitive urge state prior to engagement in the behavior (7). While many of these disorders share features with substance use disorders, others do not. The shared characteristics of some behavioral disorders and substance use disorders have raised the question of whether they would more appropriately be classified as addictive disorders. In this chapter, we will discuss shared features of behavioral and substance addictions, co-occurrence, diagnostic challenges, and treatment options. Several of the behavioral disorders are covered in depth in other chapters in this text, but we will include three of them here—compulsive buying disorder (CBD), excessive tanning, and kleptomania—as specific examples of conditions that may merit reclassification as substance use disorders. We have chosen to include these disorders because they are activities that can be considered pleasurable, exciting, and naturally rewarding at normative levels, similar to that of substance use. Others, such as skin picking or trichotillomania, are pathological even at lower levels of activity and seem to be better classified as obsessive–compulsive disorder (OCD) spectrum disorders. When the behaviors that result in such pleasurable rewards cross to the pathological level, they may be considered addictions.

COMPULSIVE BUYING DISORDER Compulsive buying was first described by Kraepelin (9), who wrote about oniomania, which is uncontrolled shopping and spending. Bleuler (10) described “buying mania” as an example of a reactive impulse or impulsive insanity. He categorized it along with pyromania and kleptomania. Although compulsive buying is not specifically described in the DSM-5, diagnostic criteria have been proposed. These include being frequently preoccupied with buying or subject to irresistible, intrusive, and/or senseless impulses to buy; frequently buying unneeded items or more than can be afforded; shopping for periods longer than intended; and experiencing adverse consequences, such as marked distress, impaired social or occupational functioning, and/or financial problems. There has long been debate about whether this is a true disorder. It was included in the DSM-III but was excluded from the DSM-IV and DSM-IV-TR. In the DSM-III-R, it was included as an “impulse-control disorder not otherwise specified.” While there has been debate about the classification of the disorder, it is widely accepted by clinicians that it is a serious condition requiring intervention. The estimated prevalence of CBD in the United States is ~5.8% (11).

Prevalence rates in the literature have been as low as 1.8% (12) and as high as 8% (13). The usual age of onset for CBD appears to be in the late teens to early 20s (14). Most subjects identified are female, but a study by Koran et al. (11) that used a large general population sample found that the prevalence of CBD between women and men was only slightly different. McElroy et al. (16) found extremely high comorbidity rates among people with CBD. She found that compulsive shopping behavior might be related to mood disorders, OCD, or ICD. Male compulsive buyers were more likely to be diagnosed with “sexual addiction” and intermittent explosive disorder (15). First-degree relatives of people with CBD are more likely to have psychiatric disorders such as alcohol or substance use, major depression, and anxiety disorders than first-degree relatives of people without CBD (16,17). Black (18) identified four phases, which are anticipation, preparation, shopping, and spending. In the first phase, the person becomes preoccupied with either purchasing a specific item or shopping in general. In the next phase, the person plans the purchase or shopping spree. This is followed by the actual shopping experience during which many of those with CBD feel intense excitement. The actual purchase completes the cycle. Following the purchase, the person often experiences feelings of disappointment, shame, or guilt. Similar to kleptomania, neurobiological theories have focused on disturbed serotonergic, dopaminergic, or opioid neurotransmission. Some argue that CBD should be included in the nosological classification as an substance use disorder. The reasoning is that some ICDs share features in common with substance use disorders: comorbidities, family histories, and brain circuitry. There is evidence that the brain circuitry in substance use disorders, namely, the “reward system” of the brain, is involved in ICDs (5). There are no definitive evidence-based treatments for CBD (19). Treatments have generally followed the same protocols as with other ICDs, namely, cognitive–behavioral therapy (CBT) and pharmacotherapies. Pharmacotherapies have included the use of SSRIs, particularly fluoxetine and citalopram. Grant et al. (20) have shown some improvements with naltrexone, suggesting that opioid antagonists might play a role in CBD. Since the medication findings are mixed, no empirically supported treatment recommendations can be made. CBT has also been recommended. Most of the CBTs that have been developed involve group therapy. Mitchell et al. (21) found that group CBT yielded significant improvement compared to a control group and that the improvements attributed to CBT were maintained during a 6-month follow-up.

Since CBD occurs mostly in developed countries, sociocultural factors have been proposed either as etiological agents or to promote the disorder. Neuner et al. (22) reported an increase in the frequency of CBD in Germany following reunification. This led to the conclusion that societal factors can contribute to the development of CBD. These factors can include the availability of goods, easily obtained credit, a market-based economy, and disposable income. Available empirical evidence is insufficient to draw conclusions about whether CBD exists as a distinct disorder or whether it is a subtype of other disorders. While many clinicians agree that the people suffer from this disorder, randomized clinical trials are needed in order to definitively study and classify CBD.

EXCESSIVE TANNING According to an 8th-century Japanese proverb, “white skin makes up for seven defects” (23). For many centuries, fair skin was celebrated as a sign of beauty and elegance in Western and Asian cultures. It was not until the early part of the 20th century that tanning was introduced as a desirable trait when Coco Chanel famously declared, “The 1929 girl must be tanned. A golden tan is the index of chic!” and, suddenly, pale became passé (24). Since then, the Western world has idolized darker skin and tanning, and only recently, we have started to question this model. In the 21st century, there is little doubt that sun exposure causes skin cancer. Whether people suntan naturally or use indoor tanning sunbeds, the risk of developing cancer has been well established (25). In response to this serious public health concern, both the government and the media have made significant efforts to educate the public, raise awareness, and promote the use of sunscreens with high sun protection factor. The result is that the new millennium has now developed a highly ambivalent relationship with the sun and its surrogates, the tanning lamps. This widespread ambivalent relationship notwithstanding, there is a subgroup of people for whom tanning is clearly excessive and seems to reflect frank psychopathology. Excessive tanning is not recognized in the DSM-5 diagnosis, nor is it mentioned as an example of an unspecified ICD. However, for this subgroup of people who tan excessively, their presentation, symptomatology, psychiatric comorbidity, consequences of behavior, and overall course of illness resemble significantly the trajectories of other behavioral

addictions and the substance use disorders. Kaur et al. (26) reported on a small study of regular sunbathers who exhibited opioid-like withdrawal symptoms upon administration of naltrexone, an opioid antagonist. In 2005, Warthan et al. (27) published a seminal article in the Archives of Dermatology with the title “UV light tanning as a type of substance-related disorder.” They interviewed 145 beachgoers using a modified CAGE questionnaire (28), a common screening instrument for unhealthy alcohol use, and found that approximately one in four participants met the criteria for a tanning-based, substance-related disorder. The article was provocative at the time and several addiction experts denounced its findings as disrespectful to people who suffer from “true” addictions like the substance use disorders (29). Since then, we have come to appreciate excessive tanning as a candidate for consideration as a behavioral addiction. While most recent research has adopted the addiction paradigm in understanding excessive tanning, there are other psychiatric disorders that may also explain the manifestations of the illness. Sansone and Sansone (30) proposed the following three disorders as “possible underlying psychopathologies” for excessive tanning: OCD, body dysmorphic disorder (BDD), and borderline personality disorder (BPD). At this time, limited research has been conducted to support or refute these explanations. Furthermore, an alternative formulation of the illness could suggest that excessive tanning may be a behavioral addiction that is often found to be comorbid with these disorders—OCD, BDD, and BPD. We have not encountered any clinical or epidemiological studies that could shed some light into these alternatives. The lack of research in this area extends to treatments. However, if we accept that excessive tanning is best appreciated as a behavioral addiction, then (a) addressing underlying or co-occurring psychiatric conditions and (b) providing CBT or motivational interviewing (MI) seem to be the most reasonable approach to treatment. A small three-group randomized clinical trial by Turrisi et al. (31) demonstrated that young women who frequently used indoor tanning facilities markedly reduced their tanning events following a oneon-one MI session using a personalized graphic feedback delivered by a trained peer counselor. Comparison groups that were provided with identical graphic feedback but through the Internet with no person-to-person or no intervention did not demonstrate any change in tanning events. A number of other psychosocial interventions have been tried in small

samples of more normative populations, including the following three, which have shown some promising results: Showing patients ultraviolet photos of skin damage (32) Showing patients “image norms of aspirational peers” (e.g., media figures and fashion models) approving paleness (33) Providing feedback on the patient’s suntanning behavioral patterns by a physician (34) In addition to treatments, prevention has to play a major role in addressing the proposed illness, especially since there is little evidence of safe and effective therapeutic interventions. Current public heath efforts go beyond raising awareness of the risk of excessive sun exposure. State, federal, and international regulations are being considered and implemented to limit indoor tanning by imposing higher taxes and prohibiting minors from using such facilities (35). At least 44 states and the District of Columbia regulate indoor tanning for minors. Sixteen states and one territory ban the use of ultraviolet tanning devices by anyone under age 18 (36).

KLEPTOMANIA The DSM-5 (6) includes kleptomania as a distinct diagnosis in the category of disruptive, impulse-control, and conduct disorders. The following symptoms are recommended for a diagnosis of kleptomania: Repeated inability to defend against urges to steal things that are not essential for private use or for their economic value. Escalating sense of pressure immediately prior to performing the theft. Satisfaction, fulfillment, or relief at the point of performing the theft. The theft is not executed to convey antagonism or revenge and is not in reaction to a delusion or a fantasy. The theft is not better accounted for by behavior disorder, a manic episode, or antisocial personality disorder. Kleptomania is characterized by recurrent episodes of compulsive stealing. Often confused with shoplifting, it differs in that those with kleptomania do not steal for personal gain. They steal in response to an overwhelming urge that they are unable to resist. The powerful urge causes feelings of anxiety, tension, or arousal. Stealing soothes these feelings. However, following this, there are often

feelings of guilt, remorse, and fear. These feelings frequently serve as barriers to treatment seeking. The discussion of kleptomania in the 19th and early 20th centuries became part of the ongoing debate in the medical community about the relationship of insanity to the female reproductive system. Because most shoplifters at the time appeared to be women, this link was made. “Hysteria” was thought to be caused by the uterus, so kleptomania was discussed along with other diseases of the female reproductive organs. By 1920, the labeling of certain shoplifters as kleptomaniacs largely disappeared. It is unclear why this occurred but might have been connected to the fact that no one in the scientific community was able to prove that female reproductive issues caused shoplifting and more men were being arrested for shoplifting. Although the DSM-5 lists kleptomania as an ICD, there is emerging evidence that suggests similarities between kleptomania and substance use disorder and mood disorders. Kleptomania is a psychiatric disorder that is poorly understood and subject of only a few empirical studies (37). While the prevalence of the disorder in the US general population is unknown, it has been estimated at 6 per 1000 people (37). It is classified as an ICD since the behavior cannot be explained by antisocial personality disorder, conduct disorder, or a manic episode, and it involves the inability to control ones impulse to steal. A core feature of ICDs is the repeated expression of impulsive acts that lead to physical or financial damage to the individual or another person. While kleptomania meets criteria for ICD, it shares many characteristics of OCD. Grant and Potenza (8) state that there is emerging evidence derived from studies of clinical characteristics, familial transmission, and treatment response that suggests that kleptomania may have subtypes that are more like OCD, substance use disorder, or mood disorders. A correlational aspect linking kleptomania to OCD is seen in the biological perspective on OCD. Studies of the brain using magnetic resonance imaging showed that subjects with OCD have significantly less white matter than did normal control subjects, suggesting a widely distributed brain abnormality associated with OCD (38). OCD is considered a result of serotonin deficiency. SSRIs have been used to treat both OCD and kleptomania and have been considered a link between the disorders. Prevalence rates between the two disorders do not show a strong relationship. The results of studies that examined the comorbidity of OCD in

subjects with kleptomania have been inconsistent with some showing a relatively high co-occurrence (45%-60%) while others showing low rates (0%-6.5%). When rates of kleptomania have been examined in subjects with OCD, a similarly low co-occurrence was found (2.2%-5.9%) (39). A connection between depression and kleptomania was reported as early as 1911. There is strong anecdotal evidence of such in case reporting. Some people report feelings of relief of depressed mood or manic symptoms after theft. Recent studies have not found that people with kleptomania are more likely than others to have major depression or bipolar disorder. Kleptomania and substance use disorders have central qualities in common. These include recurring or compulsive participation in a behavior in spite of undesirable consequences, weakened control over the disturbing behavior, an overwhelming need or desire experienced before taking part of the problematic behavior, and a positive pleasure-seeking condition throughout the act of the disturbing behavior. The anxiety, tension, or arousal that those with kleptomania experience and the relief that they feel upon stealing, followed by guilt or remorse, are consistent with opponent process descriptions (40) and wantingbut-not-liking states (41) described for substance use disorders. Similar to substance use disorders, a higher percentage of cases of kleptomania have been noted in adolescents and young adults, and a smaller number of cases among older adults. Family history data also show a likely common genetic input to substance use and kleptomania. Substance use disorders are more common in the family members of persons with kleptomania than in the general population. Treatment for kleptomania has many commonalities with treatment for substance use disorders and OCD. Treatment usually consists of a combination of therapies including pharmacotherapy and psychotherapy. While there are no medications specifically approved for the treatment of kleptomania, the similarity and suggested biological dynamics of kleptomania and OCD and ICDs led to the theory that similar groups of medications could be used for all of these conditions. Fluoxetine and other SSRIs have been widely used to treat kleptomania; however, there has not been strong evidence supporting the efficacy of SSRIs in treating the disorder. There has been some promising evidence supporting the use of mood stabilizers, antiseizure medications, and opioid antagonists, particularly naltrexone. Opioid receptor antagonists have been shown to lessen urge-related symptoms, which are a central part of ICDs and substance use disorder (42). In the past, psychoanalytic and dynamic approaches were used to treat kleptomania. Current practice usually includes CBT. CBT can include covert sensitization, exposure and response prevention,

and imaginal desensitization (42).

SHARED FEATURES OF BEHAVIORAL AND SUBSTANCE ADDICTIONS Behavioral disorders resemble substance addictions in a number of domains (43). Individuals with behavioral and substance addictions demonstrate high levels of self-reported impulsivity and sensation seeking (44). They have similar natural histories, with increased prevalence in adolescents and young adults (45), chronic relapsing patterns, and the possibility of spontaneous recovery. Gambling disorder, the most studied of the behavioral addictions, mirrors substance use disorders with higher rates seen in men. A telescoping pattern is seen in women, with later initiation of behavior, but with shortened period from initial behavior to addiction (46,47). Interpersonal conflicts are seen in both behavioral addictions and substance use disorders. The financial problems common to both can lead to illegal acts such as theft or forgery to offset the consequences of the behavior (48). Neurobiological and genetic parallels have also been shown between substance use disorders and ICDs, with implications for the role of the dopamine and serotonin neurotransmitter systems (49,50). In both types of addiction, behavior is often preceded by an urge or craving. Emotional dysregulation may contribute to cravings, and the resultant behavior can often decrease anxiety and lead to a positive mood or “high” (51). Many individuals report a decrease in these positive effects over time or a need to increase the intensity of their behavior in order to achieve the same effect, analogous to tolerance seen with substance use (52,53). In periods of abstinence from these behaviors, a dysphoric state may also be seen, analogous to withdrawal, although with no prominent medical symptoms, which does differ from withdrawal from substances. While these behaviors are initially egosyntonic, they may become more ego-dystonic over time as the act becomes less pleasurable and more motivated by negative reinforcement (41,50).

CO-OCCURRENCE OF SUBSTANCE USE AND BEHAVIORAL ADDICTIONS There are limited data from large national studies as to co-occurrence of substance use disorders and behavioral disorders. ICDs have not been measured

in most large-scale epidemiological surveys (5), in part because validated instruments for the assessment of these disorders are largely lacking. Studies of clinical samples, however, suggest high rates of co-occurrence, most notably between gambling disorder and substance use disorders (54–56). Clinical samples of other behavioral addictions suggest that co-occurrence of a substance use disorder is common, with rates of substance use disorders 22%-50% in kleptomania and ~60% in compulsive sexual behavior (57). In a study of 1600 adolescents, Chuang et al. (58) found that adolescents who endorsed either impulsivity or at least two behavioral addictions alone were more likely to have used tobacco, alcohol, or marijuana. Additionally, among those who had never tried a drug, individuals with this combined set of risk factors were the most likely to be susceptible to future drug use. High comorbidity may suggest that these disorders are part of the same spectrum and should be classified together as substance use disorder. Yet, individuals with behavioral disorders have also been shown to have higher rates of other psychiatric disorders, including mood, anxiety, and personality disorders, which are not part of the addictive process (55). Causal relationships may be behavioral (e.g., substance use disinhibits other inappropriate behaviors) or syndromal (e.g., behavioral addiction begins during abstinence from substance use as a substitute activity) (59). Psychiatric comorbidity alone does not lend support for the classification of these disorders as addictive. This does highlight, however, that individuals with substance use disorders should be assessed for the presence of ICDs.

DIAGNOSTIC CHALLENGES Historically, behavioral addictions have not shared formal diagnostic recognition with substance addictions. In the DSM-IV-TR, the term addiction was not included in the nomenclature (60), a distinction that was carried through into DSM-5 as well. Substance use disorders are classified by specific substance and described by related conditions (i.e., intoxication, withdrawal, etc.). Of the proposed behavioral addictions described above, only gambling disorder is recognized as a formal substance use disorder in the DSM-5. The diagnostic criteria are similar to those for substance use disorders, including preoccupation with the behavior, diminished control, tolerance, withdrawal, and negative consequences. Data about many of the ICDs are lacking, and more evidence is needed to

aid in the classification of these disorders. Empirically validated instruments for assessment of ICDs would allow for identification of behavioral disorders in large-scale epidemiological studies, and longitudinal assessment would be useful in mapping the temporal relationships between ICDs and other psychiatric and substance use disorders (5). Brief screening instruments would be helpful in the identification of ICDs in both clinical and research populations. Changes to the DSM-5 include the development of a category termed “Substance-Related and Addictive Disorders,” which includes a diagnosis of gambling disorder (6). Additionally, Internet use disorder has been suggested as a condition for further study. Support for use of the term “addiction” rather than the current term “dependence” has centered on confusion over different definitions of dependence. Physical dependence can occur following chronic administration of a substance and feature tolerance and withdrawal, without the experience of the negative consequences of addiction. A change in terminology may allow the focus to shift from substance use and its adaptation-associated physical consequences to the harmful effects of addiction on multiple domains of functioning. There are a number of advantages associated with categorizing certain ICDs as substance use disorders. Rates of co-occurrence are high, there are common demographic and epidemiological features, and there are parallels between presenting symptomatology. Substance use treatment programs may be more likely to assess for the presence of ICDs in their patient population than general mental health or primary care settings. By expanding the scope of addiction to include these disorders, it may increase awareness, extend treatment for these conditions in the context of substance use treatment, and increase the availability of funding and research into these disorders (59). Despite the advantages described above, several disadvantages to reclassification exist. The primary rationale for the separate classification has been the lack of substance use with the ICDs, resulting in distinct consequences from use, particularly regarding the lack of significant physical sequelae from ICDs. Additionally, categorizing ICDs as addictive may increase stigmatization. Individuals without co-occurring substance addiction may feel uncomfortable receiving treatment in a substance use treatment setting. Treatment programs that primarily treat substance use may not have a sufficient number of patients with ICDs to offer groups dedicated to their treatment (59).

TREATMENT MODELS

Behavioral and substance addictions can respond positively to the same treatments modalities. While research continues in this area, there are no currently approved medications for the treatment of behavioral addictions. Psychosocial therapies play many roles in the treatment of co-occurring substance and behavioral addictions. They are used to directly target and reduce problem behaviors in both domains directly as well as indirectly through the rationale that reductions in one type of behavior are likely to lead to reduced symptom severity and reductions in other problematic behavior. Behavioral therapies can also be used to enhance treatment engagement and promote treatment adherence and can target other psychosocial problems that may occur. Multiple psychosocial approaches have been employed in this treatment. Many treatments for behavioral addictions were originally developed for the treatment of substance use disorders, and psychosocial treatments for both types of disorders often employ a relapse prevention model, encouraging abstinence through identification of patterns of use, avoidance or coping mechanisms for high-risk situations, and lifestyle changes (61). CBT, motivational approaches, and 12-step approaches are mainstays of substance use treatment that have been successfully used in the treatment of a number of ICDs, including gambling disorder, compulsive sexual behavior, kleptomania, pathological skin picking, and compulsive buying (21,62–64). CBT focuses on learning new skills and strategies to reduce negative thoughts and behaviors, helping individuals to identify patterns associated with ongoing substance use or other behaviors. Motivational approaches are brief interventions designed to produce internally motivated change in problematic behaviors. Contingency management, in which individuals receive incentives or rewards for demonstrating observable target behaviors (such as negative urine toxicology or treatment attendance), has been shown to be effective in reducing substance use (65) and may be similarly effective when used for reducing other problematic behaviors. There is a large body of evidence demonstrating high rates of comorbidity between substance use disorders and other mental health disorders (66–69), which stresses the treatment delivery system. Individuals with co-occurring disorders have also been shown to have poorer treatment outcomes, highlighting the need for effective treatment models to address co-occurring disorders. Several options exist for the delivery of care to the patient with co-occurring substance and behavioral addiction, including deferred treatment, serial treatment, parallel/concurrent treatment, and integrated treatment. Integrated treatment, in which interventions and services are directed at both disorders by

the same treatment team at the same time, is now recommended as the standard of care for substance use and mental health disorders (68) and may also be the preferred model for co-occurring behavioral addiction and substance use disorders. Integrated treatment offers a number of advantages. Individuals receive combined treatment for behavioral and substance addiction from the same treatment team, allowing for a deeper treatment alliance, a unified treatment philosophy, and ongoing communication among providers. It also increases access to treatment by allowing individuals to receive treatment at a single facility. Integration of services is essential for individuals with significant impairment in both domains and for those whose treatment for one type of disorder is negatively impacted by the presence of the other disorder. There are challenges to this approach as well. Individuals may be in different stages of change and different phases of treatment for different disorders, necessitating distinct treatment interventions for each disorder. Given the heterogeneity of behavioral addictions, there are challenges to maintaining adequately trained staff. The increased cost of training staff to provide these interventions may be a barrier to implementation. There are few centers that specialize in the treatment of behavioral addictions, so these interventions are often delivered by programs that primarily treat substance use. It may be difficult to gather a sufficient number of patients with behavior disorders in order to offer groups dedicated to their treatment.

CONCLUSION Evidence suggests parallels between substance and behavioral addictions in many domains, including epidemiology, natural history, symptomatology, and comorbidity. The data lend support but still require more study toward consideration of compulsive buying disorder, excessive tanning, and kleptomania as representative of addiction disorders, and moving their categorization (as was done with gambling disorder in DSM-5) into the DSM’s future version of “substance-related and substance use disorders.” While controversy remains concerning the nomenclature, these shared features have treatment implications, with a number of behavior disorders responding positively to modalities initially employed in the treatment of substance use disorders. Further study is needed to fully understand the etiology of these behavioral disorders, optimize behavioral and pharmacological treatments, and

develop prevention strategies.

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CHAPTER 49

Physician Health Programs Addiction Among Physicians Paul H. Earley

and

CHAPTER OUTLINE Introduction Prevalence Characteristics of Physicians with Addiction Drugs Used Risk Factors Addiction Comorbidity Theories of Addiction Among Physicians Identification, Intervention, and Assessment Treatment Controversies Conclusion

INTRODUCTION The available research about addiction among physicians and physician health programs (PHPs) is extensive and has been well documented in several excellent overviews (1–10). Bissell and Haberman (11), Angres et al. (12), Nace (13), and Coombs (14) have written complete texts about addiction in physicians and other health professionals. Physicians are a convenient population to study; they are accessible both prior to and after treatment and are articulate about their disease. Research on physician addiction elucidates the natural course of addiction in a highly regulated and monitored population. At the same time, physicians differ from the general population in terms of education, income, and regulatory oversight; therefore, conclusions about the efficacy of addiction treatment among physician–patients cannot simply be generalized to the population at large. However, the highly structured and consistent treatment model developed for the care of this population does provide clues for treatment improvement with all populations. Less research is available about other health professionals; however, many of the issues and concepts described here may prove helpful for all healthcare workers as well as safety-sensitive workers in general.

PREVALENCE We have 20 years of debate about the actual and changing prevalence of

addiction among physicians (7). Kessler et al. (15) reported that 3.8% of the general population at any given time has any substance use disorder and 1.3% meets criteria for pre–DSM5-defined alcohol dependence and 0.4% for drug dependence. Lifetime prevalence for alcohol use disorders has been estimated at between 8% and 13% in the general population. Prevalence studies among physicians report widely varying rates dependent upon research methodology (7,16–21). Hughes et al. (20) reported a lifetime prevalence of alcohol abuse or dependence and drug abuse or dependence in physicians at 7.9%, somewhat less than the percentage reported in the general population by Kessler et al. (15). However, methodologic differences may account for the observed differences. The Hughes study surveyed 9600 physicians by mail with a lower response rate (59%) and relied on honest and denial-free reports by the physician self-report; the Kessler general population study utilized face-to-face interviews with trained interviewers. Vaillant et al. (22) reported on the types of substances physicians use in the 1960s. At that time, he noted that physicians were just as likely to smoke cigarettes and drink alcohol as the general population but more likely to take tranquilizers and sedatives. In a more comprehensive study 29 years later, Hughes et al. (18) noted that physicians were less likely to smoke cigarettes than were nonphysicians and more likely to consume benzodiazepines and opioids. This shift is striking; Mangus et al. reported in 1998 that 2% of graduating students smoked (23); a second 2002 study reported that 3.3% of medical students smoked cigarettes (24). In 1992, Hughes et al. (20) reported that physicians are more likely to drink alcohol than the general population; the authors attributed this in part to their higher socioeconomic status. They also noted that 11.4% of physicians had used unsupervised benzodiazepines and 17.6% reported the unsupervised use of opioids. Vaillant (25), in his commentary on the Hughes study, rang an alarm bell by stating “physicians are five times as likely [as the general population] to take sedatives and minor tranquilizers without medical supervision.” The use of opioids and minor tranquilizers commonly begins prior to or in medical school, since medical students are more likely to use these drugs than age-matched cohorts (26). Clark examined substance use in medical students using a 4-year longitudinal study (27). Eighteen percent met the study’s criteria for unhealthy alcohol use in the first 2 years of medical school. They reported that a family history of alcoholism was associated with unhealthy alcohol use in the medical student. Another view of physician unhealthy use of alcohol and drugs can be derived from complaints reviewed by state medical boards. Morrison and

Wickersham (28) noted that 14% of board disciplinary actions were alcohol or drug related and another 11% were due to inappropriate prescribing practices— many of which are also addiction related. In 2003, Clay and Conatser (29) reported similar disciplinary rates, with 21% due to alcohol and drug issues and 10% due to inappropriate prescribing or drug possession. Alcohol- and drug-related work impairment was the primary impetus for the formation of state PHPs in the United States and continues to account for the majority of physician impairment cases seen by most PHPs today (30). David Canavan, MD, started the first PHP (New Jersey) in 1982. Since that time, “all but three of the 54 US medical societies of all states and jurisdictions had authorized or implemented impaired physician programs” (31). The most recent PHP (Georgia) opened its doors in 2012. In 2008, California moved against this trend by dissolving its PHP, joining Delaware, Nebraska, and Wisconsin as one of the few states without a PHP (32). Please see the sidebar—The California Diversion Program: A Cautionary Tale. Ethnic variation in substance use in the general population is described in the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC): Whites, Native Americans, and Hispanics have a higher prevalence of dependence than do Asians, but no published data about physician addiction have been reported using ethnicity as an independent variable. In summary, though the prevalence of addiction to all substances appears to be about the same as in the general population, currently, physicians are less likely to consume tobacco and more likely to use opioids and sedatives. Research data suggest that physicians consume more alcohol than the general population.

CHARACTERISTICS OF PHYSICIANS WITH ADDICTION Age and Gender In a 2008 analysis of more than 1400 medical students, residents, and physicians at the same southeastern treatment program, Earley and Weaver (unpublished) noted an age range from 25.3 to 83.7 years, with a median age of 45.8, the ages distributed in a bell curve (Fig. 49-1). This was a convenience sample of physician–patients who had been mandated to treatment and is not representative

of all physicians.

Figure 49-1 Distribution of physician age at presentation to treatment. Males account for the majority of treated physician addiction cases, with reported ratios approximately 7 to 1 (33). This contrasts with the 3-to-1 male-tofemale ratio in the physician population at large (34). Although fewer females than males have drinking problems, female physicians are more likely to report unhealthy alcohol use by the end of medical school (3). A study from the United Kingdom reported that incoming female students were nearly twice as likely as the age-matched general public to be drinking at a moderate or greater risk level, while males drank at levels similar to nonmedical student controls (35). At intake into one of four PHP programs, female physicians were more likely to be younger and to have medical and psychiatric comorbidity (36). Female physicians were more likely to have past or current suicidal ideation and were more likely to have attempted suicide regardless of whether they were under the influence or not. Wunsch et al. report that female physicians are more likely to use sedative–hypnotics than are men (36).

Specialty Bissell and Jones (37), writing in 1976 about 98 physicians, were among the first to systematically parse this cohort by specialty. Using a follow-up questionnaire of physicians in Alcoholics Anonymous, she noted that psychiatrists and emergency medicine physicians were overrepresented in Alcoholics Anonymous (overrepresentation defined as a percentage of a cohort that is higher than predicted by the percentage of that cohort in the population of physicians at large). Hughes et al. (18) surveyed 5426 physicians regarding substance use; they found the self-report of pre–DSM5-defined substance abuse or dependence was highest in psychiatrists and emergency medicine physicians and lowest in surgeons and pediatricians. This questionnaire did not break down the substance used or its legality. A synopsis of the literature on addiction rates by specialty appears in Table 49-1, which covers multiple authors and modes of analysis. The combined literature looks at the breakdown by specialty from multiple angles (treatment presentation, self-report, and medical board and PHP data); the data consistently purport that psychiatry and emergency medicine physicians have higher rates of unhealthy substance use. Table 49-1 also suggests that family practice physicians might be overrepresented, and pediatricians and pathologists appear to have a lower prevalence of addiction.

TABLE 49-1 Review of Research on Addiction Rates by Specialty

PHP/MB, physician health program or medical board record study.

The problem of addiction in anesthesiologists continues to attract research and debate. Lutsky et al. (17) noted that anesthesiologists were more likely to use cannabis and psychedelics when compared with medicine and surgery physicians but suggested caution in the interpretation of these data owing to age differences between the medicine and surgery cohort and the anesthesiology cohort. Talbott et al. (38) note that anesthesiologists account for 5% of all physicians, yet they account for 13% of all physician–patients in a residential treatment program. Self-report studies by Hughes et al. noted a low overall rate of substance use in anesthesiology, both in residency (19) and after completing training (18). Prior to the widespread use of fentanyl in general medicine, Lutsky et al. (17) found that the use of fentanyl (and its congeners) occurred only in anesthesiologists. Merlo et al. (43) and McAuliffe et al. (44) have recently hypothesized that anesthesiologists may be sensitized to opioids and propofol through the inhalation of picograms of these potent agents in the operating room air. Assays of operating room air detected these agents, especially when taken near the expiration point of the anesthetized patient. This hypothesis rests on an uncertain foundation (the assumption that the quantities of these agents are sufficient to produce sensitization and that the resultant sensitization directly contributes to the etiology of addiction) but does introduce additional avenues of research. Anesthesiologists appear to use highly potent opioids more frequently and are strikingly overrepresented in treatment settings. Access to large quantities of these high-potency opioids (and other drugs) in the day-to-day practice of anesthesia is the most likely culprit for the prevalence of anesthesia personnel in treatment settings. Please refer to the section below on anesthesiologist reentry for additional information.

DRUGS USED Alcohol Two types of studies are used to assess the types of drugs used by physicians: anonymous questionnaires (7,16–18,20) and self-reports of drugs of choice of physicians as they appear in treatment or monitoring programs (38). Both types of research underscore that alcohol is, as expected, the most frequent primary substance used by physicians, just as it is in the general population.

Tobacco Tobacco use disorder has been suggested as a risk factor for alcohol and other drug use disorder in physicians (45) as in the general population (46). Tobacco use in physicians has decreased over time; Vaillant et al. (22) reported that 39% of physicians acknowledged smoking 10 or more cigarettes per day in 1953; this decreased to 25% in 1968 (47). Nelson et al. reported that smoking among physicians declined from 18.8% in 1976 to 3.3% in 1991 (48). In an earlier era, physicians took part in magazine advertising extolling the “soothing” and “cooling” properties of menthol cigarettes on the airway. In a 1996 study, Mangus reported 2% of medical school graduates were current smokers (23). From the earlier data, emergency medicine and surgery physicians are twice as likely to smoke as are other physicians (18). Preliminary data from Stuyt et al. (49) strongly correlate the continued use of tobacco with subsequent relapse into other drug or alcohol use, underscoring the association of tobacco use with addiction in physicians.

Opioids Opioids are the second most frequently used substance by physicians presenting for treatment (50). This finding has been remarkably stable over time, but the type of opioids used continues to change. Hughes et al. (18) differentiate opioid use into the major opioids (morphine, meperidine, fentanyl, and other injectable narcotics) and the minor opioids (hydrocodone, lower-dose forms of oxycodone, codeine, and other oral drugs). Discriminating in this manner, they reported that family practice and obstetrics and gynecology specialists have a higher probability of using minor opioids. When compared with all physicians, the study reports that anesthesiologists were less likely to use minor opioids, with a trend toward an increased use of major opioids. If one assumes that use of major opioids results in a more aggressive manifestation and progression of addiction, this would partly account for the overrepresentation of anesthesiologists over other specialties in physician treatment programs (38). Several authors (18,20,51) posit that exposure to drugs in the workplace leads to higher use of those workplace drugs. In a similar manner, family medicine and obstetrics and gynecology physicians are frequent prescribers and use more minor opioids than other specialties (18).

Cocaine

Older literature noted that specialties that employed cocaine in the course of their work (ophthalmology, head and neck surgery, plastic surgery, and otolaryngology) showed a trend (not statistically significant) to higher cocaine use (18). Cocaine use among physicians has shifted to illicit sources more recently, presumably due to decreased medical use and increased hospital pharmacy controls. Cocaine use is more common in emergency medicine physicians, presumably from street sources. Several authors (51,52) have speculated that the personality style of these specialties attracts them to these drugs, although most studies on the question of an “addictive personality” have not supported this theory.

Amphetamine Physicians use amphetamines from two sources, as in the general population. A subset of physicians who are prescribed amphetamine and other stimulants for attentional disorders go on to develop a substance use disorder as in the general population (53). The pressures of premedical and medical school education and prolonged hours on duty during residency may promote trial use of stimulants. Methamphetamine use is 5 to 10 times higher (54) in urban men who have sex with men. This is mirrored among physicians; most PHPs report that the vast majority of physicians who use methamphetamine are men who have sex with men.

Benzodiazepines One hypothesis of substance use among physicians suggests that the physicians themselves might more commonly use drugs that are used and helpful in a physician’s line of work. Survey-based studies report that psychiatrists have a greater misuse of benzodiazepines; 26.3% report using unsupervised benzodiazepines in the past year, in comparison with 11.4% in other physician groups (18). Although unsupervised use does not impute a substance use disorder, the high rate of benzodiazepine use is reflected in the overrepresentation of psychiatrists in treatment.

Propofol Eighteen percent of anesthesia training programs report cases of propofol use among trainees (55) and its prevalence has increased fivefold in the past decade (55). Wischmeyer et al. identified 25 anesthesia personnel with propofol use; 7

died as a direct result. This study described a positive correlation between hospitals with easy availability and subsequent propofol use. High availability was defined as little or no control over drug access within the training hospital. Although propofol use often shows up in training, use can occur later in medical practice. In contrast, propofol use in nonmedical personnel is extremely rare; only one such case has been reported in medical literature (56). Propofol use has recently gained the national attention after the death of pop star Michael Jackson in 2009. Increasing reports of propofol use (57) and research about its addicting qualities have resulted in the Drug Enforcement Administration (DEA) placing fospropofol (58) under Schedule IV and a proposed Schedule IV for propofol as well (59). Even among healthcare professionals, propofol dependence represents a small portion of the treatment population at 1.6% or 22 of 1375 treated physicians (60). Its incidence appears to be increasing over one 20-year study (60). Other characteristics of this cohort of 22 propofol-dependent physicians noted a tendency toward the female gender, higher incidence of early-life trauma, concomitant mood disorder, and physical trauma resulting from substance use (60).

Cannabis Cannabis is the second most common drug used among medical residents (21), second only to alcohol. A 2000 UK study reported 14% of male and 23% of female incoming medical students reported current use of cannabis (35). Physicians from all specialties use cannabis, with emergency medicine, orthopedics, plastic surgery, anesthesiology, and psychiatry physicians displaying elevated odds of cannabis use over physicians as a whole (18,61). When added to the trend toward legalization of cannabis in many states, a conundrum emerges: Should those in oversight positions send physicians who test positive for cannabis for clinical evaluations (62)? What if the physician has a “medical marijuana” prescription or card? Following the November 2016 elections, 63 million Americans now live in states that have legalized cannabis— even as federal regulations continue to (a) criminalize possession and (b) deny medical utility for cannabis used as medicine (so-called “medical marijuana” products).

Other Drugs

Physicians are also found to use drugs that are not generally available or not recognized as having an addictive potential by the general public. Skipper (63) reported that tramadol was the third most frequent opioid mentioned by physicians “although it was rarely the primary drug of choice” in a study of 595 physicians from two state PHPs over an 8-year period. Moore and Bostwick (64) described two cases of ketamine use in anesthesiologists; some professional treatment programs see several physicians with addiction to ketamine per year.

RISK FACTORS The risk for addiction in physicians is an area rich in speculation and poor in research.

Genetics The strongest predictor of alcohol or drug problems in physicians is the same as in the general population: a family history of alcoholism or pre–DSM5-defined drug dependence (3). Of importance in this regard is the work of Moore (45) who observed several genetic and substance use factors in medical students that later correlated with unhealthy alcohol use including non-Jewish ancestry (relative odds [RO] = 3.1), cigarette use of one pack or more per day (RO = 2.6), and regular use of alcohol (RO = 3.6).

Personality All physician specialties are burdened with common stereotypes, and it has long been tempting to speculate about causal personality factors in the development of addiction disorders among physicians, although decades of addiction research have never found evidence to support an “addictive personality.” Observed physician personality dynamics may be a consequence or an epiphenomenon to the true etiology of the addictive process. With the preceding caveats, it is still interesting to review published speculations about physician personality types and addiction. Although personality issues may or may not be causative in addiction, they often play an important role in the progression, presentation, and treatment of addiction disorders and therefore are covered below. McAuliffe et al. (7) noted “sensation seeking” as a personality factor that is correlated with drug use among physicians in training. These authors speculate that such individuals gravitate to specialties such as emergency medicine.

Emergency medicine physicians may self-select high-risk or illicit drugs owing to the same personality characteristics that draw them to their specialty. Hughes et al. (18) reported emergency medicine physicians were twice as likely to use cannabis as other specialties. Their data also suggested cocaine use was higher in this cohort. However, this hypothesis is not supported by data from other specialties also thought to attract sensation-seeking individuals, such as surgery, which is not overrepresented in treatment settings. Bissell and Jones (37) suggest perfectionist behavior and a high-class ranking are risk factors for addiction. This is supported by the work of Roche et al. (65), who noted that anesthesiologists with addiction are often in the top 10% to 20% of their class. Udel (66) notes that obsessive compulsive personality disorder (or traits) is the most common personality diagnosis of physicians presenting for treatment. No data differentiating the occurrence of compulsive traits in physicians with or without addiction are available. However, compulsive traits are beneficial in all physician training and work. Zeldow and Daugherty (51) and Yufit et al. (52) speculate that the introverted and introspective qualities as well as a drive for an internal locus of control are partially responsible for the drug of choice in this population.

Drug Access O’Connor and Spickard (1) described a subset of physicians who began using benzodiazepines and opioids only after receiving prescribing privileges. Drug access may also account for changing addictive drugs within the opioid class over time. Green et al. (67) in 1976 and Talbott et al. (38) in 1987 reported that the predominant opioid used by physicians at the time was meperidine. A more recent (2005) review of the Michigan and Alabama Physician Health Program reports hydrocodone as the number one opioid used (40% of all opioid cases), meperidine dropping to 10% of cases (63). The most likely hypothesis for shifts in the drug of choice by physicians over time is the changing prescribing patterns and availability of these drugs in the marketplace.

Biologic Effect of the Drug of Choice The neurobiologic effects of drugs used by those with an addiction color the characteristics of the addiction disorder itself. Drug-of-choice characteristics also skew the characteristics of the physician–patients arriving in treatment programs. For example, all opioids produce intense tolerance, resulting in histories of ever-

increasing doses. Drug hunger drives the progressively tolerant physician to divert increasing quantities of opioids from work and, in doing so, increases the probability of detection. This partially explains why treatment-seeking or treatment-mandated physicians tend to present disproportionately with histories of opioid use. High-potency opioids (such as fentanyl) when consumed parenterally produce a rapid downhill course owing to the development of remarkable levels of tolerance. The accelerated course of addiction from the most potent opioids can be postulated as contributing to deaths and the high percentage of anesthesiologists seen in physician treatment programs. Collins (4) has suggested that rapid onset (and the resolution of tolerance with brief periods of abstinence) and/or low therapeutic ratio may account for the high mortality rate in propofol-, fentanyl-, sufentanil-, alfentanil-, and remifentanil-using anesthesiologists. Increased awareness along with checks and balances to account for the remaindered volumes of fentanyl used in hospitals may detect diversion more rapidly and save lives of anesthesia personnel (68–70).

ADDICTION COMORBIDITY Thought and Mood Disorders Physicians suffer from a spectrum of emotional and psychiatric problems similar to the general population. Although it is unclear whether physicians have higher or lower rates of unipolar depression, physicians who successfully complete suicide are more likely to have a drug use problem in their lives, self-prescribed psychoactive substances, a recent alcohol-related problem, a history of emotional problems prior to 18 years of age, and/or a family history of unhealthy alcohol use and/or mental illness (71). Substance dependence, self-criticism, and dependent personality characteristics are associated with depression in physicians (72). Bipolar disorder (types I and II) may contribute to the intensity of addictive disease in physicians, particularly for drinking during manic intervals (73). Bipolar disorder is more often seen, probably because it is more compatible with work—as long as the mania is constrained to the hypomanic range. However, physicians with addiction rarely have comorbid primary schizophrenia and related thought disorders.

Pain

PHPs are working with an increasing number of physicians with chronic pain and analgesic opioid use, many of whom have become physiologically dependent. In turn, an unknown percentage of those go on to develop the disease of addiction. Eventual addiction is thought to be more common in patients with pain disorders (74), and, when combined with the 25% of physicians who selfprescribe (16), a perfect storm of high-risk factors emerges. Physicians who have significant pain and addiction disorders pose diagnostic, treatment, and management difficulties for assessors, treatment providers, and the PHPs. Regulatory issues cloud the treatment of addicted physicians with pain: Should a formerly addicted physician on opioid medications be allowed to practice? Is it logical for state boards to prohibit ongoing methadone or buprenorphine treatment but permit potent opioids for pain management? These complex questions often result in ideological or political conclusions rather than evidence-based answers. Scientific data on the safety of physicians practicing while taking opioids, whether addicted or not, are sorely lacking. Insufficient data are available for a definitive decision, but appropriate concern remains (75,76).

Posttraumatic Stress Disorder Posttraumatic stress disorder (PTSD) and alcohol use disorder are closely intertwined (77), and PTSD increases the probability of addiction relapse in stressful contexts (78). However, no studies about the prevalence of PTSD in physicians have been published. Physicians, like anyone else, are not immune from prior trauma histories. Several physician specialties, including emergency medicine physicians, trauma surgeons, and military psychiatrists, can be traumatized by events at work. Although combat exposure is known to increase the statistical risks of addiction in veterans, no data exist to indicate whether such trauma increases the likelihood of substance use disorders in military physicians. And, treating trauma can be, in itself, traumatizing to the caregiver.

THEORIES OF ADDICTION AMONG PHYSICIANS The natural history of addiction is, on the surface, similar in physicians to that of any other person with drug or alcohol use disorder. McAuliffe et al. (79) report that 27% of medical students and 22% of physicians had family histories of

alcohol dependence. Lutsky et al. (17) and Domino et al. (80) put this figure at almost 75%. Moreover, the genetic research literature now supports inherited genetic vulnerabilities for all major classes of addictive drugs. Clark et al. (27) reported that excessive alcohol consumption in medical students was positively associated with better grades in the first year and a strong tendency toward better scores on Part I of the National Board of Medical Examiners test. Unhealthy alcohol use was found to have no discernible impact on clinical rotations in years 3 and 4 of medical school in this study. This led Clark to speculate that hard-drinking students may be prone to discount warnings and feel invulnerable to the effects of alcohol; their own internal experience does not match cautionary information provided to them during their medical education. This may exacerbate an emerging “us” (doctors) and “them” (patients) view of the world. These findings mirror extensive research by Schuckit, who consistently demonstrated that less intense, early-life, and adolescent reactivity to alcohol increases the risk for the later development of alcoholism (81,82). Stress and burnout are often cited by the physician–patient as the primary agent that drives self-medication. Burnout is on the rise (83), but its exact correlation with substance use and addiction is unclear. However, when combined with difficulties asking for help (11), it leads to self-prescription, a slippery slope at best (84). Physicians in treatment for substance use disorders report that the stress of medical training, when combined with social isolation, provides a fertile soil for the growth of drug consumption (4). Jex et al. (85) suggest that the physician’s unhealthy response to stress is a more important determinant of addiction than the ubiquitous presence of stress itself. No evidence supports a specific professional personality type as being a determinant in addiction (86,87); however, personality dynamics specific to physicians naturally must play a role during the illness and its treatment (88,89). Vaillant et al. (90) have suggested that physicians commonly experience an emotionally barren childhood. Johnson and Connelly (91), who identified 72% of a 50-physician sample hospitalized for addiction as experiencing parental deprivation in their childhood, echo this postulate. Khantzian (92) eloquently depicts the physician’s efforts at caring for others as a partially successful sublimation; caregiving of others becomes a partial repair of deficits in parental nurturance. Tillett (89) described this dynamic in helping professionals as a drive to “compulsively give to others what he (she) would like to have for himself (herself).” When this transformation fails, the addiction-prone physician, lacking other methods of self-care, has a propensity to turn to substance use.

Physicians in the act of saving human lives develop a varying degree of omnipotence (13). This omnipotence, when combined with knowledge of the drugs they prescribe, may produce feelings of invulnerability regarding drug or alcohol use. Vaillant (25) has speculated that self-prescribing (related to physician self-sufficiency and false omnipotence) plays a permissive role in the development of addiction in physicians. Physicians’ illusion of mastery over pharmaceuticals keeps them from distinguishing their lack of control over substance use, opening the door to experimentation and, if continued, a progressive deterioration in their drug use. Genetic vulnerability and the priming effects of the drug itself remain the most evidence-based etiologies of addiction. Childhood experiences, medical school training about pharmaceuticals, and the life-and-death nature of a physician’s work certainly modify the quality and progression of a nascent addiction problem. Physicians are taught in medical school and residency (and often in their childhood) to appear self-sufficient and in control. This façade of competence establishes the framework for a secretive and duplicitous personality, and once the physician is using substances, his or her secret garden provides a fertile soil for additional substance use. Concealment and lying are not qualities that support a mature approach to marriage, life, and work. The illicit and secretive qualities of addiction promulgate additional personality regression. The physician’s behavior deteriorates first at home, then with friends, and finally surfaces at the workplace. By the time a physician exhibits problems at work, significant familial discord (marital strife, divorce, difficulties with acting out in children) commonly exists. Rarely does the family “turn in” a spouse or other family member with presumptive addiction (93). Often, a colleague or other hospital staff is the first to voice concern. The physician is then confronted at work when an undeniable incident occurs or a series of smaller incidents push colleagues and the hospital medical staff to confront the doctor. An active PHP, especially one that is supportive and confidential, can be very beneficial in reducing the threshold for reporting to punitive agencies and, thus, can promote early detection. Most physicians arrive in treatment with thin scraps of their façade remaining. They exhibit a demeanor of superiority and knowledge, deny any loss of control, and have a need to appear competent, in stark contrast to their crumbling lives.

IDENTIFICATION,

INTERVENTION,

AND ASSESSMENT Identification Physicians present with a broad spectrum of symptom severity, from a physician self-identifying a drinking problem while in couples’ therapy all the way to a physician who is found apneic and asystolic on the floor of the operating room bathroom. In the past, denial, shame, and fear of reprisal tended to keep the physician from seeking proper help until significant external consequences coalesced (2). In more recent years, the emergence of clinically oriented, supportive, and confidential PHPs has stimulated earlier reporting, by either selfor colleague referral. Physician–patients with substance problems have often had years of familial and social discord while struggling to maintain acceptable work performance, until this last refuge, too, collapses. Thus, disturbances of social or familial functioning may be more sensitive indicators of early substance use disorder in the physician. Unfortunately, the family often protects the physician with a substance use disorder who serves as the “breadwinner.” A variety of work-related behaviors can be clues to substance use. O’Connor and Spickard (1) describe conditions and warning signs that can help detect addiction (Table 49-2). Talbott and Wright (93) and Talbott and Benson (94) have independently reported a similar list of behavioral signs of addiction in the physician.

TABLE 49-2 Warning Signs of Unhealthy Substance Use in Physicians

Adapted from O’Connor PG, Spickard A. Physician impairment by substance abuse. Med Clin North Am. 1997;81(4):1037-1052.

If problems are not addressed early, the doctor’s work quality and attendance often suffer. In contrast, if a physician obtains drugs at work (eg, samples from a drug closet or drugs diverted from the OR or ICU), he or she displays the opposite behavior—volunteering for additional shifts, arriving early for work, and signing up for more complex (ie, easier drug access) cases.

Modes of Intervention Several comprehensive guides to physician intervention have been published (2,5,10,95,96). In recent years, PHPs have become very skilled at directing the physician–patient into treatment without overly aggressive confrontation and ultimatums. PHPs commonly conduct a comprehensive evaluation or send a physician for evaluation by a third party. The physician in question is told about existing concerns (often without divulging the source of information) and the importance of resolving said concerns. Ultimately, the goal of intervention is early detection of whatever problem is causing concerns. Most physicians appreciate their duty to public safety. Once a well-being committee at a hospital or the PHP points out the need to determine if a health problem is present, this sense of duty, combined with some level of self-concern, can motivate a physician to obtain a proper evaluation. A minority of physicians, especially those who have in the past felt assaulted by a legal process or have

undergone previous interventions, require additional orchestration with partners or employers who then help the physician get to the evaluation and/or treatment process. Regardless of the path to the door, physicians commonly arrive with a thinly fabricated story depicting their entry into evaluation or treatment as selfmotivated. Most states have reporting laws that require hospitals and colleagues to report a physician to the state PHP or their state medical board who is suspected of being impaired by alcohol or drugs. Treating physicians must have knowledge of the laws in their state before beginning treatment of physicians with addiction issues. In 2001, The Joint Commission pressured hospital organizations to address the wellness of their medical staff through standard MS2.6 (97). The Joint Commission standard has helped formalize a physician health process in most hospitals and formalize the support and intervention network in hospitals. Many PHPs are able to assist the hospitals in meeting this standard. Hospital wellness committees can be effective in early identification and referral of physicians if the process maintains a balance of compassion with a firm directive hand. In contrast, the primary agenda of hospital credentialing and executive committees is maintaining quality of care and risk management strategy. When concerns are raised, including concerns about potential impairment, they utilize letters of concern, sanctions, and decredentialing to protect the hospital and the public. Wellness committees, on the other hand, focus on the health of providers within the organization. If a wellness committee attempts to get a provider help, such help would be scuttled (and appear quite disingenuous) should it become known to the organization credentialing body with the potential for resultant action. Therefore, a firewall should be maintained between the wellness and credentialing/executive committees. If a substance use disorder is not caught in its early stages, the possibility of impairment arises. Thus, the primary public health goal of PHPs is to diagnose and treat physicians early in the course of their illness. Impaired supervisory physicians are no longer protected and enabled by their juniors. In a study of impairment of all types (not focused solely on substance-induced impairment), Igartua (98) reported that 7% of residents in her survey reported working with an impaired physician supervisor. Reuben and Noble (99) reported that 72% of house officers would report an impaired attending physician.

Assessment

Responses to an evaluation request vary widely. Some physicians are quickly identified and agree to cooperate with their treatment needs or at least with an outpatient evaluation. Physicians who are more entrenched in their addiction, who have more complex presentations, or who are frankly resistant need formal and more extensive assessment and a methodical, nonshaming confrontation of their denial complex. In all cases, use of the ASAM Criteria can be helpful toward determination of level of care decisions. Timely and proper diagnosis is best made by an interdisciplinary evaluation using the guidelines established by the Federation of State PHPs (100). Assessment can be completed at the least intensive level of care that results in a comprehensive view of the patient and his or her family and social system. The examination process must prevent the assessed physician from hiding continued drug use and withdrawal as well as addiction-related interpersonal behaviors. Because of the complexity and comprehensive nature of these evaluations, in some—but not all—cases, it may be helpful to conduct them in a higher level of care (such as a residential or partial hospitalization setting) where the evaluation staff are in continuous conversation about a case, able to adjust the process rapidly and obtain the broadest understanding of the individual. When the physician is removed from his or her work role, the evaluation team is able to observe the physician when they are outside of the provider role; this affords a broader understanding of the individual when the protective physician cloak is removed (101). Allowing physicians to self-select an evaluator commonly results in their choosing a friend or colleague or someone who lacks the necessary expertise in the nuances of a physician addiction evaluation. This results in an inadequate or limited evaluation and thus a missed chance at early diagnosis. Therefore, most PHPs have established criteria and maintain a list of competent evaluators. PHPs often direct physicians to an outpatient, an intensive outpatient, or a residential evaluation based upon the complexity of the case at hand. The evaluation should include information from, but should not be carried out by, a current or past therapist, psychiatrist, or other caregiver. Many PHPs direct the evaluation to a multidisciplinary team composed of an addiction medicine physician and/or an addiction psychiatrist and include psychological and neuropsychological testing, family assessment, review of previous medical records, and the collection of collateral information from coworkers, hospital employees, friends, and PHPs themselves. A broad array of information from all available resources is critical to an accurate assessment. Table 49-3 outlines the purpose of each component of a comprehensive physician addiction evaluation.

TABLE 49-3 Components of a Suggested Comprehensive Physician Addiction Assessment

a

All components of the evaluation contribute to determination of whether an addiction disorder exists, the level of care needed, and treatment planning for ongoing care, if indicated.

The team involved in a multidisciplinary evaluation meets repeatedly during the evaluation and, once again when all data have been collected. Final diagnoses and recommendations are best produced by discussion among members of the evaluation team. The patient then meets with one or all members of the evaluation team to review the diagnosis and recommendations. The patient may elect to involve a family member. The evaluation team is best served by including the PHP or other referral source in the summation session; this action decreases confusion and splitting regarding the outcome. A comprehensive, integrated report is commonly sent to both the physician–patient and other relevant parties (with appropriate Release of Information authorizations).

TREATMENT Approximately a dozen programs in the United States have experience and

specialized expertise in the treatment of physicians and other health professionals with substance use disorders; some programs have more than 30 years of experience and have treated thousands of addicted physicians. However, some states are trending toward increased law enforcement actions against addicted physicians, as opposed to treatment. California, for example, decided to “sunset” the Physician Diversion Program in 2009, and it is far from clear what kind of structures will replace it. Strong political voices are recently heard to say that addicted physicians deserve no “strikes” and that they are, in essence, disposable in a competitive medical economy.

Clinical Considerations in Treating Addicted Physician–Patients It has been alleged that physicians “make the worst patients” (102). Physicians often deny symptoms of any disease, seek substandard care, and put off appropriate care for serious symptoms (103). As in any other medical situation, the physician–patient who enters addiction treatment has difficulty giving up the provider role and assuming the obligations of a patient (101,104). In treatment settings with an admixture of physician–patients and nonphysician–patients, the treatment program must set firm limits, prohibiting the physician from providing medical advice or care to other patients. If a patient is the only physician in a given treatment setting, that patient will likely remain or lapse into his or her physician’s role the first moment another patient asks for medical advice or for stories from his or her career. This shifts focus off of the physician–patient decreasing the efficacy of his or her treatment. By contrast, when a physician falls into self-diagnosis, it is best to use this as grist for the therapeutic mill. Physicians will also attempt to fit the treatment into what they know: schooling and testing. Thus, they have little trouble learning the didactic parts of treatment. Physicians early in treatment may arrive at a group therapy session with pen and paper in hand, hoping to glean one piece of information that will rocket them into recovery or, at the very least, accelerate their discharge. At the very least, they can parrot the prevailing recovery orthodoxies to the staff. The transformation required of all patients in addiction treatment is an emotional, interpersonal, and, for many, a spiritual shift. Physicians have little experience in this area. They often become stuck trying to obtain an “A” in treatment and, in this way, miss the necessary wholesale changes that are needed to recover in earnest. When staff attempt to correct the physician’s approach to treatment, they risk becoming ensnared in the physician’s tendency toward excess perfectionism.

The resultant hostile projection produces negative transference and a thinly veiled contempt for “less educated” therapists and staff (104). Physicians work and interact in an environment filled with physical and emotional pain. To succeed, they must at times distance themselves from the strife around them. When combined with an achievement-oriented childhood, the physician–patient defaults to intellectualization of his emotional experience or, on occasion, frank alexithymia (without words for feelings) (105,106). Treatment will necessarily reacquaint the physician with the subtle nuances of feeling states, often confused or conflated with craving or “stress.” One particularly difficult emotional state is shame. Most addiction patients view their substance use and their lives through a lens of shame—and physicians seem to have a surfeit of shame. Fayne and Silvan (104) note that a key task in recovery is an honest appraisal of how the physician’s addiction has interfered with his ability to function as a physician. This requires a vigilant therapeutic group that models self-disclosure and self-examination. The physician, owing to childhood and training-induced drives for accomplishment and perfection, risks turning the task of self-examination into self-loathing. Treatment of such individuals mandates that the treatment staff and community encourage fearless self-examination without inadvertently pulling the hair trigger of the physician’s self-loathing. When in the state of shame, an additional defense of the physician–patient is to psychologically freeze. The precarious management of shame is further complicated by the patient’s transference and the therapist’s countertransference that arises when a bright physician–patient seems incapable (or willfully resistant) to the self-examination necessary for recovery. Working with addicted physicians requires understanding of the dynamics of addiction and the distinct but highly interactive elements between addiction and the personality. Inexperienced or overly biased treatment providers tend to label the psychological effects of addiction as personality issues, or, conversely, they view long-standing personality dynamics in the physician–patient as addictive thoughts and actions. A balanced understanding and therapeutic approach require a healthy respect for both schools of thought. Addiction uses the specific personality dynamics of the physician–patient to serve its own ends, exaggerating and driving maladaptive forces to ensure its own survival. Conversely, the addictive process generates complicated internal and interpersonal pathology. It is tempting to establish a cause-and-effect relationship between nonaddiction psychiatric disorders and the disease of addiction itself. Such a

path often colludes with the patient’s denial system. A more powerful viewpoint is to envision a patient’s addiction and other mood and personality issues as distinct disorders that are independent but deeply collaborative and mutually reinforcing. Social and legal issues only further confound the type and course of treatment. Because of all the aforementioned issues, treatment is by its nature different in physicians. Medical boards, the general public, PHPs, and the physician him- or herself have low tolerance for the potential public harm that can occur when a physician becomes addicted; they are exquisitely intolerant of multiple relapses. This flies in the face of the nature of addiction: a disease characterized by remission and relapse. The societal pressure to “have a perfect recovery” creates a maladaptive alliance with the physician–patient’s own perfectionism (107).

Characteristics of the Treatment Setting The treatment of physicians involves a prolonged continuum of care. When a physician leaves his or her initial treatment setting and returns to work, this is described by the unfortunate and inaccurate vernacular of having “completed treatment.” In fact, what physicians are asked to do in the second phase of treatment is in many ways more comprehensive care than what many patients receive during their primary treatment (108). This “posttreatment” monitoring commonly involves weekly group therapy sessions, peer support groups, aftercare groups, individual and family therapy, self-help group attendance, drug testing, and worksite monitor reports for 5 years or more. The confluence of known difficulties engaging physicians in treatment, the public demand for safety, and liability issues involved in allowing a physician to work while in outpatient addiction treatment have promoted physician-specific, long-term residential addiction treatment programs (101). A paucity of literature exists about the efficacy of less intensive treatment, but fair results have been reported by Dilts et al. (109) and Reading (110). Smith and Smith (111) reported a small cohort of physicians treated in low- and high-intensity care, with substantively better results when longer-term residential care was employed. DuPont et al. (30), reviewing 16 state PHPs over 5 years, noted that 78% of physicians who required treatment went to residential treatment for 30 to 90 days, followed by less intensive outpatient treatment. The remaining 22% of treated physicians went directly to outpatient treatment. Hospitals, malpractice carriers, regulatory boards, health insurance companies, and family and friends

have expectations of continuous abstinence. Most medical boards and, increasingly, malpractice insurance companies (who in many states have become a more powerful threat) penalize a physician if he or she relapses, even a single time. Owing to the research (albeit limited) on the effectiveness of residential treatment and the penalty placed upon relapsing physicians, most physician– patients are encouraged to attend longer treatment programs than are nonphysician peers (112). Skipper (112) outlined the treatment of the impaired health professional. He reported that all physician-specialized treatment programs use a 12-step philosophy as the core component of treatment. Such programs have proven effectiveness with physicians (30,108,113,114). Studies show that if abstinence is the desired outcome point, consistent involvement with 12-step meetings produces the best results (115–117). All physician treatment programs reviewed by DuPont et al. (30) utilize family therapy, and most offer a brief psychoeducational family program sometime in the physician’s treatment (1). Family participation also leads to a better outcome (118). Family members move through their own difficulties accepting the addiction diagnosis, anger at the physician–patient, and fear of loss of prestige and financial security. The initial goal of family treatment is to redirect the hostility away from the patient (as well as the treatment providers and PHP) toward the addictive illness itself, using this energy to build healthy and constructive family dynamics, focused on relapse prevention. Physician-specific groups allow self-disclosure and sharing of alcohol- and drug-related behaviors that risked or, in rare cases, caused patient harm. Such violations of the Hippocratic Oath generate shame. Once articulated, such lapses in physician responsibility are best linked to the addictive disease and away from the core self. Disclosures of the deepest violations of core values in professionspecific groups can, if properly managed, provide relief and help the physician differentiate his or her actions while addicted from their self-concept. Physicianspecific groups serve a different, more pragmatic, but equally important, purpose. Most physicians have work-related triggers (eg, drug access at work, prescription pads, and locations in the office or hospital where use occurred). In these groups, participants explore work triggers and develop medically specific relapse prevention plans. On this practical level, physician-specific groups also address the myriad of other issues physicians face when returning to practice, such as the difficulties of seeing their patients in AA, how to respond to questions from peers and other staff about their illness, Drug Enforcement Administration prescribing restrictions, and continued management of drugs and

prescriptions in the office or hospital. These needs require healthcare practitioner–specific therapy, preferably in a group setting to increase acceptance, decrease the unique aspects of shame, and teach skills of healthy interdependence (101). Addiction medicine utilizes several pharmacologic agents in the treatment of addiction. Most programs that treat physicians with alcohol use disorder utilize one or more medications including disulfiram, oral or injectable naltrexone, acamprosate, and/or topiramate. Medications are also useful in the treatment of physicians with opioid use disorder. The opioid antagonist naltrexone is prescribed for physicians who, upon return to practice, have continued easy access to opioids. It could be argued that monthly injectable naltrexone is especially desirable because the monitoring program is assured that the medication is continuously “on board” (88,119). Alternatives such as monitoring urine for the presence of naltrexone or observed administration of oral doses of naltrexone may also be used; however, observation quickly lapses replacing safeguard with false security. Physician treatment programs and PHPs are currently conflicted about the use of buprenorphine or methadone in physicians with opioid use disorder. This is covered in the section Controversies. Ultimately, long-term randomized monitoring of physicians may be the most essential component of treatment and critical for sustained recovery. Monitoring and support groups are commonly provided by PHPs or occasionally by the treatment center itself, as discussed below.

Physician Health Programs History The importance of PHPs in supporting and promoting early detection and proper evaluation and treatment of physicians cannot be overstated. The heart of the physician’s health movement can be traced back to the founding of the International Doctors in Alcoholics Anonymous (IDAA) by Clarence Pearson, in 1949 (120). IDAA has grown from 24 physicians, meeting in Pearson’s garage in Cape Vincent, New York, to an international organization attracting thousands of physicians and other doctorate-level individuals in recovery from addiction. On the regulatory side, the Federation of State Medical Boards called for a model probation and rehabilitation process for addicted physicians in 1958. However, no meaningful change occurred until 1973 with the publication of the watershed JAMA article: “The sick physician. Impairment by psychiatric disorders,

including alcoholism and drug dependence” (121). The American Medical Association (AMA) held its first conference on physician impairment in 1975. State medical societies organized committees on physician impairment. The American and Canadian Medical Associations have jointly sponsored conferences on physician impairment every other year since 1975. Concern from medical organizations, governing bodies, and hospital regulatory boards resulted in the state-by-state emergence of PHPs over a period of 25 years. By 2007, almost every state in the United States has some type of PHP, ranging from one employee with a $20000 budget to a 1.5 million dollar budget and 19 full-time employees (9,30). By 2007, PHP programs monitored more than 9000 physicians across the United States (30).

Structure PHPs have widely different organizational structures and lines of authority. More than half (54%) of PHPs are nonprofit foundations. Others are part of their respective state medical association (35%) or the licensing board itself (13%) (30). All PHPs have written agreements that guide their interaction with their state licensing boards. Most (59%) of PHPs evaluated in the DuPont et al. study from 2009 (30) have specific laws that sanction their actions and guide their operation. PHPs have evolved from two distinct sources. Some PHPs have descended from committees of a medical board itself and have evolved, with varying degrees of autonomy from a licensing body. Other PHPs emerged from a state medical society or other concerned physician groups. The independent evolution of state PHPs coalesced into a federation in 1990. Many state medical boards continue to actively monitor some physicians while referring others to the state PHP. Interestingly enough, one comparison study of a state (Oregon) with both programs noted that “voluntary diversion program for appropriately selected physicians may enhance earlier referral and intervention” (122,123).

PHP Activities Education and Referral Most PHPs provide education about all types of physician illness (including substance use disorders) and train local hospitals and physician organizations on techniques to help identify and report suspected impairment. Even more importantly, these educational programs offered by PHPs afford the PHP staff the chance to personally meet and network with medical leadership throughout

their state. This public relations and training effort carried out by PHPs is important; it helps individuals understand and trust the supportive goal of the PHP, which in turn promotes early referral. Healthcare organizations have shown increased interest in these issues, thanks to the recent Joint Commission standard (currently MS 4.80), which mandates that “the medical staff implements a process to identify and manage matters of individual health for licensed independent practitioners. This identification process is separate from actions taken for disciplinary purposes” (97). Addiction (both from substance use and gambling) continues to be the most commonly identified problem addressed by many (but not all) PHPs (30), but most PHPs address other psychiatric disorders, disruptive and distressed physicians, and physicians who suffer from other compulsive disorders such as problematic sexual behaviors. All PHPs offer consultation about substance use cases, coordinate intake into treatment, and monitor physicians after treatment through statewide systems. Some PHPs offer initial assessment, triage, and ongoing therapy groups for the physicians in their state. PHPs have become more professional, with credibility provided by their expertise, affiliation with the Federation of State Physician Health Programs, and other medical organizations, such as the AMA and the Federation of State Medical Boards. As professionalism has increased, so has their finesse and ability to carry out educational programs, expanding to a broader range of topics (stress, burnout, compassion fatigue, sexual misconduct, appropriate prescribing, etc.). The core concept of PHPs has become clear, to detect problems that lead to impairment and to intervene and encourage physicians to obtain assistance prior to damaging their careers or harming patients. Sophistication in dealing with addicted physicians has increased, in partnership with expert evaluators and treatment providers. Follow-up monitoring has become much more sophisticated with additional monitoring tools (hair testing, flexible variations in drug testing, new tests for alcohol, devices that detect alcohol consumption, and so on). New software options are facilitating the aggregation and analysis of physician monitoring records, obtaining reports through online reporting and real-time oversight. Participant satisfaction with the PHP process, irrespective of whether they entered voluntarily or through mandate, is quite satisfactory (124).

Abstinence Monitoring All PHPs track the abstinence status of physicians who enter their program with substance use disorders; some monitor other addiction disorders. All programs use random witnessed body fluid analysis (most frequently through urine drug

screens but often including hair, nail, and blood analysis) through an organized monitoring program. Screens commonly taper in frequency over the course of monitoring, for a period of 5 or more years (50). Participation in PHP monitoring is contingent upon the physician “calling in” or checking a confidential website each day to see whether he or she has been selected for screening. Urine screening in physician populations requires considerable expertise and accuracy, since physicians with addiction can use their knowledge to evade detection (125). Most physician drug panels test for 20 to 25 drugs, including a wide variety of opioids. Specialty screens for fentanyl, alfentanil, and sufentanil are necessary in physicians who have used these drugs in the past and/or who have future access to such compounds. Hair testing can be important in this regard because fentanyl and its congeners have very brief half-lives but are readily detected in hair for weeks or months. Physicians also occasionally use more unusual drugs (ketamine, propofol, tramadol, and dextromethorphan); these physicians need assessment panels specifically designed to prevent a lapse in their abstinence to such substances. The screening is also broad as to the drug types. This breadth prevents switching from one substance to another, as commonly occurs during the natural course of the addiction disease. More recently, PHPs began more sensitive testing for alcohol use by assaying for ethyl glucuronide (EtG) (126,127) and ethyl sulfate (EtS) (128), liver and lung tissue metabolites of ethyl alcohol. Newer testing for blood phosphatidylethanol (PEth) has provided a longer detection window for ethanol consumption. False-positive test results for EtG, EtS, and PEth have been reported, owing to a combination of environmental exposure and the sensitivity of the tests (EtG, EtS, PEth) and the low-level production of EtG by urine bacteria (EtG) (129). The two most common culprits in false positives are incidental ingestion of ethanol-containing substances (eg, mouthwash) and topical application of ethanol-based hand sanitizers (especially if inhaled). Physicians under monitoring are counseled to avoid these compounds. Using an alternative to ethyl alcohol–based hand sanitizer, such as isopropyl alcohol– based sanitizers, should be considered. The length of time a physician should remain in monitoring is unclear. The best outcome data follow physicians for 5 years or more (50,80,113,114). Looking at relapses, Domino et al. reported 58% occurred in the first 2 years and 28% in years 3 to 5 and 14% relapsed after year 5. This suggests a cutoff of 5 years or more may be prudent. Using a 60-year prospective study of men with an alcohol use disorder (not physicians, per se), Vaillant suggested “…analogous to cancer patients, a follow-up of 5 years rather than of 1 or 2 years would appear

necessary to determine stable recovery” (130). Lastly, a 1995 policy of the Federation of State Medical Boards stated physicians involved in PHP should be supervised for a minimum of 5 years; this policy was reiterated in 2011 (131). Thus, limited data, when combined with a near mandate of regulatory agencies, have set a time frame of 5 years for PHP monitoring. Additional research would assist in developing more granularity in monitoring and help determine which individuals with which conditions and co-occurring disorders need what intensity of monitoring for what length of time. Some PHPs place selected participants on career-long monitoring, especially if their substance use has led to workplace involvement or has caused significant life consequences.

Recovery Support In addition to urine monitoring, most state PHPs provide some type of group experiences and behavioral monitoring (eg, attendance records at support groups and therapy). The most common of these are caduceus groups, a vague moniker that varies from peer-led groups like 12-step meetings to large therapist-led groups whose focus varies from discussing a member’s pragmatic concern to emotional process work in a large group setting. Unlike in Alcoholics Anonymous meetings, direct feedback and discussion is encouraged in most caduceus groups. Newcomers may obtain recovery sponsors or guidance from physicians that are more senior in the network of PHP support groups. All long-term studies of physicians underscore the importance of 12-step meetings (primarily AA and NA) as a central part of recovery (50,132,133). In a study of 100 physicians with an average of 33.4 months after treatment admission, Galanter et al. (133) noted, “A.A. was apparently perceived by respondents as the most potent element of their recovery.” Outcome studies in physicians show impressive abstinence rates, with one study, based upon selfreport, extending to 21 years (117).

Relapse Significant consequences to the physician and the public can result from relapse. PHPs have developed models of assessing relapse severity. DuPont et al. (30) describe a three-category system derived from the earlier work of one of the authors (Skipper): Level I relapse consisted of missing therapy meetings, support groups, dishonesty, or other behavioral infractions.

Level II relapse involved the reuse of substances but outside the context of medical practice. Level III relapse includes substance use within the context of practice. This relapse system highlights the most frequent downhill slide for professionals in a monitoring system: problems with recovery maintenance precede substance use. This helps a PHP stage its interventions prior to substance use. The downside of this classification system is that a level I “relapse” obfuscates a commonly accepted term (relapse) and might be better described as a compliance failure. Thus, this particular relapse classification should be seen as unique to monitoring programs. Hankes (reported in Domino et al. (80)) has developed a more extensive relapse management decision tree for the Washington State PHP that classifies relapse and provides decision support for managing seven distinct categories of relapse. It is common for physicians in the first year after treatment to have a brief relapse or slip. If the slip is short-lived, the physician is often best placed in short-term relapse prevention programming. Here, the antecedents of substance use are explored and relapse prevention skills are strengthened. It is not uncommon for deeper or earlier life issues to emerge during this time as well. Slips (and the resultant treatment), if managed quickly with appropriate psychotherapy, can deepen the physicians’ acceptance of their disease and solidify subsequent recovery. If managed properly, singular slips are most often helpful in the long run and are not indicators of failed treatment (134). Should a physician have a more extended relapse, he or she should have a more comprehensive disease management response including one or more of the following: Evaluation of the physician’s safety to practice until he or she is more stable in recovery Longer and tighter monitoring contract that includes behavioral monitoring, support group attendance, and more extensive toxicology testing Reexamination of the patient’s psychiatric status, to determine whether an as yet undiagnosed co-occurring psychiatric disorder, other addictive process, or past unaddressed trauma is present Reassessment of the patient’s family dynamics and support system Determination of the need to return to a higher level of care (ASAM Level 2.1, 2.5, 3.1, or 3.5) Reevaluation of the need for relapse prevention medications

Relapse is part of the disease of addiction. Because of real (and at times imagined) concerns about patient safety, physicians who have difficulty maintaining abstinence should be removed from the workforce until evaluators skilled in physician addiction determine that the physician is safe to return. The point in time when a physician is safe to practice is best established by a joint decision of the physician’s treatment provider and the monitoring PHP. All stakeholders must be prudent and err on the side of caution when considering readiness to return to work in safety-sensitive occupations. Like it or not, the stability of an entire state PHP can rest on the outcome of a few highly visible cases.

Return to Work Most PHPs insist on an initial removal from the workplace during the first phases of treatment and after any sustained relapse. The point in time when a physician is safe to practice is best established by a joint decision of the physician’s treatment provider and the monitoring PHP. All stakeholders must be prudent about when to return physicians to their safety-sensitive occupations. Parameters to consider when returning a physician to his safety-sensitive occupation are reviewed in Table 49-4. In many cases, it is crucial to address conditioned cues in the work environment (70,135).

TABLE 49-4 Factors to Review When Considering Returning a Physician with a Substance Use Disorder to Work

PHPs and treatment providers have a wide variety of thoughts on how to structure the physician’s work and home life once a return to work date has been determined. Issues to be considered include workplace conditions, physician’s initial workload and whether shift work with rotating time frames should be allowed, his or her safety to practice around addicting substances, whether solo or group practice should be considered, any restrictions on prescribing DEA scheduled drugs, and the need for remedial training. In an effort to increase consensus on this topic, an instrument called the Medical Professional Addiction Recovery Inventory has been developed to balance recovery status and the workplace environment (136).

Treatment Outcome Data Physicians have been the subject of multiple outcome studies focused on the efficacy of extended, multimodal addiction treatment and monitoring. Most addiction treatment outcome studies are plagued by subjects being lost to followup. However, owing to the tight monitoring of PHPs, physician-based studies have excellent follow-up rates, approximating 90% in some studies (113). Physicians appear to have responded very well to their unique treatment and monitoring process. More sophisticated outcome analyses (42,50,80,113,114)

attempt to define why physician treatment is so successful. The natural progression of this line of thought is to identify which components of the physician treatment process can be generalized to the public at large (134). Gallegos et al. (137) reported a 77% sustained abstinence rate in physicians followed for 5 years. In the North Carolina PHP, Ganley et al. (138) noted 65% of physicians had a good outcome (as defined by completing an aftercare contract), and another 26% had a good outcome with complications (eg, relapsed but eventually completed a monitoring contract) in a 6-year study from 1995 to 2000, resulting in a 91% good outcome. In 2002, Lloyd (117) reported an impressive follow-up of physicians with alcohol-dependence in the United Kingdom over 21 years, noting a mean sustained duration of abstinence of 17.6 years in 68 of 80 physicians reporting. He conservatively scored the 20% lost to follow-up as negative outcomes, and even with this, he noted that 73% of the physicians in his study of 80 physicians were in recovery. Domino et al. (80) noted that 25% of physicians in the Washington State PHP (1991 to 2001) had at least one relapse. Family history, comorbid psychiatric disorder, and a previous relapse increased the probability of relapse. The use of major opioids increased the probability of relapse but only in the presence of a comorbid psychiatric disorder. McLellan et al. (50) evaluated the outcomes among 904 addicted physicians treated in 16 PHPs and found 78% were continuously abstinent throughout the 5- to 7-year period of evaluation; more than 90% of those physicians were still practicing medicine. Among those physicians who did relapse, 74% had only one episode of substance use.

CONTROVERSIES Conflicts between Privacy and Public Safety Physician treatment with its mandated abstinence monitoring illustrates the conflict between the physician–patient’s need for privacy and the public’s need for safety. Added to this is a stigmatized view of addiction; the result is that the addicted physician has become the “whipping boy” of physician impairment. Many other problems among physicians can and do lead to mistakes and patient harm (eg, sleep deprivation, overwork, poor communication with hospital staff, intemperate affairs), but they are not as directly addressed and do not receive a fraction of the public or regulatory board outcry or concern. Ironically, confidentiality for treatment of physician mental illness, including substance use

disorders, actually increases patient safety by encouraging early referral and safe passage into treatment (122,123). During the first several years of implementing a state PHP, the new program commonly sees a flood of early participants who are identified by colleagues or family due to the privacy afforded by the PHP. Conversely, many states have laws that mandate caregivers to report suspected physician impairment (a term that is not synonymous with addiction but is often confused as such—more accurately stated—impairment is a consequence of addiction if it is left untreated). Some states mandate that treatment providers report physicians to the medical board, regardless of whether impairment has been proven. In many cases, a default board action ensues. Although this may appear on superficial examination to protect patients, an excessively broad mandate for reporting actually decreases the probability that a physician will seek or accept a referral for assessment and treatment. If the perceived consequences of referral are sufficiently prejudicial, referral is delayed and ultimately only occurs when a major incident signals the transition from illness to impairment. In states with PHPs, regulatory boards allow PHP intercession, holding off disciplinary proceedings if the physician effectively addresses his disease in an appropriate, structured, and accountable manner. As soon as regulatory boards tilt toward law enforcement and away from treatment, physicians who develop addiction, their colleagues, and care providers become reluctant to report. The physician with addiction and his or her family delay or avoid treatment. An uninformed provider may hide behind the confidentiality of their profession and lose the benefit of the organized monitoring and peer support provided by a PHP. The structure of PHPs, on the other hand, facilitates a proper balance between the privacy that is critical for treatment and the public’s need for safety. They hold the awkward middle ground between their medical board and treatment providers. PHPs provide confidentiality if the physician’s illness does not pose a threat to public safety but report to the medical board should a patient become uncooperative or a risk to the public at large. The promise of protected and effective treatment encourages all parties to refer to the PHP before the physician who uses substances deteriorates to the point of a potential safety risk.

Complaints about Coercion and Control As with other areas in medicine, concerns have been expressed by the public, the media, and others that conflicts of interest could compromise decision-making and undermine the availability, utilization, and reputation of PHPs. Boyd and

Knight (139) argued that impressive results do not obviate the need for scrutiny. Boyd followed this with several commentaries (140,141). Most PHPs address these needs through external reviews, oversight by their respective Medical Boards and a Board of Directors with expertise in balancing effective treatment with ethical care. Their commentary describes other trepidations such as a higher dose of initial treatment than the general public. Some of these issues appear valid on the surface but fail to account for the dual roles of PHPs in protecting the public and unrealistic expectations many oversight bodies place on physicians, where a minor relapse can result in loss of a job, hospital privileges, a medical license, or an entire career. Research, albeit limited, as opposed to opinion points to good outcomes and a high degree of participant satisfaction (124). However, there is no available research comparing PHP care versus nonPHP, or less restrictive or expensive care in matched physician populations. Beginning in 2015, the Federation of State Physician Health Programs (FSPHP) developed evolving guidelines for state members that address potential conflicts of interest and national standards of care (142). The FSPHP is working to standardize best practices among its members (who have varying staffing, funding, and experience) through scientific exchange and the development of guidelines that define best practices.

Is Monitored Recovery the Same as SelfGuided Recovery? Physicians frequently enter treatment claiming they are there only to protect their medical license(s). A central goal in such cases is to shift the physician from this external driver to an internalized state of recovery as a lifelong journey. During treatment and subsequent monitoring, a number of physicians do not make this shift. Once the initial ravages of addiction remit, such individuals are held in a drug-free state by the oversight of drug screens and behavioral monitoring. In such cases, the internalization of recovery (an ongoing process of changing behaviors, attitudes, and beliefs) slows or stops; the transition into the self-motivated journey of recovery does not replace the holding cell provided by monitoring. The term disease stasis syndrome has been applied to this small subset of physicians. Such physicians have a high probability of returning to substance use, when and if monitoring is discontinued. In the disease stasis syndrome, the individual has made a commitment to abstinence only as a temporary means to an end. Such physicians may be quite compliant, assuming a false persona of acceptance to treatment providers, monitors, and PHP personnel.

Unfortunately, disease stasis is a by-product of external pressure and the intense treatment and monitoring that physicians undergo. Treatment providers should avoid pressuring patients to conform because physicians are, after all, good students who know how to give “correct” answers. Instead, providers should encourage patients to verbalize their resistance and dissatisfaction with treatment and to praise honest self-disclosure, especially when the participant is describing how he or she is stuck in the process of change. Physician–patients should be encouraged to disclose remnants of the central fallacy of the addicted mind: the fantasy that they may return to drinking or using drugs in a controlled and sociable manner once they are “strong enough” or have “learned enough about myself.” Open discussion regarding recovery ambivalence should be a recurrent theme in group therapy with this population. Psychodynamic psychotherapy may help such individuals integrate how past survival techniques of false compliance to authority figures are at play in their relationship with the current authority figures, including their therapists, treatment centers, and PHPs (143). In the meantime, monitoring holds the physician behaviorally accountable and, if properly framed as appropriate supportive care, is not only justifiable but also a good medicine. In their treatment, individuals with the disease stasis syndrome should remain on random screens, until this syndrome improves. Some cases may need to remain on screens for an indefinite time. Merlo and DuPont have completed a preliminary study that attempts to differentiate between stasis and recovery, to wit: What happens after PHP monitoring is discontinued? Working with several PHPs, they contacted individuals at 5 or more years after they completed PHP monitoring. Of 139 anonymous respondents, 95% (n = 121) self-reported no illicit or nonmedical use of drugs since PHP completion (144). If validated by additional research, these data suggest that the extended treatment and disease monitoring process in this cohort create lasting change and not just temporary interruption of the addiction illness.

Should Physicians Receiving Opioid Agonist Treatment Return to Practice? All addiction treatment programs in the United States that specialize in physicians see discontinuation of opioid agonist treatment as the most desirous end goal of treatment for opioid use disorder in most cases (30). Most, but not

all, state PHPs also consider the use of opioid agonist and partial agonist medications carefully and avoid their routine use; this stands in contrast to the standard of care in the general population. Four issues come into play with this decision. First, despite their widespread use, the research on their effects on cognition, insight, and emotional integration are unclear. Like any CNS-active medication, buprenorphine and methadone have the potential to affect cognition. Both decrease delayed recall (especially due to intrusion errors) and decrease sustained attention, especially in older adults (145). There are suggestions that even after maintenance has been established, methadone, but not buprenorphine, affects attention during driving simulation tests as well (146). While the effect size may not in itself be large, concerns remain. Hamza and Bryson (75) reviewed the current literature, concluding that cognitive changes of indeterminate consequence do occur. Second, public perception of safety is central to an efficient medical system. Addiction still has a negative connotation in society, and maintenance opioids (more so with methadone than buprenorphine) draw attention to a physician’s recovery: a recovery that is never as private and protected as the general public. Concerns exist in other safety-sensitive industries as well. Pilots cannot fly airplanes (commercial or private) if they are taking methadone or buprenorphine (147). Although consensus is shifting, commercial driver’s licenses may be denied to individuals on opioid treatment medications. The malpractice industry is one type of public attention physicians avoid at all cost; maintenance opioids open the door to medical–legal issues. Gray (Gray R, Personal communication, 2007) states, “At least one major statewide malpractice carrier has indicated that they will not insure an addicted physician if he is on opioid maintenance therapy, due to the difficulties in defending such a physician in a malpractice case.” Like it or not, our management of addiction among physicians is modified by public opinion. It is temerarious to try to educate the public to become more openminded about opioid agonist therapy among physicians in the current climate of oft misguided and injudicious scrutiny. Third, current screening technology cannot monitor dosage adherence to agonist medications. Fourth, and most important, physicians with opioid use disorder have the same sustained success rates when compared to physicians addicted to other substances (50,80,113,114,137) when agonist and partial agonist medications are not used. This stands in sharp contrast outcome studies in the population at large.

Thus, from this efficacy perspective, the use of buprenorphine or methadone is unnecessary in the majority of physician cases. Said another way, the high success rates reported in the PHP literature render long-term agonist and mixed agonist/antagonist medications unnecessary in the majority of cases. Despite these general statements, exceptions make sense when based on clinical need. Opioid agonist treatment does occur in the treatment of physicians, but there is no clear consensus on which cases should be treated with opioid agonists (or partial agonists). An earlier study of 904 physicians from 16 PHPs (50) reported that only 1 physician was reported to be receiving opioid agonist treatment. Skipper (Skipper GE, Personal communication, 2008) surveyed PHPs and reported that 14 of the 36 PHP who responded indicated they were following up at least one physician receiving opioid agonist treatment. This issue becomes more complex when one considers cases of physicians with opioid use disorder who have chronic, nonmalignant pain. Opioids may be necessary to maintain the quality of life in such an individual. However, that same individual may have a history of inappropriate opioid use or even opioid diversion. In this case, the PHP and treatment providers are balancing the physician’s need for pain control with the safety of the public and, importantly, the fear of reprisal by an uninformed public. The decision about a physician’s ability to practice in such situations should be approached with caution and a complete knowledge of the research and clinical knowledge in this area. Although the use of chronic opioids may be necessary in such cases, loss of control from prescribed doses does occur. The resolution of this conundrum should rest upon the effect the medication has on the brain and behavior of physicians who take such medications, not upon the disease for which they are prescribed. It must be stated, however, that the public and regulatory agencies are far more tolerant of opioids for analgesia than they are for the treatment of opioid use disorder. A second conundrum occurs in the small percentage of physicians with opioid use disorder who are unable to maintain abstinence from illicit drug use. In such cases, should physicians be treated using opioid agonist treatment with methadone or buprenorphine? Different PHPs approach this controversy from different angles. A few approve the use of opioid agonist treatment in practicing physicians. In such states, the PHP collaborates with care providers in deciding who is a proper candidate. Other states strongly oppose the use of opioids, mostly due to concerns of how it might affect their program as a whole. Still other states see opioid agonist treatment as a last resort and follow such cases carefully and/or limit that physician’s scope of practice to mitigate real or

perceived danger. No published studies have addressed this issue to date.

Re-entry of Physicians Diagnosed With Opioid Use Disorders Multiple conflicting publications debate the advisability of anesthesiologists and other physicians who both misused and have high opioid access returning to the operating room or other arena of high access. Menk et al. (148) reported a successful re-entry rate of only 34% for parenteral anesthesiologists using opioids versus 70% for not using opioids. This oft-quoted 1990 study promulgated a pessimistic view of anesthesiologists returning to work but has been criticized because it was essentially a retrospective survey of anesthesia training directors, subject to recall bias. Of the 159 anesthesia training programs surveyed, 113 responded, providing 180 case reports, with most programs providing only a single case report of a resident having been addicted. Critics contend that if most programs reported only a single case, it is likely that such reports were skewed toward disasters. Collins et al. (149) also surveyed anesthesiology residencies in 2001, noting that 50% of treated anesthesiologists remained in anesthesiology after treatment, with 91% completing training and 9% dying of relapse-related incidents. Paris and Canavan (150) compared 32 anesthesiologists with 36 physician controls for an average of 7.5 years; they showed no difference in the relapse rates between these two groups. When stratified by residents versus attending physicians, no significant difference was found. Domino et al. (80) examined the risk of relapse over 11 years and 256 participants in a Washington State PHP, including 32 anesthesiologists. The relapse rate for anesthesiologists was not statistically significantly different from other physicians. Additionally, there was not a single episode of patient harm or death from overdose by any anesthesiologist in this study. A similar report from Pelton and Ikeda (40) involving 255 physicians who had participated in the California Diversion Program over 10 years showed no difference in relapse rates for anesthesiologists. Domino et al. (80), evaluating physicians in the Washington State PHP, noted that physicians who had used fentanyl had a slightly lower incidence of relapse than those who had used other major opioids. Individuals who used potent opioids (excluding fentanyl) had a higher risk of relapse as did physicians with an existing comorbid psychiatric disorder or a family history of addiction.

They conclude that anesthesiologists who used potent opioids and do not have other risk factors (family history, comorbid psychiatric disorder, and history of relapse) are good candidates to return to the practice of anesthesiology. A more recent study by Skipper (114) reviewed data from PHPs in 16 states, culling information about anesthesia providers. They noted that anesthesiologists had outcomes similar to other physicians, with no higher mortality, relapse rate, or disciplinary rate and no evidence in their records of patient harm. These authors postulated that the type of treatment and monitoring that these physicians received from the 16 state PHPs accounts for the differences from earlier reports. Oreskovich and Caldeiro imply there are two approaches to managing opioid addiction among anesthesiologists (151). One, more common early on, involves low-dose initial treatment and minimal or noncomprehensive drug screening and medication assistance. The second is composed of aggressive treatment and long-term oversight, has sophisticated hair and nail testing for fentanyl, and involves placement on depot naltrexone. These authors purport that the literature supports the latter construct. Studies that followed anesthesiologists under close monitoring in PHPs or by regulatory boards (Domino (80),Washington State; Paris and Canavan (150), New Jersey; Pelton and Ikeda (40), California; Skipper (114), 16 different states with active PHPs) describe outcomes for anesthesiologists that are similar to other physicians, whereas earlier studies that are based upon a survey of the memories of anesthesiology program directors (where patients had uncertain or limited treatment and monitoring) describe poor, and at times, life-terminating outcomes. The controversy about returning anesthesiologists to practice underscores the importance of sophisticated PHPs in maintaining recovery for their participants and ensuring public safety. Several studies point to the importance of opioid antagonists in the long-term management of the anesthesiologist with opioid use disorder. Merlo et al. (119) in a naturalistic crossover study in one PHP showed the risk of relapse on opioids was significantly decreased when physicians who used parenteral opioids are given injectable naltrexone upon initial return to a high-risk practice environment. Many providers working with this cohort suspect that exposure to conditioned environmental cues while protected by naltrexone diminishes conditioned cue craving (70).

What Happens when a Physician Relapses? Addiction is often characterized by periods of abstinence alternating with relapse. In contrast, the expectation by medical boards and the public is that

physicians should never relapse, placing another burden of perfectionism upon a cohort who are already perfectionist and harshly self-critical. For some physicians, the experience of recovery feels more like a jail of perfectionism instead of a journey where one learns to accept imperfections. The consequence of relapse for any person with addiction entails a loss of self-efficacy. For the physician, it may involve a loss of livelihood and facing possible board or legal sanctions. Physicians early in their recovery often experience a brief “discovery” relapse (a return to drug use where the individual’s relapse experience validates and internalizes a heretofore poorly accepted diagnosis) (80,152). PHPs are familiar with such occurrences; medical boards and the public at large are not. Research into, and standardization of, interventions in the event of an early recovery relapse should improve outcomes and at the same time increase public trust. Repeated relapses that run the risk of public harm should be managed by removing such an individual from his or her practice. Physicians who experience multiple relapses may need a sustained period of remission prior to a return to practice. Involvement in support systems and length of remission predict the best prognosis moving forward (153).

CONCLUSION Physicians were the first professional group to address addiction within their profession; this leadership continues today. The disease of addiction in physicians follows a similar course as in the public at large, with several notable exceptions. The access to potent drugs is one of the most important of these exceptions. The identification, evaluation, initial treatment, and subsequent addiction monitoring in this population may afford useful elements of disease management that can be adapted to the treatment of addiction in the public at large (134). The treatment of physicians is different (especially in the United States), partly driven by public outcry for complete and sustained remission in a disease that is chronic and relapsing by nature. PHPs remain integral elements in the comprehensive disease management of physician addiction. Controversies in the management of addiction in physicians abound and call for further research in this interesting and complex population.

The California Diversion Program: A Cautionary Tale In 1978, the California Board of Medical Quality Assurance (BMQA) developed a Diversion Program to assist physicians with alcohol and drug problems, “diverting” them from disciplinary action if they followed the requirements of the program. Authorizing legislation was passed in 1979 and the program opened on January 1, 1980. The participation of physicians who entered the program was not publicly disclosed. In the ensuing 27 years, up to 350 physicians at a time were managed in the Diversion Program. Even at its peak, the Diversion Program monitored only 0.47% of licensed physicians in the state. As part of a standard oversight process required by the state, the program underwent audits every few years. At first, the audits were conducted by a state agency. In 2003, a consumer group, the Center for Public Interest Law (CPIL) (154), was approved to be the auditor of the Diversion Program. These audits were more critical, eventually alleging that several physicians had harmed patients. Stories appeared in newspapers; one example was about a “diversion-protected” physician who used drugs, who in fact had been dropped from the Diversion Program for failure to comply with program requirements. He had previously been turned over to the disciplinary arm of the California Medical Board. Hearings were held where CPIL speakers repeated their opinion that keeping names of the physicians in the Diversion Program from the public was contrary to the public protection mission of the Medical Board of California. Legislation required the board to complete a semiyearly renewal authorization for the Diversion Program. In 2007, the MBC voted unanimously to deny renewal, under tremendous pressure from the CPIL, the media, and some legislators. The program was closed on June 30, 2008. In response to a gaping hole in physician monitoring, local medical societies and hospital systems attempted to continue to provide such services. This makeshift approach continues to this day. Reacting quickly, the California Medical Association (CMA), California Hospital Association (CHA), California Society of Addiction Medicine (CSAM), California Psychiatric Association (CPA), the University of California, California’s malpractice liability insurance carriers, providers of care, and others came together to promote legislation to rebuild a PHP in

California. In 2009, the resultant work group created a new 501(c)(3) organization, California Public Protection and Physician Health, Inc (CPPPH), independent of its parents. Its work ever since has been to further assist the parent organizations prepare for a full state-sanctioned PHP and to promote physician health (155). After five attempts and thousands of man-hours, legislation was finally passed to repair the system for providers and patient safety. At the time of this writing, the Medical Board is writing regulations to govern the new organization. Many lessons come from this cautionary tale. First, even though the duty of PHPs is the health and safety of all, they are sustained or destroyed by public opinion and politics. Second, physicians are safety-sensitive workers and are appropriately held to a higher standard. Effective treatment and monitoring decreases but does not eliminate public fear, even though it does not have a basis in reality. Third, the outcome of a few physicians can affect the entire organization—even after being ejected from the safe haven of a PHP and turned over to disciplinary bodies.

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121. The sick physician: impairment by psychiatric disorders, including alcoholism and drug dependence. JAMA. 1973;223(6):684-687. 122. Nelson HD, Matthews AM, Girard DE, Bloom JD. Substance-impaired physicians-probationary and voluntary treatment programs compared. West J Med. 1996;165(1):31-36. 123. Shore JH. The oregon experience with impaired physicians on probation: an eight-year follow-up. JAMA. 1987;257(21):2931-2934. 124. Knight JR, Sanchez LT, Sherritt L, et al. Monitoring physician drug problems: attitudes of participants. J Addict Dis. 2002;21(4):27-36. 125. Jaffee WB, Trucco E, Levy S, et al. Is this urine really negative? A systematic review of tampering methods in urine drug screening and testing. J Subst Abuse Treat. 2007;33(1):33-42. 126. Skipper GE, Weinmann W, Thierauf A, et al. Ethyl glucuronide: a biomarker to identify alcohol use by health professionals recovering from substance use disorders. Alcohol Alcohol. 2004;39(5):445449. 127. Wurst FM, Skipper GE, Weinmann W. Ethyl glucuronide—the direct ethanol metabolite on the threshold from science to routine use. Addiction. 2003;98(s2):51-61. 128. Wurst F, Dresen S, Allen J, et al. Ethyl sulphate: a direct ethanol metabolite reflecting recent alcohol consumption. Addiction. 2005;101:204-211. 129. Helander A, Dahl H. Urinary tract infection: a risk factor for false-negative urinary ethyl glucuronide but not ethyl sulfate in the detection of recent alcohol consumption. Clin Chem. 2005;51(9):17281730. 130. Vaillant GE. A 60-year follow-up of alcoholic men. Addiction. 2003;98(8):1043-1051. 131. Federation of State Medical Boards. Policy on Physician Iimpairment—2011, 2011. Available from: https://www.fsmb.org/Media/Default/PDF/FSMB/Advocacy/grpol_policy-on-physicianimpairment.pdf. Cited November 21, 2016. 132. Galanter M, Dermatis H, Mansky P, et al. Substance-abusing physicians: monitoring and twelve-stepbased treatment. Am J Addict. 2007;16(2):117-123. 133. Galanter M, Talbott D, Gallegos K, et al. Combined alcoholics anonymous and professional care for addicted physicians. Am J Psychiatry. 1990;147(1):64-68. 134. DuPont RL, Skipper GE. Six lessons from state physician health programs to promote long-term recovery. J Psychoactive Drugs. 2012;44(1): 72-78. 135. Hamza H, Bryson EO. Exposure of anesthesia providers in recovery from substance abuse to potential triggering agents. J Clin Anesth. 2011;23(7):552-557. 136. Earley. Mpari History, Part One, 2009. Available from: http://www.earleyconsultancy.com/portal/mpari/mpari-history-part-one. Cited June 10, 2012. 137. Gallegos K, Lubin B, Bowers C, et al. Relapse and recovery: five to ten year follow-up study of chemically dependent physicians—the Georgia experience. MD Med J. 1992;41(4):315-319. 138. Ganley OH, Pendergast WJ, Wilkerson MW, et al. Outcome study of substance impaired physicians and physician assistants under contract with North Carolina physicians health program for the period 1995–2000. J Addict Dis. 2005;24(1):1-12. 139. Boyd JW, Knight JR. Ethical and managerial considerations regarding state physician health programs. J Addict Med. 2012;6(4):243-246. 140. Boyd J. State physician health programs require national standards and external oversight. J Psychiatry. 2016;19(346):2. 141. Boyd JW. A call for national standards and oversight of state physician health programs. J Addict Med. 2015;9(6):431-432. 142. FSPHP. Performance Enhancement Review Guidelines, 2015. Available from: http://www.fsphp.org/resources/guidelines/2016-performance-enhancement-review-guidelines. Cited November 23, 2016. 143. Malan D. Individual Psychotherapy and the Science of Psychodynamics. London, UK: Hodder Education, 1995. 144. Merlo L, DuPont R. Essential Components of PHP Participation: Perspectives of Participants Five Years Post-Mandatory Monitoring. Institute for Behavior and Health and University of Florida,

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SECTION 6

Management Withdrawal

of

Intoxication

and

CHAPTER 50

Management of Intoxication Withdrawal: General Principles Tara M. Wright, Jeffrey S. Cluver and Hugh Myrick

and

CHAPTER OUTLINE Introduction Intoxication States Recognizing the Impact of Ever Changing Drug Trends Withdrawal States Special Populations Conclusions

INTRODUCTION Recognition of intoxication and withdrawal states is critical for the appropriate management of individuals with substance use disorders. In addition to being able to recognize the unique intoxication and withdrawal states of particular substances, the treatment of patients who are under the influence of, or experiencing withdrawal from, substances requires an understanding of many variables. These variables include an appreciation of the natural history and variants of such syndromes, a complete assessment of the patient’s individual medical, psychiatric, and social issues, and knowledge of the uses and limitations of a variety of behavioral and pharmacological interventions. All therapies must be individualized to each patient’s needs and adjusted to reflect the patient’s response to treatment. The number of referrals to emergency departments (EDs) due to complications from acute intoxication or withdrawal states remains at all-time highs. Data from the Drug Abuse Warning Network revealed that the total number of drug-related ED visits increased from 2004 (626 470 visits) through 2011 (1 428 145 visits). In regard to pharmaceuticals, the most commonly involved were opioid analgesics and sedative–hypnotics (1). While pharmaceuticals continue to be involved at a higher rate than illicit drugs, findings of the DAWN 2011 revealed an increase in the involvement of illicit drugs. Between 2009 and 2011, the rate of visits involving illicit stimulants increased 68%, and the rate of visits involving marijuana rose 19% (1). Drug overdose is now the leading cause of accidental death in the United States, with 55 403 lethal drug overdoses in 2015. Opioid use disorders are driving this epidemic, with 20 101 overdose deaths related to prescription pain relievers and 12 990 overdose deaths related to heroin in 2015 (2). In addition, it is imperative

to differentiate between those emergent visits involving a single drug and those involving multiple drugs. Among opioid analgesic-related ED visits involving nonmedical use that occurred in 2011, only 44% involved opioid pain relievers solely. In the remaining 56% of these visits, additional drugs were involved, the most common other pharmaceutical class involved being benzodiazepines (3). This chapter serves as an introduction to the identification and management of intoxication and withdrawal states, with the management of specific substances to be reviewed in subsequent chapters in this section.

INTOXICATION STATES Intoxication is the result of being under the influence of, and responding to, the acute effects of alcohol or another drug. It typically includes feelings of pleasure, altered emotional responsiveness, altered perception, and impaired judgment and performance. The recognition of intoxication states is of paramount importance in the appropriate treatment of substance-using patients. Intoxication states can range from euphoria or sedation to life-threatening emergencies when overdose occurs. Typically, each substance has a set of signs and symptoms that are seen during intoxication. Identification and treatment of intoxication can lead to appropriate management of the withdrawal phenomenon and provide an avenue for entry into treatment. The initial challenge to the clinician, however, is diagnosis, because intoxication can mimic many psychiatric and medical conditions.

Identification Intoxication

and

Management

of

The identification of intoxication begins with the collection of patient data through a patient history, physical examination, and laboratory screening. Of immediate concern is life-threatening intoxication or overdose. Thus, the first priority is general supportive care and resuscitative actions. It is important to determine not only the severity of the substance ingestion but also the patient’s level of consciousness, the substances involved, and any complicating medical disorders. Often, more than one substance is involved, and it is critical to know what substances have been ingested, as well as how much of each substance. Historical information regarding substance use usually can be obtained from the patient. Questions regarding the quantity and frequency of substance use

provide valuable information to the clinician. Discovering chronic patterns of substance use may aid in subsequent referral to addiction treatment. Acute intoxication may impede an individual’s ability to provide such information. In these cases, the patient’s companions or family may be able to provide important information. Standardized questionnaires for self-administration by the patient or for use by the clinician are designed to elicit answers related to alcohol or substance use. Toxicology screens provide valuable information regarding the type or types of substances used. When screening for substances used, urine is the most widely used specimen because of the ease with which a sample is obtained, the relatively high concentrations of drugs and metabolites present in urine, and the stability of metabolites when frozen. Drug testing can aid in the differential diagnosis when atypical symptoms are present. Such testing can be particularly helpful in cases where little clinical history is available. Having knowledge of the sensitivities, specificities, and cross-reactivities of the particular urine drug test being used is of vital importance to the appropriate interpretation. In addition, one must have an understanding of the usual duration of detectability of particular substances. However, the duration of detectability can be significantly impacted by the amount of substance ingested, individual rates of metabolism and excretion, as well as fluid ingestion of the individual. It is equally important to note that the rise in the use of synthetic or “designer” drugs can make identification of the causative substance(s) more difficult, as these substances are frequently not detected by routine toxicology testing. Testing for alcohol is most frequently accomplished by breathalyzer or blood alcohol levels; however, urine tests are also available that detect metabolites of alcohol. Laboratory assays that measure increases in liver enzymes—such as gamma-glutamyl transferase, aspartate aminotransferase, and alanine aminotransferase—can be helpful in indicating possible heavy alcohol use. Although alcohol is not the only cause of an increase in gamma-glutamyl transpeptidase (GGT), and GGT frequently does not increase in younger drinkers, this assay may help clinicians consider that the patient may be drinking alcohol excessively. A biological assay to monitor alcohol intake involves percent carbohydrate-deficient transferrin (%CDT), a more sensitive and specific indicator of heavy alcohol consumption (4). The conjugated ethanol metabolites ethyl glucuronide (EtG) and ethyl sulfate (EtS) are other measures that can also be used to confirm or rule out recent drinking. Although EtG and EtS account for only 20% of patients newly admitted to inpatient addiction treatment reported using benzodiazepines at least weekly, 73% of people using heroin reported greater than weekly use, and >15% of those using heroin used benzodiazepines daily (68). It is uncommon for a patient with drug addiction to use a benzodiazepine as an initial or primary drug (69). Instead, benzodiazepines are used in combination with other psychoactive drugs. In addition, a high rate of benzodiazepine use in methadone maintenance clinics is supported by numerous clinical surveys. Consequently, clinicians must be aware of, and suspect, benzodiazepine use in patients with any substance use disorders. Conversely, in persons using highdose benzodiazepine, other substance use must be assumed until ruled out.

Family History of Alcohol Use Disorder Mood changes associated with lability or benzodiazepine misuse (and increased propensity to develop dependence) have been reported after controlled clinical administration of diazepam and alprazolam in adult sons of patients with severe alcohol dependence (DSM-III-R) (64,70,71). Similar findings with alprazolam

have been reported in adult daughters of patients with alcohol dependence (DSM-III-R) (72). This predisposition to misuse benzodiazepines is important, because at least one study implicates a linkage of paternal history of alcohol use disorder with increased withdrawal severity in patients discontinuing alprazolam use (56).

Concurrent Medical Conditions Benzodiazepine withdrawal should be avoided during acute medical or surgical conditions because the physiological stress of withdrawal can adversely and unnecessarily affect the course of the medical condition. On the other hand, continued benzodiazepine use rarely has a negative effect on acute medical conditions. In an acute medical situation, the goal of therapy for a patient dependent on benzodiazepines is to provide adequate stabilization of the benzodiazepine dose so as to prevent withdrawal. Clinicians need to be secure in their understanding of the indications for discontinuing long-term benzodiazepine use in patients with chronic medical, including mental health, conditions. This understanding is particularly critical when evaluating the discontinuation of benzodiazepines in patients with conditions that are significantly influenced by adrenergic and psychological stress factors (such as cardiac arrhythmia, asthma, systemic lupus erythematosus, and inflammatory bowel disease). The risks of exacerbating the medical condition through acute withdrawal or a protracted withdrawal course may outweigh the longer-term benefits of benzodiazepine discontinuation. Patients with chronic medical conditions may experience benzodiazepine withdrawal more severely than others. Clinicians and patients must be aware that, during withdrawal, difficulties in managing the medical condition (diabetes, cardiovascular disease, thyroid disease, and arthritis) may emerge. The rate of discontinuation is an important factor. Slower rates can improve the success of withdrawal management. Achieving lower doses of benzodiazepine use is an acceptable intermediate (and, in some patients, final) goal. It is important to stabilize both the patient’s physical and psychological health at reduced benzodiazepine levels before proceeding with further reductions.

Age Anxiolytic use peaks between the ages of 50 and 65, whereas hypnotic use is most frequent in the oldest age range (14). Because hepatic microsomal enzyme oxidase system efficiency decreases with age, elderly patients may have

elimination half-lives that are two to five times slower than their younger counterparts for most benzodiazepines (excepting lorazepam, temazepam, and oxazepam). The withdrawal syndrome for elderly persons who are discontinuing oxidatively metabolized benzodiazepines may be quite prolonged or approach the severity of high-dose withdrawal secondary to the pharmacokinetic factors of aging. The withdrawal course can become especially pernicious after discontinuation of long-acting benzodiazepines that are metabolized to sedative– hypnotic compounds with longer elimination half-lives (such as diazepam, chlordiazepoxide, and flurazepam). In general, younger age is associated with favorable withdrawal outcomes (73).

Sex Worldwide, women are prescribed benzodiazepines twice as often as men; hence, twice as many women as men are likely to become dependent (74). Possibly compounding this trend are reports that female sex is a significant predictor of increased withdrawal severity in patients undergoing tapered cessation of long-term, therapeutic benzodiazepine use (55). However, sex has not been implicated as an influential factor in abrupt cessation of long-term, therapeutic dose use (52).

Bariatric Surgery Studies show reduced serum levels of phenobarbital after Roux-en-Y gastric bypass surgery. This is significant when using phenobarbital in medically assisted withdrawal as will be later discussed. Such patients will require higher doses of phenobarbital than anticipated (75).

Pregnancy While medically assisted opioid withdrawal is contraindicated in pregnancy, sedative–hypnotic–anxiolytic withdrawal can be accomplished however only with caution and regular monitoring. Prenatal benzodiazepine use can exacerbate neonatal abstinence syndrome (NAS) in the presence of opioid use disorder and can cause seizures in the newborn. Neonatal benzodiazepine withdrawal syndrome can present as floppy infant syndrome (hypotonia, hypothermia, and suckling difficulties) or with tremors, irritability, hyperactivity, and cyanosis (76). Severe benzodiazepine withdrawal symptoms during pregnancy can place the fetus in distress, potentially causing miscarriage, and may induce preterm labor.

All classes of benzodiazepines (and phenobarbital) cross the placenta and are excreted in breast milk. Most have a pregnancy Category D rating (positive evidence of human fetal risk), but the benefits from use in pregnant women may be acceptable despite the risk. Four benzodiazepines (flurazepam, estazolam, temazepam, and quazepam) have a Category X rating (contraindicated in pregnancy). Taking into account the possible adverse effects to the growing fetus, it is advised to limit the number of ancillary medications used in medically assisted withdrawal. Studies on epileptic patients taking phenobarbital showed an increased risk in congenital abnormalities but a later study showed that phenobarbital use in patients without epilepsy did not seem to pose a significant risk for congenital anomalies (77). It is therefore advised to use these medications and taper down as quickly and safely as possible.

PATIENT EVALUATION MANAGEMENT

AND

Evaluation and Assessment Evaluating patients for benzodiazepine cessation and withdrawal management requires a combination of clinical, diagnostic, consultation and liaison, counseling, and pharmacological management skills. To be effective, the clinician must be flexible and able to tolerate ambiguities and variations in the course of withdrawal while supporting the patient (who generally experiences significant apprehension and anxiety). Clinical evaluation and assessment of the patient typically include the following steps.

Step 1 Determine the reasons the patient or referral source is seeking evaluation of sedative–hypnotic use and/or discontinuation. Determine the medical indications for the sedative–hypnotic. If there is a referring or prescribing physician, a discussion with that physician should occur to co-manage his or her sedative– hypnotic treatment. Discussion with any other referring person or close family members often is helpful. Seek evidence to answer the question as to whether the patient’s use is improving his or her quality of life or is causing a significant disability or helping or exacerbating the original condition. Discuss the patient’s expectations.

Step 2 Take a sedative–hypnotic use history, including, at a minimum, the dose, duration of use, substances used, and the patient’s clinical response to sedative– hypnotic use at present and over time. The history should include attempts at abstinence, including previous episodes of withdrawal , symptoms experienced with changing the dose, and reasons for (and responses to) increasing or decreasing the dose. The history should include behavioral responses to sedative–hypnotic use and adverse or toxic side effects. For persons who used sedative–hypnotics long term, clinicians should determine the clinical efficacy and risks and benefits of sedative–hypnotic continuation or discontinuation.

Step 3 Elicit a detailed accounting of alcohol and other psychoactive drug use, including medical and nonmedical use, prescribed and over-the-counter drug use, current and past use, as well as the sequelae of such use. In addition to prior withdrawal experiences, the history also should include prior periods of abstinence and abstinence attempts.

Step 4 Take a psychiatric history, including current and past psychiatric diagnoses, hospitalizations, suicide attempts, trauma history, prior treatment, psychotherapy, and therapists (names and locations). Ask if alcohol or other drugs were used during or near the time any psychiatric diagnoses were made. Ask if the referring clinician was aware of any patient alcohol or other psychoactive substance use. The Minnesota Multiphasic Personality Inventory may be helpful for the dependence subscale scores. Early taper dropouts had higher Minnesota Multiphasic Personality Inventory dependence subscale scores than did late taper dropouts and completers of a taper (78). Personality assessments may help identify patients who may be more suitable to attempt withdrawal. High levels of dependency, passivity, neuroticism, and harm avoidance on the Minnesota Multiphasic Personality Inventory contributed to increased withdrawal severity (79).

Step 5 Take a family history of substance use, psychiatric, and medical disorders.

Step 6 Take a medical history of the patient, including illnesses, trauma, surgery, medications, allergies, and history of loss of consciousness, seizures, or seizure disorder. Some medications, such as beta-blockers, may mask withdrawal symptoms or limit pharmacological intervention for withdrawal.

Step 7 Take a psychosocial history, including adverse childhood experiences, current social status, and support system.

Step 8 Perform a physical and mental status examination.

Step 9 Conduct a laboratory urine drug screen for addictive substances. An alcohol breath test (if available) often is helpful in providing immediate evidence of alcohol use that was not disclosed in the history. Remember that these are therapeutic tools. Trust the patient, but check the urine. Unfortunately, most urine drug screens test for oxazepam and therefore only screen for benzodiazepines that are metabolized to oxazepam. Such screens fail to identify alprazolam, lorazepam, and clonazepam; these must be tested for specifically if indicated. Depending on the patient’s profile, a complete blood count (CBC), blood chemistry panel, liver enzymes, viral hepatitis panel, HIV test, tuberculosis test, pregnancy test, or electrocardiogram test may be indicated.

Step 10 Complete an individualized assessment, taking into account all aspects of the patient’s presentation and history and, in particular, focusing on factors that would significantly influence the presence, severity, and time course of withdrawal.

Step 11 Arrive at a differential diagnosis, including a comprehensive list of diagnoses that have been considered. This greatly aids clinical management decisions as the patient’s symptoms diminish, emerge, or change in character during and after

drug cessation.

Step 12 Determine the appropriate setting for withdrawal management. In addition to the usual considerations for placement of any patient with the appropriate level of care for addiction treatment, patients dependent on alcohol and sedative– hypnotics or opioids and sedative–hypnotics should undergo medically assisted withdrawal in an inpatient (24 hours medically monitored) setting due to risk of sedation and overdose.

Step 13 Determine the most efficacious withdrawal management method. In addition to proven clinical and pharmacological efficacy, the method selected should be one that the physician and clinical staff in the withdrawal management setting are comfortable with and experienced in administering.

Step 14 Obtain the patient’s informed consent.

Step 15 Initiate withdrawal management. Ongoing physician involvement is central to appropriate management of withdrawal. Subsequent to the patient assessment, development of the treatment plan, and obtaining patient informed consent, the individualized discontinuation program should be initiated. The physician closely monitors and flexibly manages, adjusting as necessary, the dosing or withdrawal management strategy to provide the safest, most comfortable, and efficacious course of withdrawal . To achieve optimal results, the physician and patient should establish a close working relationship. A written and signed withdrawal agreement can be a useful tool.

Management Strategies for discontinuation fall into two categories: minimal intervention and systematic discontinuation. Minimal intervention delivers simple advice to discontinue the benzodiazepine. This can be done as part of an office visit, in a letter to the patient, or in a group setting. Several studies have investigated this

tool and have found it effective in fostering benzodiazepine discontinuation. Oude Voshaar et al. (80) reviewed 29 articles and found an improved odds for discontinuation (odds ratio 2.8) by using a simple letter or group information session. After receiving a letter with advice to quit gradually, 49% (53/109) of patients using benzodiazepines did so in 30 general practice clinics maintained abstinence for more than 2 years (819 ± 100 days) (81). Cormack et al. (82) showed a two-thirds reduction in the benzodiazepine dose used by using a letter advising the gradual reduction of the benzodiazepine. Minimal interventions are more effective in patients prescribed low doses of sedative–hypnotic medications.

Systematic Discontinuation For patients who are dependent on sedative–hypnotics, there are two primary options for the withdrawal management process: tapering or substitution and tapering. Gradual dose reduction (tapering) is the most widely used and most logical method of benzodiazepine discontinuation. The taper method is indicated for use in an outpatient ambulatory setting, patients with therapeutic dose benzodiazepine dependence, patients who are dependent only on benzodiazepines, and patients who can reliably present for regular clinical follow-up during and after withdrawal (50,62,69,78,83–88).

Tapering With the taper method, the patient is slowly and gradually weaned from the benzodiazepine on which he or she is dependent, using a fixed-dose taper schedule. This is ideal if the benzodiazepine being used is long acting. The dose is decreased on a weekly to every-other-week basis. The rate of discontinuation for patients who used benzodiazepines for the long term (>1 year) should not exceed 5-mg diazepam equivalents per week (12.5-mg chlordiazepoxide or 15mg phenobarbital equivalents) or 10% of the current (starting) dose per week, whichever is smaller. The first 50% of the taper is usually smoother, quicker, and less symptomatic than the last 50% (52,78). For the final 25%-35% of the taper, the rate or dose reduction schedule should be slowed to half the previous dose reduction per week and the reduction accomplished at twice the original tapering interval. If symptoms of withdrawal occur, the dose could be increased slightly until the symptoms resolve and the subsequent taper schedule commenced at a slower rate. Some patients may want to accelerate the reduction. This acceleration is

better tolerated and can be encouraged early in the reduction (78). In general, patients tolerate more dose reduction and with shorter intervals early in the tapering process and then require decreased dose reduction over longer intervals as the taper progresses and the dose is reduced. A common error is trying to push the taper process too quickly (86,87). Brief office visits should be conducted at least weekly to facilitate regular assessment of the patient for withdrawal symptoms, general health, taper compliance, and use of supportive therapy. Standardized advice from the physician doing the taper is an essential component (88). Taper medications should be closely controlled by prescribing an amount sufficient only for the time until the next visit. The prescriber should give a clear message to the patient that lost, misplaced, or stolen medication will invoke a reevaluation of the current treatment plan and could lead to an alternative discontinuation paradigm and/or higher level of care. A written withdrawal agreement between the patient and clinician, signed by the patient, is strongly advised. A copy of the written schedule of daily doses, covering multiple weeks to months, may help the patient adhere to the reduction plan. A reliable support person who is in daily contact with the patient is very helpful. The patient will need to give written consent for contacting the support person. Patients who are unable to complete a simple taper program should be reevaluated and, if indicated, an alternative withdrawal management method and/or higher level of clinical care chosen. Some patients may require a substitution and taper program or a period of hospitalization to receive more intensive monitoring and support to complete drug discontinuation.

Substitution and Taper Substitution and taper methods employ cross-tolerant long-acting benzodiazepines (such as chlordiazepoxide or clonazepam) or phenobarbital to substitute, at equipotent doses, for the sedative–hypnotics on which the patient is dependent (Table 52-3). Chlordiazepoxide, clonazepam, and phenobarbital are the most widely used substitution agents for a number of important reasons:

TABLE 52-3 Sedative–Hypnotic Substitution Dose Conversions

Withdrawal

At steady state, there is negligible interdose serum level variation with these medications; with tapering, there is a more gradual reduction in serum levels, reducing the risk that withdrawal symptoms will emerge. Each of the medications has low addictive potential (phenobarbital and chlordiazepoxide are lowest followed by clonazepam). While this point is generally accepted, there is regional variability in this potential. For example, anecdotally, clonazepam is often misused in the Northeast and is particularly popular among patients in opioid agonist treatment and with opioid use disorder. Phenobarbital offers the added advantage of rarely inducing behavioral disinhibition and possesses broad clinical efficacy in the management of withdrawal from all classes of sedative–hypnotic agents. Clinical experience shows that phenobarbital is most useful and effective in patients with dependence on more than one drug, in patients with high-dose dependence, and in patients with unknown dose or erratic “polypharmacy” drug use. Benzodiazepines need GABA to work. Because in chronic benzodiazepine use GABA production is down-regulated and GABA receptors are altered in expression, phenobarbital is a better option to manage withdrawal symptoms. Barbiturates directly activate GABAA receptors, resulting in prolonging the duration that chloride channels remain open. With impaired hepatic function or elevated liver tests, oxazepam may be a good substitute (69). Lorazepam could be considered, but its addiction liability is higher than that of oxazepam (68). However, if a patient is in an inpatient setting with close monitoring, one can use longer-acting agents while monitoring for sedation and adjusting dosing accordingly.

Uncomplicated Substitution and Taper This method is used in outpatient settings for patients who are discontinuing use of short half-life benzodiazepines or for those who are unable to tolerate gradual tapering: 1. Calculate the equivalent dose of chlordiazepoxide, clonazepam, or phenobarbital using the Substitution Dose Conversion Table (Table 52-3). Individual variation in clinical responses to “equivalent” doses can vary, so close clinical monitoring of patient response to substitution is necessary.

Adjustments to the initially calculated dose schedule are to be expected. 2. Provide the substituted medication in a divided dose. For chlordiazepoxide, oxazepam, or phenobarbital, give three to four doses per day. For clonazepam, two to three doses per day usually are sufficient. 3. Provide the patient with smaller as-needed (PRN) doses of the substituted medication. This will help to suppress breakthrough symptoms of withdrawal. Do this for the first 2-3 days only, and then discontinue PRN dosing. Be cautious and conservative on the amount of benzodiazepine given while being mindful that undertreatment is the main reason for treatment failure at this stage. Avoid using different types of benzodiazepines concurrently as it makes it difficult to identify the stabilizing dose and increase a patient’s risk of overdose. A rescue dose of intermediate-acting benzodiazepine (lorazepam) may be used in the setting of severe withdrawal symptoms or risk of impending seizure as a bridging dose until the long-acting medication takes effect. Do not use phenobarbital in combination with benzodiazepines in an outpatient setting. 4. Stabilize the patient on an adequate substitution dose (same dose on consecutive days without the need for regular PRN doses). This usually is accomplished within 1 week. 5. Gradually reduce the dose. The dose is decreased on a weekly to everyother-week basis, as in the simple taper model. The rate of discontinuation is 5-mg diazepam equivalents per week (or 12.5-mg chlordiazepoxide equivalents or 15-mg phenobarbital equivalents), as shown in Table 52-3, or 10% of the current (starting) dose per week. The first half of the taper usually is smoother, quicker, and less symptomatic than the latter half. 6. For the final 25%-35% of the taper, the rate, or dose reduction, should be slowed. This may be a good time to introduce ancillary medications such as gabapentin into the treatment regimen. If symptoms of withdrawal occur, hold the taper for 3-4 days to stabilize the patient, and then resume the process. Some patients may wish to accelerate the reduction. This is better tolerated early in the taper. Care should be taken not to push the taper too quickly. 7. Support the patient with short but frequent visits, as described above. Taper medication should be closely controlled by prescribing only enough medication for the time period until the next visit.

Phenobarbital Induction and Taper Protocol Based on the Sedative–Hypnotic Tolerance Test developed by Drs. Smith and

Wesson (40–42), this protocol is ideal when the degree of dependence is difficult to determine. Such a situation is common in high-dose, erratic-dose, illicit source, “polysubstance,” or alcohol plus sedative–hypnotic use. It is best done in a setting that offers 24-hour medical monitoring. Phenobarbital is used because of the adaptive changes that occur with chronic benzodiazepine use discussed previously. Also it boasts rapid onset of action, long half-life, and ease with which signs of toxicity can be monitored: 1. A 60-mg phenobarbital dose is given orally every 2 hours PRN CIWA-Ar > 15 for up to 48 hours. 2. Doses are held for signs of toxicity (intoxication), which develop in the following progression at increasing serum levels: fine lateral sustained nystagmus, coarse nystagmus, slurred speech, ataxia, and somnolence. Doses are held with the development of coarse nystagmus and slurred speech and subsequently resumed with the resolution of the signs of toxicity. 3. The patient is monitored hourly to ensure adequate dosing and to prevent oversedation. Ideally, a balance is achieved between the signs and symptoms of withdrawal and those of phenobarbital intoxication. 4. After 48 hours, the total amount of administered phenobarbital is divided by the number of days it was administered. This amount is the 24-hour stabilizing dose that was administered in the first 48 hours to stabilize the patient. 5. The taper is started after the first 48 hours of stabilization by reducing the stabilizing dose by 20%-30% every day for the first half of the taper and a gentler 10% every other day for the second half of the taper. 6. The total daily dose should be divided so that the largest dose is administered in the evening to help with sleep while avoiding sedation throughout the day.

Example of Phenobarbital Taper If the total 48-hour dose is 600 mg, then the 24-hour stabilizing dose is 300 mg. The initial taper dose would be 210-240 mg (correlate with clinical presentation to guide dose choice).

The taper may be extended or decreased depending on patient’s presentation. Patients often can be transferred from an inpatient setting to an intensive (medically monitored) outpatient program after they are stabilized and well established on the tapering portion of the protocol.

Combination Therapy Using Anticonvulsants and Phenobarbital While acute benzodiazepine withdrawal can be managed with a combination of anticonvulsants and phenobarbital in an inpatient setting, it is falling out of favor because of adverse effects of the anticonvulsants and increased risk of medication interactions. An example of such a protocol appears here: 1. Phenobarbital is begun with a loading dose of 60 mg orally every 4 hours for 4 or 5 doses. This is followed by a maintenance dose of 60 mg four times per day for 2 days and then 30 mg four times per day for 1 or 2 days. For elderly (over 60 years of age) or in compromised health, start with a

loading dose of 30 mg every 4 hours for 4-5 doses, followed by 30 mg four times per day for 3-4 days. 2. An anticonvulsant is started at the same time as the phenobarbital. Commonly used anticonvulsants are carbamazepine, sodium valproate/valproic acid, and gabapentin. Carbamazepine is started at 200 mg three times per day, sodium valproate/valproic acid is started at 250 mg three times per day, and gabapentin is started at 300 mg three times per day. All have similar efficacy. Gabapentin seems to have the lowest side effect profile. Anticonvulsants can be continued for 2-4 weeks after acute withdrawal management and then tapered; longer use of these agents could be considered on a case-by-case basis. Physical observation (sedation, rash) and laboratory monitoring (CBC, liver function tests [LFTs]) are indicated with use of these medications past several weeks. 3. Breakthrough withdrawal occurring in the first few days to 1 week can be effectively treated with a short course (2-3 days) of a long half-life benzodiazepine such as chlordiazepoxide (25 mg three times per day for 1 day, followed by 25 mg two times per day for 1 day, and then 25 mg one time on the third day). Breakthrough withdrawal occurring after the first week and usually when phenobarbital has stopped can be treated with a short course of low-dose phenobarbital (30-60 mg/d divided into 2-3 doses), which is then tapered over 5-7 days. Another point of concern is that phenobarbital and carbamazepine are both strongly associated with Stevens-Johnson syndrome and their concomitant use may markedly increase this risk.

Appropriate Clinical Setting Patients who have dependence on multiple substances (including sedative– hypnotics), mixed alcohol and other sedative–hypnotic use, high-dose sedative– hypnotic use, erratic behavior, incompatible/unreliable substance use histories, involvement with illicit sources, and extensive mental health issues are best served in an inpatient facility that offers 24-hour medical monitoring.

Adjunctive Measures

Withdrawal

Management

Anticonvulsants Since the 1980s, anticonvulsants have been studied and used to treat sedative– hypnotic withdrawal, especially benzodiazepine withdrawal. The use of anticonvulsants grew from the success of treating certain psychiatric disorders and the improved understanding of kindling mechanisms for withdrawal. Some anticonvulsants were also beneficial in treating alcohol withdrawal and cocaine intoxication. There appears to be no addiction potential with anticonvulsants, and this is a great advantage (89).

Carbamazepine Carbamazepine’s actions have been associated with the neurotransmitters serotonin, GABA, excitatory amino acids, and glutamate (89–92). It inhibits glutamate release. Adjunctive carbamazepine therapy is not widely used, although clinical protocols and patient selection for this method have been studied. Initial reports on small clinical trials using carbamazepine showed encouraging but mixed effectiveness and utility (59,93–97). Pages and Ries (98) reviewed further use of carbamazepine and found it to be an effective adjunct. Schweizer et al. (92) studied 40 patients with a history of difficulty discontinuing long-term therapeutic benzodiazepines. Significantly, more patients treated with carbamazepine were benzodiazepine-free at 5 weeks. Patients receiving carbamazepine (but not the clinicians evaluating them) reported a larger reduction in withdrawal severity compared with patients taking placebo. Ries et al. (94) and Pages and Ries (98) reported protocols for the use of carbamazepine: 600 mg/d (usually 200 mg three times per day) is used alone or in combination with a 3-day benzodiazepine taper. Chlordiazepoxide is useful because of its longer half-life and low potential for misuse. Phenobarbital can be added PRN to this protocol for breakthrough withdrawal symptoms. Carbamazepine is continued for a minimum of 2-3 weeks after the 3-day benzodiazepine taper is completed and can be tapered to monitor for return of withdrawal symptoms. Elderly patients who are discontinuing benzodiazepines have been treated successfully with carbamazepine at doses of 400-500 mg/d. Adverse consequences of carbamazepine use can include gastrointestinal upset, neutropenia, thrombocytopenia, and hyponatremia, necessitating initial and ongoing laboratory evaluation and monitoring. In pregnancy, it is a risk Category D and should be avoided during the first trimester because of the risk of neural tube defects.

Sodium Valproate Reports indicate that sodium valproate is effective in attenuating the benzodiazepine withdrawal syndrome. Valproate possesses GABAergic actions and anticonvulsant effects (99,100). It is believed to increase brain GABA concentrations by unknown mechanisms. Valproate also may suppress NMDA and reduce L-glutamate responses (92,99,101). Rickels et al. (102) found that although valproate did not reduce acute withdrawal severity, valproate-treated patients were 2.5 times more likely to be benzodiazepine-free at 5 weeks after taper, compared with a placebo group. Valproate doses of 250 mg three times per day (250 mg two times per day if older than age 60) can be used in combination with a 3-day benzodiazepine taper. Chlordiazepoxide is a useful choice because of its long half-life and low addictive potential. Calculate the equivalent chlordiazepoxide dose for the amount of current benzodiazepine being discontinued. Give one-half to twothirds of this dose spaced equally (divided in two to three doses) over the first day (24 hours), one-third spaced equally over the second day (second 24 hours), and 10%-20% spaced equally over the third day (third 24 hours). Phenobarbital can be used for breakthrough withdrawal symptoms. Valproate is continued for a minimum of 2-3 weeks after the 3-day benzodiazepine taper is completed. Longer treatment may improve the proportion of patients who remain benzodiazepine-free. Valproate can be tapered to monitor for return of withdrawal symptoms. Valproate has been used to treat anxiety. It has fewer side effects than carbamazepine. It can be used both inpatient and outpatient. For these reasons, further studies may strengthen the role of valproate in the treatment of benzodiazepine withdrawal. Side effects (including elevated LFTs, thrombocytopenia, bone marrow suppression, and pancreatitis), drug reactions (including rash and erythema multiforme), gastric upset, and behavioral changes require close monitoring. Like carbamazepine, it is a Category D drug in pregnancy, and its use in the first trimester is associated with increased risk of neural tube defects.

Gabapentin By binding to the alpha-2/delta subunit of voltage-sensitive calcium channels, gabapentin closes N and P/Q presynaptic calcium channels, diminishing excessive neuronal activity and neurotransmitter release. It is structurally related to GABA, but there are no known direct actions on GABA or its receptors. It is

useful as adjuvant therapy in alcohol and benzodiazepine withdrawal. Unlike carbamazepine and valproate, gabapentin is a pregnancy Category C medication. It still should be avoided during pregnancy but appears to be a safer option. Of note, however, its addictive potential in people with addiction has been recently recognized, which may limit some of its advantages. Gabapentin, topiramate, and lamotrigine have been tried in several small studies. Gabapentin seems to be interchangeable with carbamazepine and with sodium valproate/valproic acid. Lamotrigine is limited by its need for a slow buildup in dose. Most of the studies using these anticonvulsants involved patients with alcohol use disorder. More studies are needed (89,103–105).

Flumazenil Flumazenil is useful for complications of acute intoxication with benzodiazepines as discussed earlier in this chapter. Caution must be used as it is capable of causing marked withdrawal symptoms and seizures. Flumazenil is not useful as an adjunct to tapering. Because of its weak agonist properties, it may be useful to reduce cravings after the tapering is complete (106). Flumazenil’s antagonist properties may help prevent relapse, but no studies support this indication.

Propranolol Tyrer et al. (49) clearly demonstrated that propranolol alone does not affect the rate of successful benzodiazepine discontinuation or the incidence of withdrawal symptoms for discontinuation of chronic benzodiazepine use. However, propranolol treatment did diminish the severity of adrenergic signs and symptoms of withdrawal. Propranolol is not cross-tolerant with sedative– hypnotic medications and should not be used as the sole therapeutic agent in managing sedative–hypnotic withdrawal. Propranolol can be used, in doses of 60-120 mg/d, divided three or four times per day, as an adjunct to one of the aforementioned withdrawal methods, when additional control of autonomic signs and symptoms is deemed important. However, clinicians need to be mindful that propranolol treatment will diminish some of the very symptoms and signs that are monitored to determine substitution doses. One must be mindful of side effects such as weight gain, sedation, and depression.

Clonidine

Clonidine has been shown to be ineffective in treating benzodiazepine withdrawal. Doses sufficient to decrease serum levels of norepinephrine metabolites had minimal attenuating effect on the benzodiazepine withdrawal syndrome. One significant result of this study was the demonstration that increased norepinephrine activity plays a small role in the overall benzodiazepine withdrawal syndrome. In some cases when autonomic dysregulation persists after acute withdrawal, clonidine can be used to control symptoms in the post-acute withdrawal state.

Buspirone Buspirone is a nonbenzodiazepine anxiolytic medication that is not crosstolerant with benzodiazepines or other sedative–hypnotic medications. Schweizer and Rickels (107) and Ashton et al. (108) demonstrated that buspirone substitution in patients undergoing abrupt or gradual benzodiazepine discontinuation failed to protect against the symptoms of withdrawal.

Trazodone Trazodone is useful in the management of benzodiazepine withdrawal. Trazodone decreased anxiety in benzodiazepine-tapered patients (109). Trazodone improved patients’ ability to remain benzodiazepine-free after a 4week taper of the benzodiazepine. In one study, two-thirds of the patients treated with trazodone, compared with 31% of patients treated with placebo, were benzodiazepine-free at 5 weeks after taper (102). Trazodone can be used to improve sleep during benzodiazepine tapering and when benzodiazepine-free. Side effects may include dry mouth, morning hangover, drowsiness, dizziness, and priapism.

Mirtazapine Mirtazapine has been used in a similar way as trazodone and found to be useful (110).

Cognitive–Behavioral Therapy Two studies (111,112) demonstrate that, in patients with panic disorder, adding cognitive–behavioral therapy (CBT) to alprazolam discontinuation improved the rate of successful alprazolam discontinuation. Spiegel et al. (111) reported that patients in the combined taper and CBT groups had greater rates of abstinence

from alprazolam at 6 months than did those who underwent taper alone. A cognitive group approach improved attrition rates and long-term outcomes for benzodiazepine withdrawal (113). Oude Voshaar et al. (114) reported that adding cognitive–behavioral group therapy did not improve benzodiazepine discontinuation success. Patients must maintain abstinence from benzodiazepines in spite of recurrences of the symptoms of the disorder that led to benzodiazepine use. Benzodiazepine tapering must be completed before psychological treatment concludes. Cognitive–behavioral treatment can support the withdrawal taper and help with exacerbations of the initial disorder (115). Of note, it is important to consider psychosocial therapy for the underlying disorder that was the indication for the benzodiazepine in the first place.

Prolonged Benzodiazepine Withdrawal Some physicians report (40–42), and clinical experience confirms, that a small proportion of patients, after long-term benzodiazepine use, experience a prolonged syndrome in which withdrawal signs and symptoms persist for weeks to months after discontinuation. This prolonged withdrawal syndrome is noted for its irregular and unpredictable day-to-day course and qualitative and quantitative differences in symptoms from both the prebenzodiazepine use state and the acute withdrawal period. Patients with prolonged withdrawal often experience slowly abating, albeit characteristic, waxing and waning symptoms of insomnia, perceptual disturbances, tremor, sensory hypersensitivities, and anxiety. Smith and Wesson (40) propose that protracted symptoms reflect long-term receptor site adaptations. Higgitt and Fonagy (116) propose that a comprehensive etiological model of the prolonged syndrome must include a psychological component that can be explained through cognitive and behavioral models. They observe that many patients with persistent withdrawal symptoms resemble patients with somatization disorders. The patients often experience acute withdrawal more severely and may be “sensitized to anxiety.” In addition to a potential lack of effective coping mechanisms away from benzodiazepines, such patients often possess a perceptual or cognitive style that leads to apprehensiveness, body sensation amplification and mislabeling, and misinterpretation.

Management

Before entertaining the existence of a prolonged withdrawal syndrome, physicians must rule out psychiatric conditions. A distinguishing characteristic of protracted withdrawal from anxiety disorders is the gradual diminution and eventual resolution of symptoms with benzodiazepine withdrawal. Propranolol in doses of 10-20 mg four times per day often is helpful in attenuating anxiety or tremors. Extended use of anticonvulsants with eventual slow tapering should be considered. Gabapentin is well tolerated and helps relieve anxiety and insomnia. Start with 100-300 mg three times a day and increase dose every week depending on symptomatology. A higher dose in the evening to help with insomnia may be advised. Lower doses of sedating antidepressant medications—such as trazodone, amitriptyline, imipramine, or doxepin—are helpful in treating insomnia. Frequent clinical follow-up for education, supportive psychotherapy, and regular reassurance are strongly advised. Frequent reassessment of the working diagnosis is recommended.

COMMON TREATMENT ISSUES Treatment is indicated for nearly all patients with substance use disorders. Among persons with sedative–hypnotic dependence, treatment most often is indicated for those who use multiple substances, use high-doses, or patients in whom addiction is diagnosed. The support, education, and recovery training available in most addiction specialty treatment programs are valuable to many patients who are dependent on sedative–hypnotics. On the other hand, patients with long-term, therapeutic use problems should not be coerced to participate in specialty programs designed to treat substance use disorder, as they often feel out of place and unable to relate to their peers. Participation in specific components of treatment, tailored to each patient’s individual needs, can be helpful and nonthreatening. Patients who choose to participate in treatment often discover an immense source of support and encouragement, in addition to learning and practicing coping skills that facilitate drug discontinuation and abstinence.

Prevention The best prevention for licit (prescribed) benzodiazepine dependence is careful prescribing (85,86). In England, the Committee on the Review of Medicines reported in 1980 that the hypnotic effect of benzodiazepines diminishes after 3-

14 days and the anxiolytic effect diminishes after 4 months (20). A good understanding of the mental health disorders with anxiety symptoms and their psychological and pharmacological therapies is important. Knowledge of a patient’s risk factors for addiction, including his or her family’s substance use disorder history is also important. Benzodiazepines are rarely the first-line treatment for any of the anxiety disorders. CBT, group therapy, relaxation therapy, stress management, structured problem solving, selective serotonin reuptake inhibitors, tricyclic antidepressants, and buspirone are all potential options that should be employed as appropriate based on the level of severity. If used, benzodiazepines should be closely monitored for effectiveness and duration. A plan to reassess or taper the benzodiazepine when it is first given is wise. Reevaluate the need for the benzodiazepine when the initial indication has changed or the patient shows improvement (85,117). A benzodiazepine taper should be strongly considered in the long-term management of chronic anxiety with benzodiazepines even if it is only useful to determine whether continued treatment is required or not (78).

SUMMARY Sedative–hypnotics are among the most extensively prescribed medications in the United States. They are widely used and misused; hence, they are the second most frequently reported drug class to cause emergency department visits, surpassed only by opioids. They utilize the same biochemical and neurological pathways as alcohol, have similar dependence and withdrawal characteristics, and exhibit cross-tolerance. Intoxication is characterized by impaired motor activity and immediate memory impairment and may progress to stupor and coma. Toxicity associated with older nonbenzodiazepine medications is progressive and can ultimately lead to respiratory arrest or cardiovascular collapse, while benzodiazepines and Z-drugs do not cause death unless used in combination with other CNS depressants (such as alcohol or opioids). Their use can result in physical dependence and abrupt abstinence leads to a withdrawal syndrome that can be life-threatening. Benzodiazepine withdrawal syndromes are similar to that of alcohol. Benzodiazepine withdrawal is characterized by autonomic hyperactivity and can lead to seizures and death. Treatment of sedative-hypnotic withdrawal can be achieved by either gradual tapering of the drug or symptom-driven substitution with phenobarbital or a long-acting benzodiazepine. Other medications may have an ancillary role in treatment but are not indicated as monotherapy.

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CHAPTER 53

Management of Opioid Intoxication and Withdrawal Jeanette M. Tetrault and Patrick G. O’Connor

CHAPTER OUTLINE Introduction Opioid Intoxication and Overdose Opioid Withdrawal Conclusions

INTRODUCTION Opioids include substances that are derived directly from the opium poppy (such as morphine and codeine), the semisynthetic opioids (such as heroin), and the purely synthetic opioids (such as methadone and fentanyl). These compounds share several pharmacological effects, including sedation, respiratory depression, and analgesia, and common clinical features of intoxication and withdrawal. This chapter reviews the clinical features of opioid intoxication and withdrawal. Although all drugs in the class are associated with clinical withdrawal syndromes, those most commonly encountered in clinical practice include heroin, methadone, morphine, oxycodone, codeine, hydrocodone, and meperidine (1).

OPIOID OVERDOSE

INTOXICATION

AND

Clinical Picture The prevalence of opioid use in the United States continues to increase. According to the results of the National Survey on Drug Use and Health, among individuals 12 years of age or older, self-reported lifetime heroin use has increased from 1.2% in 2000 to 1.9% in 2015 (1). Similarly, there has been an increase in the lifetime nonmedical use of prescription opioids among individuals 12 years of age and older from 8.6% in 2000 to 13.6% in 2014. After 2014, there was a change in methodology of the National Survey of Drug Use making it challenging to make comparisons for certain questions (1,2). Opioid

intoxication and overdose may present in a variety of settings. Although mild-tomoderate intoxication, characterized by euphoria or sedation, usually is not life threatening, severe intoxication or overdose is a medical emergency that causes many preventable deaths and thus requires immediate attention (3). Opioid overdose is characterized by the classic signs of depressed mental status, decreased respiratory rate, decreased bowel sounds, and miotic pupils. In a retrospective analysis of consecutive cases of presumed opioid overdose in patients initially managed by emergency medical services personnel in an urban setting, 16% were either dead or in full cardiopulmonary arrest at the time of the initial emergency medical service evaluation (4). As the prevalence of opioid use has increased in the United States, the incidence of opioid overdose has increased as well. Among almost 48,000 substance related overdose deaths that occurred in the United States in 2014, 61% were due to opioids and opioid death rates increased by 15.6% from 2014 to 2015 (5). Additionally, for patients prescribed opioids for chronic, noncancer pain, overdose risk increases in a dose-dependent fashion. Of 9,940 patients receiving prescription opioids in a managed care organization from 1997 to 2005, 51 overdoses were noted, 6 of which were fatal. Compared to patients receiving 1 to 20 mg/d of morphine equivalents, those receiving 50 to 99 mg/d had a 3.7-fold increased risk of overdose, and those receiving 100 or more mg per day had an 8.9-fold increase in overdose risk (6). Accidental overdose may occur in a variety of settings. Of increasing concern are accidental overdoses occurring in several US cities where heroin or other substances are mixed with more potent opioids (eg, fentanyl) (7–10). Despite these increases, opioid overdose can be treated successfully, if patients present in a timely manner and general principles of overdose management (as well as specific therapies for opioid overdose) are employed. In a retrospective analysis in Finland, the survival-to-hospital discharge rate of cardiopulmonary arrest after heroin overdose (16%) was found to be similar to that of other poisonings (11%) (11). Nonfatal opioid overdose is an additional cause of significant morbidity, and the true prevalence may not be well understood because many nonfatal overdoses are not brought to medical attention (12). The prevalence of nonfatal overdose ranged from 10% to 69% as reported in recent literature (12). The factors associated with nonfatal opioid overdose include injection as the route of administration, sporadic heroin use, needing help with injection, prior overdose, and multiple drug use. The pharmacological actions responsible for opioid intoxication and overdose involve central nervous system (CNS) mu, kappa, and delta opioid

receptors (13,14) that also interact with endogenous substances, including the endorphins (15). Of primary concern in the management of overdose are interactions with mu receptors, which can lead to sedation and respiratory depression. The mechanism of respiratory depression with opioids presumably is direct suppression of respiratory centers in the brain stem and medulla (14). The level of tolerance to opioids can have a significant effect on an individual’s risk of opioid overdose. In addition, tolerance to respiratory depression may be slower than tolerance to euphoric effects, thus explaining why overdose occurs so often, even among “experienced” opioid users (16,17). Patients who have undergone medically supervised withdrawal or those who have experienced intentional or unintentional abstinence from opioids for any reason (eg, incarceration) may be particularly susceptible to death from heroin overdose (18–20). Nonfatal overdose is also common among patients undergoing medically supervised withdrawal—occurring in 27% of a cohort of 201 patients with opioid use disorder patients followed for 2 years after withdrawal. Among this group, prior overdose attempts and depressive symptoms were risk factors for nonfatal overdose (21). Although injecting opioids may be the route of administration associated with the highest risk of overdose, increasingly popular noninjection routes are associated with significant risk as well (22). Additionally, case reports of fatal opioid overdose among opioid-naive patients who use cocaine have been published whereby these patients have unknowingly used pure fentanyl instead of cocaine (7). Persons who administer opioids of potency that they are unaccustomed to may experience opioid overdose. Finally, patients who administer opioids in addition to other substances known to exacerbate the opioid effect (eg, benzodiazepines, sedatives) may be more prone to overdose.

Diagnosis As with most clinical challenges, evaluation of opioid intoxication begins with the collection of patient data through a detailed history and physical examination (Table 53-1). An important issue in the patient with moderate to severe respiratory depression is the immediate institution of pharmacological and supportive therapies to ameliorate morbidity and prevent mortality.

TABLE 53-1 Diagnosis of Opioid Overdose

ause multiple sources of information (family, hospital recrods,etc) to obtain complete history.

When available, historical information can be obtained concerning opioid use (including the specific drug, amount, and time of last use) either directly from the patient or from friends and family members; this information can supplement available hospital records. In addition to opioids, it is important to ask about use of other drugs or alcohol because of the likelihood use of more than one drug (23–25). Identification of multiple drug use has important implications for patient management; for example, identification of the frequent co-occurrence of opioid and benzodiazepine overdose may indicate the need for additional therapy directed at reversing the benzodiazepine component of the overdose with flumazenil (26,27). This also is true in cases of suspected opioid overdose in children who are at high risk of co-occurring opioid and benzodiazepine toxicity and who thus may require management of both on presentation for medical care (28). Multiple drug overdose often accounts for significant morbidity and mortality. More than half of all drug overdose deaths result from multiple drug overdose with opioids, alcohol, and cocaine (29,30). Physical examination of the opioid-intoxicated patient may find CNS and respiratory depression, as well as miosis and direct evidence of drug use, such as

needle tracks or soft tissue infection. The heroin overdose syndrome, described as a triad of altered mental status, depressed respiration, and miotic pupils, has a sensitivity of 92% and a specificity of 76% for the diagnosis of heroin overdose (3). Additional evidence supports the use of clinical characteristics in the diagnosis of heroin overdose. In a study of 730 patients in Los Angeles receiving naloxone for suspected heroin overdose, the presence of one of the three clinical signs—respirations 92%, have a respiratory rate >10 breaths/min and 35.0°C and 50 beats/min and 102°F orally) is a marker for poor prognosis and should be

managed aggressively to avert hyperthermic crisis (as by cold water sponging, cooling blankets, ice packs, ice water gastric lavage, or cold peritoneal lavage) (5,51). Untreated hyperthermia may result in rhabdomyolysis and renal failure. Intravenous benzodiazepines (diazepam 5-10 mg or lorazepam 2-10 mg over 2 minutes, repeated as needed) are recommended to control seizures stemming from stimulant intoxication (48,51). Fosphenytoin (15-20 mg/kg at 100-150 mg/min) or phenobarbital (15-20 mg/kg over 20 minutes) also can be used. However, the latter may cause hypotension or prolonged sedation. Excretion of amphetamine can be increased by acidifying the urine to pH < 6.6 (as with 500 mg of oral ammonium chloride every 3-4 hours), which inhibits renal reabsorption of amphetamine (52). The actual clinical usefulness of this maneuver is uncertain (16). Acidification is contraindicated in the presence of myoglobinuria, if renal or hepatic function is abnormal, or in overdose situations, when plasma acidification may compromise cardiovascular function (31).

Stimulant Withdrawal Abrupt cessation of stimulant use is associated with depression, anxiety, fatigue, difficulty concentrating, anergia, anhedonia, increased drug craving, increased appetite, hypersomnolence, and increased dreaming (because of increased REM sleep) (53–55). The initial period of intense symptoms is commonly termed the “crash,” but most symptoms are mild and self-limited, resolving within 1-2 weeks without treatment. Hospitalization for stimulant withdrawal is rarely indicated on medical grounds and has not been shown to improve the short-term outcome for stimulant addiction (56,57). Pharmacological treatment has focused more on long-term treatment of addiction than on short-term treatment of acute withdrawal (58,59). Most clinical trials that used medication during the early withdrawal period have continued to use such medication for at least several weeks, with the additional goal of treating the addiction itself.

Medical Effects of Stimulant Withdrawal The 1st week of stimulant withdrawal has been associated with myocardial ischemia (60), possibly because of coronary vasospasm. Other medical effects of stimulant withdrawal are relatively minor, including nonspecific musculoskeletal pain, tremors, chills, and involuntary motor movement (61). These rarely require

specific medical treatment.

Management of Stimulant Withdrawal The stimulant withdrawal syndrome has been hypothesized to be the result of decreased levels of brain dopamine activity resulting from chronic stimulant exposure. This so-called “dopamine deficiency” hypothesis of withdrawal has not been consistently supported by clinical studies (62–64) but has generated the use of dopamine agonists to treat cocaine withdrawal, most commonly bromocriptine and amantadine. However, no medication has been shown to be consistently effective in controlled clinical trials (65) or is any medication approved for the treatment of stimulant withdrawal by any national regulatory authority. Administration of a cross-tolerant or similarly acting stimulant has not been systematically evaluated as a short-term treatment for stimulant withdrawal (22). No controlled clinical trial has directly compared the benefits of medication versus a supportive milieu. Two small controlled clinical trials found modafinil (100-200 mg daily over 7 days) not different from placebo (66) and electrical or auricular acupuncture (thrice weekly over 4 weeks) significantly more effective than no treatment (there was no sham control) (67). Symptoms of stimulant withdrawal are best treated supportively with rest, exercise, and a healthy diet (5,22). Short-acting benzodiazepines such as lorazepam may be helpful in selected patients who develop agitation or sleep disturbance. Severe (suicidal ideation) or persistent (>2-3 weeks) depression may require antidepressant treatment (5) and psychiatric admission. The risk of relapse is high during the early withdrawal period, in part because drug craving is easily triggered by encounters with drug-associated stimuli. This issue is better addressed by psychosocial treatment, such as supportive therapy, cognitive– behavioral therapy, relapse prevention, and contingency management, rather than by medication.

HALLUCINOGENS Hallucinogen Intoxication Hallucinogens have in common the ability to change or distort sensory perceptions in a clear sensorium. Most hallucinogens fall into one of two chemical groups (see Chapter 14). Indolealkylamine hallucinogens (including

LSD, psilocybin, or N,N-dimethyltryptamine) are structurally related to serotonin; phenylethylamine hallucinogens (including 3,4,5trimethoxyphenethylamine [mescaline], 3,5-dimethoxy-4-methylamphetamine [DOM, STP]) are structurally related to norepinephrine (68–70). Both indolealkylamine and phenylethylamine hallucinogens generate psychedelic (LSD-like) experiences and thus are often categorized together. In contrast, 3,4methylenedioxymethamphetamine (MDMA, “ecstasy”) has characteristics of both a hallucinogen and a stimulant and is considered separately (see also Chapter 14). PCP and its close analog ketamine are anesthetics that are used for their dissociative and euphoric effects. Both MDMA and PCP are considered in their own section below (see also Chapter 15).

Psychological and Behavioral Effects of Hallucinogen Intoxication The acute psychological and behavioral effects of hallucinogen intoxication are summarized in Table 54-3. The subjective experience is influenced greatly by set and setting, that is, the expectations and personality of the person who uses hallucinogens, coupled with the environmental and social conditions of use. Mood can vary from euphoria and feelings of spiritual insight to depression, anxiety, and terror (71,72). Perception usually is intensified and distorted, with alterations in the sense of time, space, and body boundaries. While illusions (visual and auditory distortions of perception) are common, true hallucinations (perceptions that do not have any basis in reality) are not. Synesthesia, a blending of the senses wherein colors are heard and sounds are seen, is a common perceptual distortion. Cognitive function may range from clarity to confusion and disorientation, although reality testing usually remains intact. Acute LSD intoxication may last up to 12 hours, with little evidence of acute tolerance (73).

TABLE 54-3 Acute Psychological and Behavioral Effects of Intoxication With LSD, Marijuana, PCP, or MDMA

Relative weighting: X = mild; XX = moderate; XXX = marked; /= common/rare; ? = insufficient research. MDMA, 3,4-methylenedioxymethamphetamine. Sources: Brust, JCM. Neurologic complications of illicit drug abuse. Continuum (Minneap Minn). 2014;20:642-656; Frecska E, Luna LE. The adverse effects of hallucinogens from intramural perspective. Neuropsychopharmacol Hung. 2006;8:189-200; Abraham HD, Aldridge AM, Gogia P. The psychopharmacology of hallucinogens. Neuropsychopharmacology. 1996;14:285-298. Refs. (69–71).

A “bad trip” usually takes the form of an anxiety attack or panic reaction, with the person feeling out of control (71). An experience of depersonalization may precipitate the fear of losing one’s mind permanently. Panic reactions are more common in those who have limited experience with hallucinogens, but previous “positive” experiences provide no protection against an adverse reaction (74). While higher doses are associated with more intense experiences, adverse reactions are less a function of dose than of context and environment. Hallucinogens may trigger a transient psychosis even in persons who are psychologically normal; however, a true psychotic episode is rare. Hallucinogeninduced psychosis may resemble acute paranoid schizophrenia. The two usually can be distinguished because patients with schizophrenia tend to have auditory (rather than visual) hallucinations and a history of prior mental illness. Persons who use hallucinogens, unlike patients with schizophrenia, usually retain at least partial insight that their symptoms are drug related. However, hallucinogen use can trigger or exacerbate psychotic disorders or result in persisting or delayed symptoms (73,74). The specific risk factors for these adverse outcomes are poorly understood. Hallucinogen ingestion may result in an acute toxic delirium that is characterized by delusions, hallucinations, agitation, confusion, paranoia, and inadvertent suicide attempts (eg, attempts to fly or perform other impossible activities).

Medical Effects of Hallucinogen Intoxication Acute medical complications of hallucinogen intoxication are summarized in Table 54-4. Sympathomimetic effects are common, particularly pupillary dilation, hyperreflexia, piloerection, tachycardia, and increases in blood pressure. Dizziness, paresthesias, headache, nausea, or tremor may occur. Body temperature should be monitored and any elevation treated promptly (75). Dry skin, increased muscle tone, agitation, and seizures are warning signs of a potential hyperthermic crisis. Patients may not respond to anticonvulsant medication until body temperature is lowered. Complications that require treatment are rare in the absence of overdose (76,77).

TABLE 54-4 Acute Medical Complications of Intoxication with LSD, MDMA, Marijuana, or PCP

MDMA, 3,4-methylenedioxymethamphetamine; HR, heart rate; BP, blood pressure. Sources: Ghuran A, Nolan J. Recreational drug misuse: issues for the cardiologist. Heart. 2000;83:627633; Brust JCM. Neurologic complications of illicit drug abuse. Continuum (Minneap Minn).

2014;20:642-656; Frecska E, Luna LE. The adverse effects of hallucinogens from intramural perspective. Neuropsychopharmacol Hung. 2006;8:189-200; Kalant H. The pharmacology and toxicology of “ecstasy” (MDMA) and related drugs. Can Med Assoc J. 2001;165(7):917-928; Schuckit MA. Drug and alcohol abuse. A Clinical Guide to Diagnosis and Treatment. 6th ed. New York: Springer, 2006; Selden BS, Clark RF, Curry SC. Marijuana. Emerg Med Clin North Am. 1990;8:527-539. See Refs. (75,76).

Oral LSD is rapidly absorbed, so that ipecac-induced vomiting or gastric lavage usually is not helpful and may exacerbate the patient’s psychological distress. There is no evidence that LSD binds to charcoal. Gastric lavage may be useful in psilocybin ingestion or when there is doubt as to the identity of the ingested mushrooms (78).

Management of Hallucinogen Intoxication Initial treatment is supportive. The patient should be placed in a quiet environment with minimal sensory stimulation but should be observed because of the risk of unintended self-injury (as the result of delusions or hallucinations) or of suicide (as the result of depression). The presence of a familiar person usually is comforting. Unless the patient presents in an acutely agitated or threatening state, physical restraints are contraindicated because they may exacerbate anxiety and increase the risk of rhabdomyolysis associated with muscle rigidity or spasms. The use of “gentle restraints” in combination with muscle massage and individualized counseling may be helpful (77). The “talk down” or reassurance technique may be helpful. The clinician, in a concerned and nonjudgmental manner, discusses the patient’s anxiety reaction, stressing that the drug’s effects are temporary and that the patient will recover completely. For patients who do not respond to reassurance alone, oral benzodiazepines such as lorazepam (1-2 mg) or diazepam (10-30 mg) are the drugs of choice (68). When oral medication is too slow, or the patient will not take oral medication, intramuscular lorazepam (2 mg, repeated hourly as needed) may be effective. If benzodiazepines are insufficient, a high-potency antipsychotic such as haloperidol (0.25-10 mg per dose) may be needed. The role of secondgeneration antipsychotics in this situation remains unclear, but 5-HT2A receptor antagonism may be a useful property (68–70). Phenothiazines should be avoided because they are associated with poor outcomes (77) and may exacerbate unsuspected anticholinergic poisoning. Patients usually recover sufficiently after several hours and may be released into the care of a responsible relative or friend. If psychosis does not resolve

within 1 or 2 days, ingestion of a longer-acting drug such as PCP or DOM should be suspected. Symptoms that persist beyond a few days raise the strong likelihood of a preexisting or concurrent psychiatric or neurological condition. Psychiatric problems that last more than a month probably are related to preexisting psychopathology. Treatment for hallucinogen-induced delirium generally follows the guidelines for simple intoxication: isolate the patient, and minimize sensory input until effects of the drug have worn off. Reassurance that the delirium will abate as the drug is metabolized also may be helpful. Pharmacological treatment is not necessary in most cases and may confuse the clinical picture. If medication is needed, neuroleptic agents such as haloperidol (0.25-10 mg per dose), risperidone (0.25-4 mg per dose), or olanzapine (1.25-20 mg per dose) may be useful in attenuating agitation.

Hallucinogen Withdrawal Withdrawal symptoms, including fatigue, irritability, and anhedonia, are reported by about 10% of persons who use hallucinogens (76). There is no evidence to suggest a clinically significant hallucinogen withdrawal syndrome (68,79), and such a syndrome is not recognized in the DSM-5 (80). The rapid development of tolerance (within 3-4 days) may explain in part why use of LSD-like drugs generally is intermittent. There is no role for medication in the treatment of hallucinogen withdrawal. Some persons who use hallucinogens describe experiencing flashbacks, vivid memories, or brief recurrences of sensory distortions reminiscent of intoxication, during periods of sobriety. Flashbacks can occur spontaneously long after cessation of use and thus are not truly a withdrawal syndrome. In the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, 5th ed. (DSM-5), these patients are diagnosed as “hallucinogen persisting perception disorder” (73,74). Initiation of selective serotonin reuptake inhibitors (SSRIs) or neuroleptics is associated with recurrences of flashbacks in at-risk individuals (73,81). Supportive measures, as well as the symptom-based pharmacological interventions prescribed to manage hallucinogen intoxication, may be effective in managing such symptoms.

MARIJUANA

Marijuana Intoxication The major psychological and physiological effects of marijuana are mediated by the interaction of delta-9-tetrahydrocannabinol (THC) , the primary psychoactive compound in the Cannabis plant (82) with specific cannabinoid (CB1) receptors on nerve cells (83–85), the regional distribution of which in the human brain is consistent with the known effects of marijuana. Other cannabinoids found in marijuana (eg, cannabidiol, cannabinol) do not produce these typical marijuana effects (82). In animal and human studies, acute THC effects are reduced or blocked by CB1 receptor antagonists (86).

Psychological and Behavioral Effects of Marijuana Intoxication The initial—usually desired—psychological effects of marijuana intoxication include relaxation, euphoria, slowed time perception, altered (often intensified) sensory perception, increased awareness of the environment, and increased appetite (87). Undesired effects may include impaired concentration, anterograde amnesia, and motor incoordination (87,88). As with hallucinogens, psychological set and social setting and prior experience with the drug can substantially influence the quality of the experience. Higher doses, repeated use, or a stressful setting is associated with adverse effects such as hypervigilance, anxiety, paranoia, derealization and depersonalization (commonly associated with altered time sense), acute panic (associated with anxiety), illusions or hallucinations (usually auditory or visual), psychosis, or delirium (87,88). Acute marijuana-associated psychosis can be difficult to distinguish from schizophrenic psychosis other than by its transient time course (89). Marijuanaassociated psychosis may be more likely to exhibit derealization/depersonalization experiences and visual, rather than auditory, hallucinations (90). Preexisting psychopathology increases the risk of adverse events such as panic attack or psychosis (94). Table 54-3 summarizes the acute adverse psychological effects of marijuana intoxication. Oral ingestion of marijuana can produce the same adverse reactions as does smoking, including psychosis (91–94).

Medical Effects of Marijuana Intoxication The acute physiological effects of oral or smoked marijuana intoxication include conjunctival injection (“red eye”) due to vasodilation, tachycardia (sometimes

with palpitations), orthostatic hypotension (sometimes resulting in syncope), and dry mouth (see Table 54-4). Neurological signs include poor motor coordination, head jerks, and impairment of smooth pursuit eye movements (95). These generally are mild, are self-limiting, and do not require medical treatment. There are no well-established cases of human fatalities from exclusive marijuana overdose (88), although one prospective case series found an association between recent marijuana use and myocardial infarction and an increased risk of subsequent death (96). Marijuana smoking has been associated with atrial fibrillation (97,98). Intravenous use of marijuana, although rare, can be associated with cardiovascular shock and renal failure (99).

Management of Marijuana Intoxication Adverse effects of marijuana intoxication tend to be self-limited and often can be managed without medication. The patient should be kept in a quiet environment and offered supportive reassurance. If immediate pharmacological intervention is needed to control severe agitation or anxiety, benzodiazepines are preferred to antipsychotics, although there are no controlled studies to confirm this. Psychosis usually responds to low doses of second-generation antipsychotics. No medication is approved by the U.S. FDA (or any other national regulatory authority) for the treatment of marijuana intoxication (100). The selective cannabinoid CB1 receptor antagonist/inverse agonist rimonabant (developed for weight loss) blocked the acute psychological and cardiovascular effects of smoked marijuana in human laboratory studies (86). However, rimonabant and several similar medications were withdrawn from the market and from clinical development in 2008 because of psychiatric side effects. Small clinical trials suggest that propranolol (120 mg orally) may reduce some of the subjective and cardiovascular effects of acute marijuana intoxication (101) and that both first- and second-generation antipsychotics are effective in relieving marijuana-induced psychosis (102,103).

Marijuana Withdrawal Acute marijuana withdrawal is reported by up to one-third of those with heavy marijuana use in the community and more than half of those seeking treatment for marijuana (DSM IV) dependence (104) and is a recognized clinical syndrome in DSM-5 (80). Symptoms are primarily psychological, including irritability, anxiety, depression, restlessness, anorexia, insomnia, and disturbed sleep (105). Much less common are physical symptoms such as gastrointestinal

distress, diaphoresis, chills, nausea, shakiness, muscle twitches, and increased blood pressure (106). The syndrome is usually mild, comparable to tobacco withdrawal (107), and rarely needs medical attention but may impair some normal activities of daily life. It may warrant clinical attention in the treatment of cannabis use disorders because withdrawal symptoms can serve as negative reinforcement for relapse among those trying to maintain abstinence (105).

Management of Marijuana Withdrawal Marijuana withdrawal rarely requires treatment for intrinsic medical or psychiatric reasons, although treatment might be warranted in some cases to reduce the risk of relapse in persons trying to abstain while experiencing distressing withdrawal symptoms. No medication is approved by the U.S. FDA (or any national regulatory authority) for the treatment of marijuana withdrawal (100). In controlled clinical trials involving treatment-seeking adults with moderate–severe cannabis use disorder, dronabinol (oral synthetic THC, 30, 40, or 60 mg daily) (109,110), gabapentin (1200 mg daily in divided doses) (108), and nabiximols (1:1 mixture of THC + cannabidiol as a sublingual spray, not available in the United States) (111) significantly reduced marijuana withdrawal symptoms, although only gabapentin significantly reduced marijuana use. For sleep disturbance associated with marijuana withdrawal, small clinical trials suggest that zolpidem (12.5 mg extended release at bedtime) or nitrazepam (10 mg at bedtime) may be helpful (100).

DISSOCIATIVE ANESTHETICS Phencyclidine, Ketamine, Dextromethorphan Intoxication

and

PCP and its molecular analog ketamine are dissociative anesthetics (112,113); DXM is widely available as an antitussive in over-the-counter cough and cold medicines (114). The chemical agents in this class are relatively old, with PCP first synthesized just under 90 years ago and both ketamine and DXM ~50 years ago (115). Of the three, ketamine has received considerable attention in recent years because of its apparent ability to rapidly treat unipolar and bipolar depression (116) and various pain syndromes (117). There is a rich literature for the misuse of these three dissociative agents, and new psychoactive analogs

frequently appear on the illicit drug market (113). Both PCP and ketamine are considered controlled drugs in the United States; PCP is a Schedule II and ketamine is a Schedule III drug (118). The related drug DXM is not controlled and is widely available as an ingredient in over 100 different over-the-counter cough and cold medicines (119). At the recommended antitussive dose of 15-30 mg every 6-8 hours, adverse reactions are rare. However, about 5%-10% of those of white European ethnicity are unable to demethylate DXM to dextrorphan (an active metabolite) because of a deficit in the liver cytochrome P450 CYP2D6 isoenzyme. Thus, in the context of megadose use of DXM, this subset of individuals is at increased risk of toxicity from an acute excess in DXM levels (119). The main effects of PCP and ketamine are mediated by their action as noncompetitive antagonists of the NMDA glutamate excitatory amino acid neurotransmitter receptor (112,113). In addition, direct effects on other neurotransmitter systems (such as dopamine) may occur at high doses (see Chapter 15). In addition to NMDA antagonism, DXM has activity at the sigma receptor, which likely contributes to its therapeutic effects as a cough suppressant.

Psychological and Behavioral Effects of Dissociative Anesthetic Intoxication Dissociative anesthetics produce a range of intoxicated states that can be grouped into three stages: stage I, conscious, with psychological effects but (at most) mild physiological effects; stage II, stuporous or in a light coma yet responsive to pain; and stage III, comatose and unresponsive to pain. Table 54-3 summarizes the acute psychological and behavioral effects of PCP intoxication and overdose. The time course of psychological effects is highly variable and unpredictable, so that even a recovering patient should be kept under observation until all symptoms have resolved (typically at least 12 hours) (120,121). Patients may “emerge” from one stage of intoxication to the next; that is, a stuporous or comatose patient in stage II or III may enter stage I and become agitated and delirious (120,121). Similarly, a conscious patient in stage I may suddenly become comatose. The entire clinical episode may require up to 6 weeks to resolve. The psychiatric manifestations of stage I intoxication can resemble a variety of psychiatric syndromes, making differential diagnosis difficult in the absence of toxicology results or a history of recent PCP, ketamine, or DXM intake.

Common syndromes seen in treatment settings include delirium, psychosis without delirium, catatonia, hypomania with euphoria, and depression with lethargy. Agitated or bizarre behavior, with increased risk of violence, can occur with any psychiatric presentation (120–122). Because of the analgesic effect of PCP, patients may not report the existence of even serious injuries (which may be self-inflicted). Clinically significant psychological and behavioral effects of DXM begin to occur at approximately five times the therapeutic dose (119). These effects can be grouped into four dose-dependent plateaus (Table 54-5).

TABLE 54-5 Psychological and Behavioral Effects of DXM Intoxication

Adapted from Schwartz RH. Adolescent abuse of dextromethorphan. Clin Pediatr. 2005;44(7):565-568.

Medical Effects of Dissociative Anesthetic Intoxication Intoxication at the mild stage I desired by persons using dissociative anesthetic substances is associated with few serious medical complications (see Table 544). Common medical effects at this stage include nystagmus (especially horizontal), tachycardia, increased blood pressure, ataxia, dysarthria, numbness, increased salivation, and hyperreflexia. Higher stages are associated with severe medical effects, including hypertension, stroke, cardiac failure, seizures, rhabdomyolysis, acute renal failure, coma, and death (27). The acute effects of ketamine tend to be less severe and of shorter duration than those of PCP, possibly due to its shorter half-life (116). Nystagmus occurs less often than with PCP (116).

Management of Psychological and Behavioral Effects of Dissociative Anesthetic Intoxication

Treatment of intoxication with dissociative anesthetics is largely supportive and aimed at controlling or reversing specific signs and symptoms (123). No clinically useful antagonist is yet available. The anticonvulsant lamotrigine (300 mg daily), which inhibits glutamate release, reduced the psychological and cognitive effects of ketamine in a small experimental trial (124). Mild stage I intoxication is best treated without medication. The patient should be isolated in a quiet room with unobtrusive observation and minimal external stimuli. Frequent or intrusive contact or aggressive medical intervention may worsen the situation and should be avoided. Reassuring, reality-oriented communication (“talking down”) rarely works with such patients (68). Urine acidification and diuretics may increase renal clearance of PCP but are of doubtful clinical utility at this level of intoxication and may exacerbate myoglobinuric renal failure (27,122). Benzodiazepines should be used if medication is needed to control severe anxiety, agitation, or psychotic behavior (27), although they may delay renal clearance of PCP at high doses (122). If benzodiazepines are insufficient to control psychosis, high-potency firstgeneration antipsychotics, such as haloperidol or droperidol, or secondgeneration antipsychotics, such as risperidone or olanzapine, may be used (125,126). They are less likely than other antipsychotics to produce anticholinergic or cardiovascular side effects that may exacerbate PCP’s own anticholinergic and cardiovascular effects. No clinical trials have directly compared the efficacy and safety of first- versus second-generation antipsychotics or of benzodiazepines versus antipsychotics.

Management of Medical Effects of Dissociative Anesthetic Intoxication The mild medical effects commonly associated with stage I intoxication usually do not need specific medical treatment. Tachycardia and hypertension can be treated with adrenergic blockers such as labetalol or calcium channel blockers such as verapamil, although there are no controlled trials to substantiate their efficacy. Severe hypertension can be treated with IV nitroprusside (27). Stage II and III intoxications are medical emergencies that require treatment in a comprehensive medical setting to maintain life-support functions until the drug has been eliminated from the body (118). Tables 54-6 and 54-7 summarize medical treatment for acute PCP intoxication. In this context, increasing the renal clearance of PCP with forced diuresis and urine acidification (pH < 5) may

be helpful (68), although this may exacerbate myoglobinuric renal failure (27). This can be done by administering ammonium chloride—2.75 mEq/kg in 60 mL of saline every 6 hours through a nasogastric tube—and 2 g of IV ascorbic acid in 500 mL of IV fluid every 6 hours (128). IM ascorbic acid also has been used successfully (128). Caution should be exercised to avoid causing metabolic acidosis, especially in the presence of drugs such as barbiturates and salicylates, whose renal clearance is delayed by acidification. Activated charcoal may be helpful, but induced vomiting or gastric lavage is not (27,127,128). Dialysis is not helpful because these agents have a large volume of distribution.

TABLE 54-6 Procedures for Managing Acute PCP Intoxication

From Milhorn TH. Diagnosis and management of phencyclidine intoxication. Am Fam Phys. 1991;43(4):1293-1302.

TABLE 54-7 Medications for Treating Acute PCP Intoxication

From Milhorn TH. Diagnosis and management of phencyclidine intoxication. Am Fam Phys. 1991;43(4):1293-1302.

DXM toxicity may result from the other ingredients found in cough or cold preparations (eg, acetaminophen, pseudoephedrine, phenylephrine, guaifenesin, antihistamines) (119). The evaluation and treatment of patients with suspected DXM overdose must attend to the possibility of acetaminophen or other concomitant toxicities.

Dissociative Anesthetic Withdrawal Although a dissociative anesthetic withdrawal syndrome is not recognized in the DSM-5 (80), about one-fourth of persons using PCP report withdrawal symptoms (121), including depression, anxiety, irritability, hypersomnolence, diaphoresis, and tremor. It is not clear to what extent these represent a true withdrawal syndrome. DXM withdrawal has been associated with craving, dysphoria, and insomnia (120). Tricyclic antidepressants such as desipramine may reduce the psychological symptoms associated with discontinuation of PCP use, but there is no evidence that such treatment improves the outcome of PCP addiction (129). The efficacy of SSRIs, which would be safer in this context, is unknown.

Prolonged Psychiatric Sequelae Hallucinogens and dissociative anesthetics (PCP and ketamine) have the

potential to trigger psychiatric sequelae that last beyond the period of acute intoxication, including prolonged states of anxiety, depression, psychosis, and cognitive dysfunction. The risk of a prolonged psychiatric reaction appears to depend on several factors: the patient’s premorbid psychopathology, the number of prior exposures to the drug, and past use of multiple drugs (68,74). Prolonged reactions occasionally are reported in apparently well-adjusted individuals with no obvious risk factors. Prolonged psychotic reactions to PCP are almost always associated with premorbid psychopathology (126). Treatment of prolonged anxiety or depression usually is psychosocial but may involve medication if symptoms become sufficiently severe. Treatment of prolonged psychosis essentially follows guidelines for treatment of chronic functional psychosis. Patients may present with wide-ranging symptomatology: apathy, insomnia, hypomania, dissociative states, formal thought disorder, hallucinations, delusions, and paranoia. An observation period of at least several days with no or minimal medication (such as sedatives) is helpful to ensure an accurate diagnosis. The term “flashback” (hallucinogen persisting perception disorder in the DSM-5) has been given to brief episodes (often lasting a few seconds) in which perceptual aspects of a previous hallucinogenic drug experience are unexpectedly reexperienced after acute intoxication has resolved. Flashbacks are associated principally with LSD, although they can occur after use of other hallucinogens, MDMA, PCP, and, occasionally, marijuana (74). Flashbacks can precipitate considerable anxiety, particularly if the original drug experience had negative overtones. Reexperience of perceptual effects may be accompanied by somatic and emotional components of the original experience. Flashbacks may occur spontaneously or be triggered by stress, exercise, another drug (such as marijuana), or a situation reminiscent of the original drug experience. Flashbacks usually are brief and self-limiting. Treatment may involve no more than alleviating anxiety with supportive reassurance. Over time, flashbacks tend to decrease in frequency, duration, and intensity, as long as no further hallucinogens are taken (68). There have been no clinical trials of pharmacological treatment for flashbacks (74). Benzodiazepines are helpful in treating secondary anxiety. Small case series suggest that clonazepam, clonidine, and haloperidol may be helpful, whereas case reports suggest that phenothiazines, risperidone, and SSRIs may worsen the condition. Prolonged psychiatric sequelae also include dissociative drug-induced

cognitive deficits and depressed mood. For example, a number of studies have consistently demonstrated ketamine-induced cognitive dysfunction (129–133); depressed mood has also been identified in persons with active ketamine use (132,133). Conversely, one study found no compelling evidence of long-term ketamine-induced changes in cognitive function (135), while another (136) proposed that a lower level of education in persons who use ketamine contributed to the apparent ketamine-induced cognitive impairment. A recent study of 100 persons with current or past ketamine use in Hong Kong (135), which controlled for level of education, demonstrated deficits in mental and motor speed, visual and verbal memory, and executive function in persons with current (N = 49) but not with past use (no use for the past 30 days, N = 51) (135). Significant increases in depression (Beck Depression Inventory) were found in 72% of the persons with current ketamine use (135). The above studies collectively suggest that repeated ketamine use produces cognitive deficits as well as depressed mood in the majority of persons actively using ketamine, though not in those who had prior use (136); the issue of reversibility remains unclear. Recent neuroimaging studies of persons chronically using ketamine found reduced frontal gray matter volume (137) and bilateral frontal and left temporoparietal white matter abnormalities (138).

INHALANTS Inhalant Intoxication Inhalants are a chemically heterogeneous group of volatile hydrocarbons (found in glue, fuel, paint, aerosol propellant, and other products) that can be inhaled for psychoactive effect (139,140). Inhalant intoxication produces initial euphoria or “rush,” followed by lightheadedness, excitability, and perceptual changes (139,140). Significant mood changes or cognitive impairment is rare. Higher doses or more prolonged exposure may cause dizziness, slurred speech, and motor incoordination, followed by drowsiness and headache. Intoxicated persons rarely seek medical attention, in part because exposure tends to be self-limited and the duration of effect from a single exposure is usually only a few minutes. Even a single episode of inhalant use can result in sudden death (141,142). Inhalant-induced brain neurotoxicity (143,144), especially to the white matter (145), as well as kidney, heart, and nerve damage (146,147), may complicate the clinical presentation of acute inhalant intoxication.

There is no specific treatment for inhalant intoxication (148). The patient should be assessed, stabilized, and monitored (especially cardiopulmonary status and hydration) in accordance with their clinical condition. Inhalants may sensitize the myocardium, so pressor medications and bronchodilators are relatively contraindicated.

Inhalant Withdrawal Inhalant withdrawal is not a recognized clinical syndrome in the DSM-5 (80), yet a growing literature describes an inhalant-induced withdrawal process. One study found that over 11% of patients evaluated for inhalant use reported withdrawal-like symptoms (149). Presumed inhalant withdrawal symptoms include depressed mood, fatigue, anxiety, difficulty concentrating, tachycardia, diaphoresis, muscle trembling or twitching, increased tearing and nasal secretions, headache, nausea and vomiting, and craving for inhalants (139,149,150). Some persons using inhalants report further use of these substances to avoid experiencing these symptoms, suggesting that symptoms served as negative reinforcement for continued use (150). There is no specific treatment for inhalant withdrawal (148).

CLUB DRUGS “Club drugs” are a pharmacologically heterogeneous group of drugs associated with a youth subculture that revolves around late-night dance parties known as “raves” or “trances” (151). The illicit use of these substances was popularized in this setting because of their perceived ability to enhance the sensory experience and allow for long periods of dancing to repetitive music. Common club drugs include MDMA (“ecstasy”), an amphetamine analog with stimulant and hallucinogenic properties, and GHB and flunitrazepam (Rohypnol, no longer marketed in the United States, Canada, or UK), both of which are CNS depressants. Pharmacological interactions from the concurrent use of multiple club drugs substantially increase the risk of toxicity (152).

MDMA (“ECSTASY”) “Ecstasy” is the common street name for MDMA (see Chapter 14). Related amphetamine analogs such as 3,4-methylenedioxyethylamphetamine (“eve”);

3,4-methylenedioxyamphetamine; and N-methyl-1-(3,4methylenedioxyphenyl)-2-butanamine may also be present in street preparations. The effects of MDMA are those of a stimulant combined with a mild hallucinogen (153,154). “Herbal ecstasy” often refers to preparations containing the stimulant ephedrine. “Liquid ecstasy” is a street name for GHB (see the following section). MDMA often is taken concurrently with other drugs, such as LSD (in a combination called “candyflipping”), for enhanced effect. DXM (available in over-the-counter cough medicines) is a frequent concomitant drug and may be substituted for MDMA in street preparations (120). “Stacking” is the practice of taking multiple MDMA doses over a short period, often alternating with other drugs to enhance the experience. Menthol, camphor, or ephedrine may be applied to the nasal mucosa or chest wall to enhance the drug experience (153). MDMA has good oral bioavailability and readily crosses the blood–brain barrier (153,154). The onset of action is within 30 minutes; peak plasma concentrations are achieved in 1-3 hours (154). The elimination half-life is 7-8 hours. Because MDMA is a weak acid, this is delayed to 16-31 hours with alkaline urine. MDMA is metabolized by several hepatic microsomal enzymes, chiefly CYP2D6. Individuals who are genetically deficient in CYP2D6 (up to 10% of whites) are theoretically at increased risk of developing MDMA toxicity (155), though some studies suggest this risk is minimal (156). MDMA appears to have nonlinear kinetics because the higher affinity enzymes become saturated at relatively low drug concentrations (157). This results in disproportionately large increases in drug concentrations in response to small increases in dose (155) and may account for the poor correlation between plasma concentration and toxicity (158). However, psychological effects may not increase proportionally with plasma concentrations, suggesting acute tolerance (153). A major MDMA metabolite is 3,4-methylenedioxyamphetamine (MDA), which also is pharmacologically active and has a longer elimination half-life of 16-38 hours (159).

MDMA Intoxication The diagnosis of MDMA intoxication is made by history of drug intake and/or analysis of unused drug. Most signs and symptoms are not specific to MDMA but resemble those of stimulants or hallucinogens. MDMA is not detected by

routine urine or blood drug screens, which may be positive for amphetamines (products of MDMA metabolism) (154,155). Gastric lavage with activated charcoal may be helpful within the first hour after ingestion, especially if other drugs also have been taken. Induced emesis is not recommended because of the risk of CNS depression. Acidification of urine would quicken MDMA elimination but usually is contraindicated because it increases the risk of metabolic acidosis, thereby exacerbating renal toxicity from rhabdomyolysis.

Psychological and Behavioral Effects of MDMA Intoxication Low to moderate oral doses of MDMA (50-150 mg) typically produce an intense initial effect (known as “coming on” or “rush”), especially if taken on an empty stomach, that may last 30-45 minutes (160). Desired effects include increased wakefulness and energy, euphoria, increased sexual desire and satisfaction, heightened sensory perception, sociability, and increased empathy and sense of closeness to others (157,160,161). The initial phase is followed by several hours of less intense experience (“plateau”), during which repetitive dancing is common. Persons using MDMA often start to “come down” 3-6 hours after ingestion (154). Undesired effects may occur with repeated use or at higher doses (162). These include hyperactivity, fatigue, insomnia, anxiety, agitation, impaired decision-making, flight of ideas, hallucinations, depersonalization, “derealization,” and bizarre or reckless behavior. Some persons develop panic attacks, brief psychotic episodes, or delirium, which usually resolve rapidly as the drug effect wears off (163). Initial treatment is the same as for hallucinogen intoxication: placement in a quiet, reassuring environment, with observation to reduce the risk of unintended self-injury. Physical restraints are contraindicated because they may exacerbate anxiety and increase the risk of rhabdomyolysis. If severe or persisting symptoms require medication, benzodiazepines are preferred. Antipsychotics should be avoided as much as possible because they increase the risk of hyperthermia and seizures. A high-potency antipsychotic such as haloperidol should be used if necessary. The role of second-generation antipsychotics remains unclear. A few persons who use MDMA may develop persisting depression or recurrent psychotic symptoms or panic attacks, which require psychiatric treatment.

Medical Effects of MDMA Intoxication The acute physical effects of MDMA at low to moderate doses resemble those of a stimulant: increased muscle tension, jaw clenching, tooth grinding (bruxism), restlessness, insomnia, ataxia, headache, nausea, decreased appetite, dry mouth, dilated pupils, and increased heart rate and blood pressure (157,160,161). Doses >200 mg are associated with life-threatening toxicities that can be grouped into four major syndromes (164). The most dangerous is hyperthermia, which results from a combination of direct thermogenic effects of the drug (probably via adrenergic mechanisms), increased physical activity (as through vigorous dancing), warm environment (as in a crowded, poorly ventilated dance club), and disruption of thermoregulation by the drug, often exacerbated by dehydration (75,165). The syndrome may resemble that of severe heatstroke. The high body temperature causes rhabdomyolysis (with resulting myoglobinuria and renal failure), liver damage, or disseminated intravascular coagulation (resulting in hemorrhage). Treatment is based on early recognition, close monitoring of serum creatine kinase levels (to detect rhabdomyolysis), and reversal of the hyperthermia. Core body temperatures >102°F call for urgent measures such as ice water sponging, gastric or bladder lavage with cool liquids, and intravenous infusion of chilled saline. Muscle paralysis with intubation may be required for refractory, ongoing rhabdomyolysis. Rhabdomyolysis treatment includes vigorous hydration and alkalinization of the urine to minimize myoglobin precipitation in the renal tubules. Benzodiazepines help control both the hyperthermia and agitation. Antipsychotics should be avoided because they interfere with heat dissipation and lower the seizure threshold. Recent case series suggest that dantrolene (1 mg/kg IV) may be helpful. Because of similarities between MDMA toxicity and the serotonin syndrome (see the following section entitled Serotonin Syndrome), serotonin antagonists such as methysergide and cyproheptadine have been used successfully. Acute hepatic toxicity from MDMA may be related to metabolism into reactive intermediaries that deplete hepatic glutathione, resulting in cell death (157,159). The clinical picture can vary from a mild hepatitis (marked by enlarged, tender liver and elevated serum liver enzymes) that resolves spontaneously over several weeks to fulminant liver failure requiring transplantation. Liver toxicity may be exacerbated by hyperthermia. Acute cardiovascular toxicity from MDMA is the result of increased catecholamine activity (157,166). This may cause hypertension, with risk of

blood vessel rupture and hemorrhage, or tachycardia and cardiac arrhythmia. The preferred treatment is an adrenergic antagonist with both alpha- and betablocking activities, combined with a vasodilator such as nitroglycerin or nitroprusside if needed to control blood pressure. A pure beta-adrenergic blocker should be avoided because of the remaining unopposed alpha-adrenergic stimulation, resulting in vasoconstriction and worsening hypertension. Hypertensive crisis unresponsive to mixed adrenergic blockers and vasodilators should be treated with an alpha-adrenergic antagonist such as phentolamine (33). Cardiac ischemia or arrhythmia should be treated by standard clinical protocols. Agitation should be controlled with a short-acting benzodiazepine such as lorazepam. In addition to direct MDMA-mediated neurotoxicity (167), acute toxicity can result from hyponatremia (“water intoxication”), which may cause seizures and intracranial fluid shifts that compress the brain stem into the foramen magnum (75). The hyponatremia is caused by loss of sodium in sweat (as during vigorous dancing in a warm environment) and hemodilution from drinking large amounts of water and the antidiuretic effect of MDMA. The conservative initial treatment is fluid restriction. Profound hyponatremia has been treated with hypertonic saline solution (168). Intravenous benzodiazepines should be used to control seizures.

MDMA Withdrawal Symptoms during the first few days after MDMA use may resemble a mild form of stimulant withdrawal or “crash,” with depression, anxiety, fatigue, and difficulty concentrating (75,157). These usually resolve without treatment. Prevalence of withdrawal (DSM-IV criteria) was 1% in a convenience sample of 214 Australian MDMA users (169).

Medical Effects of MDMA Withdrawal There is no evidence of a physically prominent or distinctive withdrawal syndrome associated with MDMA that would require specific pharmacological treatment. Persons withdrawing from MDMA may complain of muscle pain and stiffness in the jaw, neck, lower back, and limbs for the first 2-3 days after use (75,157), which may be the result of MDMA-induced muscle tension and the vigorous dancing often associated with MDMA use. There is some evidence of increased variability of heart rate and blood pressure for several days after MDMA use.

GAMMA HYDROXYBUTYRATE GHB (sometimes termed “liquid ecstasy”) is a naturally occurring metabolite of the neurotransmitter gamma-aminobutyric acid (GABA) that may itself function as an agonist at both the GABA-B receptor and a putative GHB receptor (170,171). It is approved for the treatment of narcolepsy (sodium oxybate (Xyrem), Schedule III controlled substance) but is also used recreationally. GHB became popular in the late 1980s, when it was marketed and sold in health food stores as a supplement for body building and other putative health effects. Use of GHB increased well beyond the supplement market, in part because of its reputed euphoric, aphrodisiac, disinhibitory, and amnestic effects. GHB’s short duration of action, minimal “hangover” effects, and nondetectability by standard drug screens contributed to its popularity. The legal precursors gammabutyrolactone (GBL, an industrial solvent found in floor strippers and some household products) and 1,4-butanediol (1,4-BD), which are readily metabolized to GBH in the body, are also used recreationally (172), as are structural analogs such as β-phenyl-GABA (phenibut), developed in the Soviet Union as a sedative/anxiolytic but now readily available in the United States and Europe as a nutritional supplement (173). GHB is taken orally as a liquid or in a powder mixed into drinks. A typical dose is 1-3 teaspoons or capfuls, though variations in concentration make it challenging to determine the actual dosage of GHB in recreational preparations. GHB is rapidly absorbed from the gastrointestinal tract and readily crosses the blood–brain barrier. Effects begin within 15 minutes of ingestion and last 2-4 hours (174). The blood elimination half-life is about 30 minutes, largely because of rapid redistribution into other tissues.

GHB Intoxication The diagnosis of GHB intoxication is based on clinical suspicion, a history of drug ingestion, or analysis of unused drug. The signs and symptoms of GHB intoxication are not specific and are difficult to differentiate from other CNS depressants. GHB is not detected by routine drug toxicology assays. Definitive detection requires fluid analysis utilizing gas chromatography/mass spectrometry (175), which commonly takes 7-14 days. There is no proven antidote for GHB intoxication. Physostigmine, naloxone, and flumazenil have reversed some GHB effects in small case series or animal

studies (176) but should be considered experimental. Gastric lavage usually is not helpful because of rapid gastrointestinal absorption, but activated charcoal may be.

Psychological and Behavioral Effects of GHB Intoxication The desired acute effects of GHB at low oral doses (30 mg/kg) may cause incontinence, myoclonic movements, bradycardia, hypotension, hypothermia, generalized tonic–clonic seizures, and coma (27,180). Concurrent ingestion of other drugs, including alcohol, substantially increases the severity of GHB intoxication (180). Most patients with pure GHB intoxication recover completely within several hours with supportive care and do not require intubation. However, death may result from respiratory depression, so that intubation and mechanical ventilation may be indicated in severe cases. Seizures should be controlled with benzodiazepines, symptomatic bradycardia with atropine, and symptomatic hypotension with intravenous saline.

GHB Withdrawal Cessation of chronic GHB or GBL use leads to a discrete withdrawal syndrome resembling that of sedative–hypnotic withdrawal, presumably mediated by unopposed excitation in the neurotransmitter systems ordinarily inhibited by GABA-B (and GHB) receptors (180). Anxiety, restlessness, insomnia, tremor,

nystagmus, tachycardia, and hypertension usually appear 2-12 hours after the last dose (181–183). Mild symptoms usually resolve gradually over 1-2 weeks. More severe withdrawal may cause delirium with hallucinations, psychosis, agitation, and autonomic instability (180) and may present similarly to delirium tremens (182). GHB withdrawal seizures are rare but have been reported (185). Physical dependence may develop within 1 week of repeated daily dosing. Most cases of GHB withdrawal can be managed with a long-acting benzodiazepine, tapering the dose after the symptoms are controlled (as for sedative–hypnotic withdrawal) (184). Severe cases may require high doses (several 100 mg) or parenteral administration. Patients unresponsive to benzodiazepines may benefit from barbiturates, slow tapering with GHB itself (185), or baclofen (30-60 mg daily) (186), although toxic interactions between GHB and high doses of baclofen have been reported (187). It has been proposed that a single class of medications, including benzodiazepines, gabapentin, or antipsychotics, may not provide sufficient protection to avoid “life threatening complications” (182). Because of the unpredictability of GHB withdrawal and vulnerability to severe complications such as delirium and potential lethality (174,180,181,188), withdrawal management is best undertaken in a hospital setting. Mild withdrawal syndromes may be managed in an outpatient setting with close supervision (184).

MISUSE OF HERBS Herbs are plants used for medicinal, culinary, or spiritual purposes. Many herbs contain psychoactive compounds with stimulant, anxiogenic, anxiolytic, hallucinogenic, euphoric, or dissociative effects (189,190). These properties have long been recognized in many indigenous cultures. The psychoactive profile of herbs, combined with the fact that production, sale, and purchase of most herbs are largely unregulated, has contributed to a growing market for their recreational use (190). Internet distribution of herbs makes them widely available to minors (191). The perception that herbs are safer than illicit drugs, coupled with the absence of clearly established dosing parameters, contributes to their misuse (192). Routine toxicology screens do not detect many of these substances, so that identifying specific intoxication syndromes may be challenging. Accurate diagnosis may rest on collateral information from family, friends, and first responders, in addition to a thorough clinical examination.

Intoxication Herbs prone to misuse often contain multiple psychoactive compounds, so that intoxication syndromes may not fit neatly into distinctive classifications. For clarity, these herbs may be categorized as predominantly hallucinogenic or stimulating. Table 54-8 describes basic characteristics of some of the commonest herbs being misused.

TABLE 54-8 Commonly Misused Herbal Drugs

DMT, N,N-dimethyltryptamine; GABA, γ-aminobutyric acid; LSA, lysergic acid amide; MA, methamphetamine; MAO, monoamine oxidase. Sources: Richardson WH, Slone CM, Michels JE. Herbal drugs of abuse: an emerging problem. Emerg Med Clin N Am. 2007;254:35-57; Halpern JH. Hallucinogens and dissociative agents naturally growing in the United States. Pharmacol Ther. 2004;102:131-138.

Hallucinogenic herbs achieve their psychotomimetic effects principally through activity at serotonergic or cholinergic receptors. Stimulating herbs generally augment the activity of norepinephrine or dopamine. Thus, the manifestations

and management of intoxication syndromes for this varied group of substances generally follow that for hallucinogen or stimulant intoxication.

Management of Psychological, Behavioral, and Medical Effects Management of intoxication with hallucinogenic herbs is largely supportive because most symptoms, including psychosis, are self-limited. The goal is to maintain safety, preventing patients from physically harming themselves or others. A quiet environment, with calm counseling and guidance, often avoids the need for pharmacological interventions. Medications with anticholinergic properties are best avoided to minimize exacerbating substance-induced delirium. Physical restraints should be avoided because they increase psychological distress and may contribute to rhabdomyolysis. Patients who are agitated, in severe panic, or having distressing psychotic symptoms may be relieved by benzodiazepines (eg, lorazepam 2 mg PO/IM every 1-2 hours, titrated to mild sedation). In cases where predisposing factors or heavy chronic use contributes to prolonged psychotic symptoms, antipsychotic agents may be useful. Management of intoxication with stimulant herbs is similar to that with hallucinogenic herbs, except that the former are more likely to generate hyperexcitable, agitated, and psychotic states. Patients with unstable vital signs should be closely monitored, including cardiac function, blood pressure, and body temperature. Beta-adrenergic blockers are generally avoided due to concern about unopposed alpha-adrenergic activity. With one exception, there are no specific antidotes to intoxication with psychoactive herbs. Intoxication with herbs having anticholinergic activity (eg, jimsonweed) has been successfully treated with physostigmine, a short-acting acetylcholinesterase inhibitor (176). Severe intoxication with betel nut, which has cholinergic activity, can be treated with atropine, a cholinergic antagonist.

Withdrawal Most persons withdrawing from psychoactive herbs do not consume large enough amounts for long enough periods to develop physical dependence or a withdrawal syndrome. Some persons who use khat and betel nuts do experience a withdrawal syndrome, often including irritability, fatigue, and rhinorrhea (190).

Protracted withdrawal symptoms (eg, psychosis, depression, anxiety) should be treated symptomatically while the patient is evaluated for an underlying psychiatric disorder.

FLUNITRAZEPAM Flunitrazepam (Rohypnol, also known as “roofies” or the “date rape pill”) is a potent, fast-acting benzodiazepine that frequently causes anterograde amnesia (193). It is legally manufactured and marketed in Europe and Latin America but is illegal in the United States, Canada, and several European countries because of its association with “date rape,” although the epidemiological evidence for this is limited (193). Flunitrazepam is difficult to detect with routine toxicology screens because of the low concentration needed for pharmacological effects.

Flunitrazepam Intoxication Flunitrazepam intoxication resembles intoxication with other benzodiazepines and features sedation, disinhibition, anterograde amnesia, confusion, ataxia, bradycardia, hypotension, and respiratory depression (193). Overdose, alone and/or particularly concurrently with alcohol ingestion can be lethal (193). When respiratory depression or circulatory compromise is severe, the benzodiazepine antagonist flumazenil (Romazicon) may be used, albeit cautiously. Flumazenil precipitates acute withdrawal in patients who are physically dependent on benzodiazepines and lowers the seizure threshold, thus increasing the risk of withdrawal seizures. Flumazenil is effective for about 20 minutes, so that repeated dosing is necessary to avoid resedation by flunitrazepam.

Flunitrazepam Withdrawal A typical sedative–hypnotic withdrawal syndrome can develop after cessation of chronic flunitrazepam use. Withdrawal symptoms can develop up to 36 hours after the last dose and include anxiety, restlessness, tremors, headache, insomnia, and paresthesias. Treatment of withdrawal involves supportive measures and substitution with cross-tolerant medications such as lorazepam or clonazepam, followed by gradual tapering.

SEROTONIN SYNDROME

The serotonin syndrome is a potentially lethal condition associated with increased serotonergic activity in the CNS. Substances that increase serotonin activity, directly (MDMA), indirectly (SSRIs), or in combination, can trigger this syndrome. The serotonin syndrome is a triad of signs and symptoms, consisting of mental status changes (eg, anxiety, confusion, agitation, lethargy, delirium, coma), autonomic hyperactivity (eg, low-grade fever, tachycardia, diaphoresis, nausea, vomiting, diarrhea, dilated pupils, abdominal pain, hypertension, tachypnea), and neuromuscular abnormalities (eg, myoclonus or clonus, nystagmus, hyperreflexia, rigidity, trismus, tremor) (194,195). The clinical presentation is highly variable, making diagnosis difficult, but neuromuscular signs are usually prominent, particularly in the lower extremities (194–198). The Hunter Toxicity Criteria Decision Rules are 84% sensitive and 97% specific for serotonin syndrome when compared with the gold standard of diagnosis by a medical toxicologist (197). The Hunter Criteria include recent ingestion of a serotonergic agent and at least one of the following: 1. Spontaneous clonus 2. Inducible clonus plus agitation or diaphoresis 3. Ocular clonus plus agitation or diaphoresis 4. Tremor plus hyperreflexia 5. Hypertonia plus temperature above 38°C plus ocular clonus or inducible clonus The differential diagnosis includes neuroleptic malignant syndrome (with which it is most commonly confused), sepsis, heat stroke, delirium tremens, and sympathomimetic or anticholinergic poisoning (198). Patients with neuroleptic malignant syndrome differ from those with serotonin syndrome in that they are more likely to present with extrapyramidal signs and autonomic instability and rarely present with the neuromuscular changes common in serotonin syndrome (198). The serotonin syndrome is the result of excessive stimulation of 5-HT2A, possibly with some contribution from 5-HT1A, receptors. This occurs through several different pathways: activation of serotonin receptors by agonists, enhanced release of serotonin (by MDMA or amphetamines), decreased presynaptic serotonin reuptake (by cocaine or SSRI antidepressants), decreased serotonin metabolism (by amphetamines or monoamine oxidase inhibitors), and increased serotonin synthesis. The serotonin syndrome is most commonly seen after ingestion of two or more drugs with such actions but also may occur with a

single drug. The onset of the serotonin syndrome is within minutes to hours of medication initiation, increase in dose, or overdose. Laboratory abnormalities are nonspecific; no test confirms the diagnosis. Elevated creatine phosphokinase, liver transaminases, white blood cell count, serum bicarbonate, and evidence of disseminated intravascular coagulation occur in severe cases (194). In severe cases, or in the absence of appropriate diagnosis and treatment, there may be progression to rhabdomyolysis, hyperthermia, renal failure, disseminated intravascular coagulation, and death. Effective treatment of the serotonin syndrome requires early identification, immediate discontinuation of all serotonergic medications, close monitoring, and supportive care, usually including intravenous hydration. Such treatment usually results in a benign, self-limited course; many cases resolve within 24 hours. Muscle rigidity and spasm should be controlled with benzodiazepines to prevent rhabdomyolysis. Management of hyperthermia is vital to mitigate complications such as seizures, disseminated intravascular coagulation, and metabolic acidosis. Severe forms of the syndrome require more aggressive measures, including neuromuscular blocking agents, mechanical ventilation, and external cooling. Antipyretics are generally unhelpful because the source of hyperthermia is muscular activity, not alterations in hypothalamic temperature set point (196,197). Treatment with a 5-HT2A receptor antagonist (eg, cyproheptadine, olanzapine, chlorpromazine) has been effective in case series but has not yet been evaluated in controlled clinical trials.

WITHDRAWAL DRUGS

FROM

MULTIPLE

Multiple Sedative–Hypnotics Withdrawal from dependence on multiple sedative–hypnotic agents, including alcohol, is best managed in the same way as withdrawal from a single such drug: by using tapering dosages of a single, longer-acting sedative–hypnotic (5,199). It usually is safest to focus on managing withdrawal of the longer-acting drug. The time course of withdrawal from multiple sedative–hypnotics is more unpredictable than from single drugs; for example, there may be a bimodal time course of symptomatology if one drug is short acting and the other is longer

acting. The rate at which the dose is tapered usually should not exceed 10% per day. Successful withdrawal is facilitated by use of an anticonvulsant such as carbamazepine (200), although such use has not been evaluated in multiple drug withdrawal.

Sedative–Hypnotics With Other Drugs In the pharmacological management of patients withdrawing from both sedative–hypnotics and CNS stimulants, it is preferable to treat the sedative– hypnotic withdrawal first because this poses the greatest difficulty and medical risk. For concurrent addiction to sedative–hypnotics and opiates, concurrent pharmacological treatment is recommended (6,200). The patient may be stabilized on an opioid (preferably oral methadone, although codeine can be used if methadone is not available) at the same time that the sedative–hypnotic dose is tapered by 10% per day. After the sedative–hypnotic withdrawal is completed, opioid withdrawal can begin. Clonidine has been suggested as adjunctive treatment for such mixed sedative–hypnotic and opiate withdrawal, because it can alleviate withdrawal symptoms from both drug classes, but this has not been evaluated systematically.

POPULATION-SPECIFIC CONSIDERATIONS Neonates Neonatal drug exposure is a substantial public health problem. Many addictive drugs are readily transferred from the maternal circulation across the placenta to the fetus. Thus, perinatal drug use by the mother raises the possibility of drug intoxication or withdrawal in the newborn (201–203). Obtaining an accurate maternal drug use history for the period preceding delivery is essential. Meconium is the most accurate substrate for neonatal toxicology through the 3rd to 4th day of life, but such testing is not widely available. Neonatal signs and symptoms of drug intoxication or withdrawal often are nonspecific, including sedation, irritability, restlessness, hypertonia, hyperreflexia, tremors, poor feeding, abnormal sleep patterns, respiratory difficulty, and seizures. Stimulants (such as cocaine), marijuana, LSD, and PCP

all have been associated with a neonatal withdrawal syndrome, although one that usually is less intense than the opiate withdrawal syndrome (204). Perinatal use of stimulants by the mother is associated with either bradycardia or tachycardia in the newborn (205). The additive cardiovascular effects of the stimulant and the normal catecholamine surge during labor may cause fetal distress and retard delivery (203). These cardiac effects usually resolve as the drug is eliminated from the body. Neonatal stimulant intoxication is associated with irritability, tremors, hyperactivity, abnormal movements, excessive sucking, and high-pitched and excessive crying for 1-2 days, followed by a period of lethargy and hyporeactivity (206–208). Treatment of drug-exposed newborns is largely supportive, with avoidance of overstimulation. Pharmacological treatment should be used cautiously because it has its own potential for morbidity. Phenobarbital is the preferred medication for newborns with nonopioid drug withdrawal who do require pharmacological treatment, as when seizures are a factor. A loading dose of 5 mg/kg/d is given until withdrawal is controlled, with adjustments of 10%-20% every 2-3 days based on the response. Phenobarbital has a long half-life, so plasma concentrations should be checked periodically to avoid drug accumulation and overtreatment.

Older Adults Rates of illicit drug use by the elderly are low but may be increasing (209). There are few published data on the treatment of drug intoxication or withdrawal in this age group. The elderly may be more susceptible to confusion and disorientation during withdrawal and to medication-induced delirium. The recommended dosing approach is “start low and go slow”; that is, start medication at a lower dose, and increase the dose in smaller increments than would be used in younger individuals.

Adolescents Adolescence is the common age of onset for illegal drug use (210), and the developing adolescent brain may be especially vulnerable to the neurobiological effects of drugs (211). Adolescents experience symptoms of drug withdrawal similar to those in adults, including physical symptoms (212). There are few published data on the treatment of drug intoxication or withdrawal in adolescents (213,214).

Women Women often differ from men in their response to psychoactive drugs and to drug use disorder treatment (215), but there has been little systematic study of gender differences in the treatment of drug intoxication and withdrawal. Limited anecdotal evidence suggests that pharmacological treatment for women is similar to that for men, taking into account possible gender differences in medication pharmacokinetics. Two topics requiring further research are the influence of the menstrual cycle on intoxication and withdrawal and their treatment and the effects of intoxication and withdrawal and their treatment on pregnancy and the fetus.

ACKNOWLEDGMENTS Dr. Wilkins is supported by the Cedars-Sinai Medical Center LincyHeyward/Moynihan Endowed Chair in Addiction Medicine.

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SECTION 7

Pharmacological Interventions Other Somatic Therapies

and

CHAPTER 55

Pharmacological Interventions Alcohol Use Disorder Hugh Myrick, Andrew J. Saxon and Jerome H. Jaffe

for

CHAPTER OUTLINE Introduction Medications Used to Reduce or Stop Drinking Medications to Treat Co-Occurring Psychiatric Symptoms or Disorders in Patients With Alcohol Use Disorder The Use of Pharmacotherapies in the Treatment of Alcohol Use Disorder Summary and Conclusions

INTRODUCTION It has been well established that unhealthy alcohol use is associated with numerous health risks (1). In the United States, unhealthy alcohol use accounted for 1 in 10 deaths among working-age adults (2006-2009) and shortened the lives of those who died by an average of 30 years (2,3). Despite the risks, there is a lack of recognition and treatment of alcohol use disorder (4). Recent data suggest that only 7.7% of individuals diagnosed with alcohol use disorder within 12 months received treatment (5). Accordingly over the past three decades, we have seen the entry of several medications to treat alcohol use disorder. In this chapter, we review the literature on the use of medications to reduce drinking or prevent relapse in those with unhealthy alcohol use. Rather than reviewing the literature exhaustively, the focus of the chapter is on developments of current interest to the clinician or that are likely to yield important clinical advances in the future. We also refer the reader to a number of other recent reviews that augment the information provided here (6,7). The first major approach to the use of medications in the treatment of individuals with alcohol use disorders involves direct efforts to reduce or stop drinking behavior by producing adverse effects when alcohol is consumed or by modifying the neurotransmitter systems that mediate alcohol reinforcement. Table 55-1 lists the four medications or formulations that use this approach and are approved by the U.S. Food and Drug Administration (FDA) for the treatment of alcohol use disorder. The table also shows the year of FDA approval, the presumed mechanism of action, and the approved dosage for each of these. The medications are discussed individually in the sections that follow. The second main approach to the treatment of alcohol use disorder involves the treatment of persistent psychiatric symptoms, which aims to stop or reduce drinking by

modifying the motivation to use alcohol to “self-medicate” such symptoms. Medications for which this rationale underlies their use in the treatment of alcohol use disorder are discussed in the latter part of this chapter.

TABLE 55-1 Medications Approved by the U.S. Food and Drug Administration for the Treatment of Alcohol Dependence

MEDICATIONS USED TO REDUCE OR STOP DRINKING Alcohol-Sensitizing Agents Alcohol-sensitizing agents alter the body’s response to alcohol, thereby making its ingestion unpleasant or toxic. Disulfiram (Antabuse) is the only alcoholsensitizing medication approved in the United States for the treatment of alcohol use disorder and that is widely used clinically. Consequently, we focus on that agent here. Disulfiram inhibits the enzyme aldehyde dehydrogenase, which catalyzes the oxidation of acetaldehyde to acetic acid. The ingestion of alcohol while this enzyme is inhibited elevates the blood acetaldehyde concentration, resulting in the disulfiram–ethanol reaction (DER). The intensity of the DER varies both with the dose of disulfiram and the volume of alcohol ingested. Symptoms and signs of the DER include warmness and flushing of the skin, especially that of the upper chest and face; increased heart rate; palpitations; and decreased blood pressure. They may also include nausea, vomiting, shortness of breath, sweating, dizziness, blurred vision, and confusion. Most DERs are self-limited, lasting

about 30 minutes. Occasionally, the DER may be severe, with marked tachycardia, hypotension, or bradycardia; rarely, it may result in cardiovascular collapse, congestive failure, and convulsions. Although severe reactions are usually associated with high doses of disulfiram (over 500 mg/d), combined with more than 2 oz of alcohol, deaths have occurred with lower dosage and after a single drink (8,9). Concern over the potential for such effects may limit clinicians’ willingness to prescribe disulfiram. Given its intuitive appeal, disulfiram has long been used in the treatment of patients with alcohol use disorder (10), despite a lack of methodologically sound evaluations demonstrating its efficacy in the prevention of relapse. However, in selected samples of such individuals with whom special efforts, such as supervised administration, are made to ensure compliance, these medications may be useful. As discussed below, disulfiram may also limit the severity of relapse when it occurs. There are no guidelines that can be offered either to identify patients for whom disulfiram is most likely to have a beneficial effect or to match specific psychosocial interventions with particular patients to enhance compliance. Its approval for use by the FDA preceded the implementation of rigorous requirements for efficacy that now must be satisfied for a medication to be marketed in the United States. In the controlled studies conducted, the difference in outcome between subjects receiving disulfiram and those given placebo has generally been modest. The largest and most methodologically sound study of disulfiram was a multicenter trial conducted by the Veterans Administration Cooperative Studies Group. In that 1-year study, more than 600 male patients with (pre-DSM-5) alcohol dependence were randomly assigned to receive either 1 mg of disulfiram per day, 250 mg/d, or an inactive placebo (11). Patients assigned to the two disulfiram groups were told they were receiving the medication, but neither patients nor staff knew the dosage. Results showed that greater compliance with the medication regimen (in all three groups) was associated with a greater likelihood of complete abstinence. Among patients who resumed drinking, those in the group receiving 250 mg of disulfiram reported significantly fewer drinking days than did patients in either of the other two groups. Based on these findings, it appears that disulfiram may be helpful in reducing the frequency of drinking in men who cannot remain abstinent, though given the large number of statistical analyses, it is possible that this finding arose by chance. Disulfiram may be of clinical value in selected individuals with alcohol use

disorder with whom special efforts are made to ensure compliance. Specific behavioral efforts to enhance compliance with disulfiram (as well as other medications for the treatment of alcohol use disorder) include contracting with the patient and a significant other to work together to ensure compliance and the provision to the patient of incentives, regular reminders and other information, and behavioral training and social support (12). A trial program of stimulus control training, role playing, communication skills training, and recreational and vocational counseling improved outcome in disulfiram-treated patients compared with those receiving placebo (13). Supervision of patients being treated with disulfiram may be an essential element in ensuring compliance and enhancing the beneficial effects of the medication (14). In a 6-month study, Chick et al. (15) randomly assigned patients to receive disulfiram 200 mg/d or vitamin C 100 mg/d (ingested under the supervision of an individual chosen by the patient) as an adjunct to outpatient alcohol treatment. Treatment with disulfiram significantly increased abstinent days and decreased total drinks consumed, effects that were confirmed by parallel changes in levels of the hepatic enzyme γ-glutamyl transpeptidase (GGT).

Pharmacology and Clinical Use of Disulfiram Disulfiram is almost completely absorbed orally. Because it binds irreversibly to aldehyde dehydrogenase, renewed enzyme activity requires the synthesis of new enzyme, so that the potential exists for a DER to occur at least 2 weeks from the last ingestion of disulfiram. Consequently, alcohol should be avoided during this period. Disulfiram commonly produces a variety of adverse effects, including drowsiness, lethargy, and fatigue (16). Although more serious adverse effects, such as optic neuritis, peripheral neuropathy, and hepatotoxicity, occur rarely, patients treated with disulfiram should be monitored regularly for visual changes and symptoms of peripheral neuropathy and the medication discontinued if they appear. Further, the patient’s liver enzymes should be monitored monthly or at more frequent intervals during the first 3 months of treatment and quarterly thereafter to identify hepatotoxic effects, which may also warrant discontinuation of the medication. Psychiatric effects of disulfiram are uncommon and probably occur only at higher dosages of the drug, which may result in the inhibition by disulfiram of a variety of enzymes in addition to aldehyde dehydrogenase. For example, disulfiram inhibits dopamine betahydroxylase, which increases dopamine concentrations, which in turn can exacerbate psychotic symptoms in patients with schizophrenia and rarely result

in psychotic or depressive symptoms among individuals without a psychotic disorder. Such symptoms should also lead to discontinuation of the medication. Disulfiram is administered orally. There is a correlation between the risk of most adverse effects and dosage, although the risk of hepatic injury does not appear to be related to dose. This concern about dosage-related adverse events has resulted in the daily dosage prescribed in the United States being limited to 250-500 mg/d. However, efforts to titrate the dosage of disulfiram in relation to a challenge dose of ethanol have shown that some patients require in excess of 1 g/d of disulfiram to reach blood levels sufficient to produce a DER (17). In deciding whether disulfiram should be used in treatment of alcohol use disorder, patients should be made aware of the hazards of the medication, including the need to avoid over-the-counter preparations with alcohol and drugs that can interact with disulfiram and the potential for a DER to be precipitated by alcohol used in food preparation. The administration of disulfiram to anyone who does not agree to use it, does not seek to be abstinent from alcohol, has not attained at least 48 hours of abstinence prior to first administration of disulfiram, or has any psychological or medical contraindications is not recommended. Given its potential to produce serious adverse effects when combined with alcohol, disulfiram cannot be recommended for use as part of a moderation approach to alcohol treatment.

Medications That Directly Reduce Alcohol Consumption Several neurotransmitter systems appear to influence the reinforcing or discriminative stimulus effects of ethanol: endogenous opioids; catecholamines, especially dopamine; serotonin (5-HT); and excitatory amino acids (eg, glutamate) (see references (18) and (19) for detailed reviews of the literature on the role of these various neurotransmitter systems in alcohol effects). Although these systems function interactively to influence drinking behavior, many of the medications that have been employed to treat alcohol use disorder affect neurotransmitter systems relatively selectively. Consequently, these systems are discussed individually here.

Opioidergic Agents Naltrexone and, to a lesser extent, nalmefene, both of which are opioid antagonists with no intrinsic agonist properties, have been studied for the

treatment of alcohol use disorder. In 1984, naltrexone was approved by the FDA for the treatment of (pre-DSM-5) opioid dependence; in 1994, it was approved for the treatment of (pre-DSM-5) alcohol dependence. Nalmefene is approved in the United States as a parenteral formulation for the acute reversal of opioid effects (eg, after opioid overdose or analgesia).

Naltrexone The approval by the FDA of naltrexone for alcohol dependence was based on the results of two single-site studies, which showed it to be efficacious in the prevention of relapse to heavy drinking (20,21). In a 12-week trial in a sample of veterans with alcohol dependence, Volpicelli et al. (20) found naltrexone to be well tolerated and to result in significantly less craving for alcohol and fewer drinking days than placebo. Among patients who drank, naltrexone also limited the progression from initial sampling of alcohol to a relapse to heavy drinking, presumably because of their experiencing less euphoric effects of alcohol, suggesting that naltrexone blocked the endogenous opioid system’s contribution to alcohol’s “priming effect” (22). The efficacy of combining naltrexone with either supportive or cognitive– behavioral therapy (CBT) in patients with alcohol dependence was studied by O’Malley et al. (21). This 12-week trial showed the medication to be well tolerated and to be superior to placebo in increasing the rate of abstinence and reducing the number of drinking days and relapse events and the severity of alcohol-related problems. There was an interaction effect of medication and therapy. The cumulative rate of abstinence was highest for patients treated with naltrexone and supportive therapy. However, for patients who drank, those who received naltrexone and coping skills therapy were least likely to relapse to heavy drinking. Analysis of the potential mediating variables in these effects showed that naltrexone reduced craving for alcohol, alcohol’s reinforcing properties, the experience of intoxication, and the chances of continued drinking following a slip (23). During a 6-month, posttreatment follow-up period, the effects of naltrexone diminished gradually over time, suggesting that patients may benefit from treatment with naltrexone for longer than 12 weeks (24). Many, but not all, subsequent studies of naltrexone have provided support for its use in alcohol treatment. The literature on naltrexone treatment of alcohol use disorder has been reviewed in detail in a number of meta-analyses (25,26). The three meta-analyses that included the largest number of studies (26–28)

show a clear advantage for naltrexone over placebo on a number of drinking outcomes. Bouza et al. (27) included 19 studies of naltrexone and a total of 3205 participants with alcohol dependence. The large majority of these studies were of short duration (ie, ≤12 weeks). Using relapse as an outcome, these studies yielded a highly significant odds ratio (OR) of 0.62 (95% confidence interval [CI] 0.52 to 0.75), reflecting a 38% lower likelihood of relapse with naltrexone treatment (p < 0.00001). The likelihood of total abstinence also favored naltrexone (OR 1.26; 95% CI 0.97 to 1.64), though it did not reach statistical significance (p = 0.08). Outcomes identified as secondary by this meta-analysis, including time to relapse, percentage of drinking days, number of drinks per drinking day, days of abstinence, total alcohol consumption during treatment, and levels of gamma-glutamyl transpeptidase and aspartate aminotransferase, also showed a significant advantage for the naltrexone-treated group. The meta-analysis by Srisurapanont and Jarusuraisin (28) included a total of 2861 subjects from 24 randomized, controlled trials. In the short term, naltrexone significantly decreased risk of relapse to heavy drinking (relative risk [RR] 0.64, 95% CI 0.51 to 0.82) but did not reduce the likelihood of a return to any drinking (RR 0.91, 95% CI 0.81 to 1.02). Treatment with naltrexone significantly increased adverse effects, roughly doubling the likelihood of reports of nausea and dizziness and increasing the risk of fatigue by about onethird compared with placebo. However, naltrexone treatment did not significantly affect the rate of premature discontinuation of treatment (RR 0.85, 95% CI 0.70 to 1.01). The meta-analysis of Jonas et al. (26) included 44 placebo-controlled trials of naltrexone. The number needed to treat to prevent any return to any alcohol drinking was 20 (95% CI 11 to 500, n = 2347). The number needed to treat to prevent return to heavy drinking with 50 mg/d oral naltrexone was 12 (95% CI 8 to 26, n = 2875). Follow-up studies of patients treated with naltrexone or placebo for 12 weeks (24,29) or 4 months (30) have shown that the medication group differences are no longer significant at posttreatment follow-up. These findings suggest that treatment with naltrexone is warranted for longer than 4 months, though the optimal duration of treatment is unknown. An alternate approach to the use of naltrexone based on its efficacy in reducing the risk of heavy drinking among patients who continue to drink was evaluated in a study that compared the effects of naltrexone 50 mg with those of

placebo in an 8-week study of problem drinkers (31). In this study, patients were randomly assigned to receive study medication either on a daily basis or for use targeted to situations identified by the patients as being high risk for heavy drinking (with the number of tablets available for use by patients in the targeted conditions decreasing over the course of the trial). Irrespective of whether they received naltrexone or placebo, patients who were trained and encouraged to use targeted treatment showed a reduced likelihood of any drinking. There was also a 19% reduction in the likelihood of heavy drinking with naltrexone treatment, suggesting that naltrexone may be useful in reducing heavy drinking, among patients who want to reduce their drinking to safe levels. Targeted naltrexone was also used by Heinala et al. (32), who compared 50 mg/d of the medication with placebo, paired with either coping skills or supportive therapy. During an initial 12 weeks of treatment, this study showed an advantage for naltrexone in preventing relapse to heavy drinking but only when combined with coping skills therapy. During a subsequent 20-week period, subjects were told to use the medication only when they craved alcohol (ie, targeted treatment). The beneficial effect of naltrexone on the risk of relapse was generally sustained during the period of targeted treatment. Based on these findings, it appears that targeted medication administration may be useful both for the initial treatment of problem drinking and for maintenance of the beneficial effects of an initial period of daily naltrexone. O’Malley et al. (33) conducted a sequence of randomized trials in which subjects with alcohol dependence were first treated with 10 weeks of open-label naltrexone 50 mg, combined with either CBT or primary care management (PCM; a less intensive, supportive approach). Treatment responders from the PCM group and from the CBT group continued in separate 24-week, placebocontrolled studies of maintenance naltrexone. No difference was observed with respect to persistent heavy drinking, with more than 80% of both groups having a positive outcome. However, the percentage of days abstinent declined more over time for the PCM group. In the follow-up studies, there was a greater maintenance response for naltrexone than placebo when combined with PCM, but the advantage for naltrexone did not reach significance when combined with CBT. These findings suggest that the beneficial effects of treatment with naltrexone can be maintained during an extended period through the use of either a more intensive, skills-oriented treatment (ie, CBT) or a less intensive, supportive treatment combined with continued naltrexone administration. Since naltrexone only targets certain aspects of alcohol use disorder (ie, reduced alcohol reinforcement or cue-induced craving), there has been an

interest in combining it with medications that might influence other signs/symptoms of alcoholism. Symptoms often seen after alcohol cessation are difficulty sleeping, anxiety, irritability, decreased concentration, and depressed mood. This constellation of symptoms has been called protracted withdrawal. If not addressed, the symptoms of protracted withdrawal are thought to lead to relapse to alcohol use. The anticonvulsant gabapentin may help reduce these symptoms. As such, naltrexone has been evaluated in combination with the anticonvulsant gabapentin to determine if the combination was superior to naltrexone alone and/or placebo in decreasing alcohol use. Anton et al. (34) conducted a 16-week clinical trial of 150 subjects with alcohol dependence who were randomly assigned to naltrexone 50 mg/d alone for 16 weeks (Heinala = 50), naltrexone 50 mg/d with gabapentin up to 1200 mg/d for the first 6 weeks (Heinala = 50), or double placebo (Heinala = 50). All study patients received a combined behavioral intervention that combined CBT, motivation enhancement, and twelve-step facilitation techniques. The results indicated that during the first 6 weeks, when gabapentin was combined with naltrexone, the combination group had a longer interval to heavy drinking than did the naltrexone alone group (which was similar to placebo), had fewer heavy drinking days than did the naltrexone alone group (which had more than did the placebo group), and had fewer drinks per drinking day than did the naltrexone alone group and the placebo group. The findings in the combination group faded over the remaining weeks of the study. There was some suggestion that the combination may work best in individuals who had previously experienced alcohol withdrawal. The investigators hypothesized that the lack of efficacy for naltrexone versus placebo may have been due to the robust psychosocial intervention (30). Poor compliance with oral naltrexone has been shown to reduce the potential benefits of the medication (35). This has generated interest in the development and evaluation of long-acting injectable formulations of the medication. The rationale behind this approach is that monthly, compared with daily, administration would improve medication adherence and that parenteral administration would increase bioavailability by avoiding first-pass metabolism. In addition to the formulations evaluated in published studies, which are reviewed in the following sections, there are long-acting naltrexone formulations that are under development for use in the United States, Europe, and Australia. In a pilot study, patients with alcohol dependence treated with a subcutaneous depot formulation of naltrexone had detectable plasma concentrations of the medication for more than 30 days after the injection (36).

In this study, naltrexone was superior to placebo in reducing the frequency of heavy drinking. Two long-acting naltrexone formulations administered intramuscularly have also been tested for safety and efficacy in patients with alcohol dependence. In the first study, naltrexone depot (at a dosage of 300 mg in the first month and then 150 mg monthly for 2 months) was administered in a 12-week, placebo-controlled trial in 315 patients who also received motivational enhancement therapy (37). Although naltrexone did not reduce the risk of heavy drinking, it significantly delayed the onset of any drinking, increased the total number of abstinent days, and doubled the likelihood of abstinence during the 12-week study period. Two dosage strengths of a second formulation were evaluated over 6 months of treatment in combination with a low-intensity psychosocial intervention in more than 600 individuals with alcohol use disorder who received 6 monthly injections of either long-acting naltrexone (380 mg or 190 mg) or matching volumes of placebo (38). Abstinence from alcohol was not required for study participation. The medication and the injections were well tolerated. Compared with placebo, treatment with the 380-mg naltrexone formulation reduced the event rate of heavy drinking by 25%, a statistically significant effect. The 17% reduction in the rate of heavy drinking produced by the 190-mg formulation did not reach statistical significance. On the basis of these findings, the FDA approved long-acting naltrexone for monthly administration at a dosage of 380 mg. Because the analysis also showed that the most robust effects of the medication were seen in patients who were abstinent (by choice) for at least a week before randomization, the package insert states that the medication should be used only in individuals with alcohol use disorder who are abstinent at treatment initiation. A secondary analysis of data from this study examined efficacy in the subgroup of 82 patients with 4 days or more of voluntary abstinence before treatment initiation (39). This shorter period of abstinence made it possible to include a larger percentage of the study sample in the analysis than was possible initially with the use of a 7-day interval. In this study, there was a significant advantage for the 380-mg formulation compared with placebo on a number of self-report outcome measures, including greater likelihood of total abstinence (32% vs. 11%), greater median time to a first drinking day (41 days vs. 12 days), greater median time to a first heavy drinking day (>180 days vs. 20 days), lower median number of drinking days per month (0.7 vs. 7.2), and lower median heavy drinking days per month (0.2 days vs. 2.9 days). There was also a significantly greater improvement in gamma-glutamyl transpeptidase levels in the 380-mg naltrexone group. Outcomes for the 190-mg group were generally

intermediate between the high-dose and placebo groups. Based upon hopes for a personalized medicine approach to using naltrexone, the moderating effect of a polymorphism (A118G or Asn40Asp) in the gene encoding the μ-opioid receptor on naltrexone treatment response in subjects with alcohol dependence has been examined with resulting contradictory preliminary evidence (40,41). However, a rigorous prospective double-blind study that randomized both on the presence or absence of the polymorphism and to active naltrexone versus placebo found no evidence of a genotype by treatment interaction effectively dashing any further considerations of the utility of this particular personalized medicine approach (19).

Clinical Considerations in the Use of Naltrexone The clinical use of naltrexone is relatively straightforward, despite the presence of a “boxed” warning in the label concerning hepatotoxicity for the oral formulation. The medication should be prescribed at the time that psychosocial treatment is initiated. Because of adverse effects of the medication that could compound the adverse effects of alcohol withdrawal, the initiation of naltrexone therapy is probably best delayed until after the acute withdrawal period. Initial testing for liver enzyme abnormalities is warranted to avoid prescribing the medication in the context of extreme elevations. Ongoing monitoring is required only if symptoms warrant it because the consistent effect of naltrexone in studies of alcohol use disorder has been to decrease liver enzyme concentrations. Oral naltrexone should be administered initially at a dosage of 25 mg/d to minimize adverse effects. The dosage can then be increased in 25-mg increments every 3-7 days to a maximum dosage of 150 mg/d using desire to drink or another symptom that the patient identifies as reflective of risk of relapse to heavy drinking. It should be noted, however, that there is no clear evidence that a higher dosage is more efficacious than is the FDA-approved dosage of 50 mg/d. Nausea and other gastrointestinal symptoms are most common early in treatment, as are neuropsychiatric symptoms (eg, headache, dizziness, lightheadedness, weakness), and are usually transient. Delaying or avoiding a dosage increase can be used to address more persistent adverse events. In a few patients, flu-like symptoms occur, and the patient may not be willing to consider options other than discontinuation. Long-acting naltrexone is only available as a 380-mg dose, which should be administered as a deep intramuscular injection in the upper, outer quadrant of the gluteal muscle of the buttock every 4 weeks. With repeated administrations, the

injection should be alternated to the side contralateral to the immediately preceding injection. The medication is approved for use in patients who are abstinent from alcohol and who are also receiving psychosocial treatment. The precise length of the period of abstinence is not specified, and there is no evidence of any risk of consuming alcohol with naltrexone. Adverse effects with this formulation are similar to those of the oral medication, though pain and inflammation at the injection site may also occur. Local interventions, such as warm compresses, and nonsteroidal anti-inflammatory medications can be used to treat such injection site reactions.

Nalmefene Nalmefene has also been evaluated as a treatment for alcohol use disorder. As with naltrexone, nalmefene is an opioid antagonist without agonist properties. Nalmefene’s affinity for the μ- and κ-opioid receptors is similar to that of naltrexone, though its affinity for the δ-opioid receptor is greater than that of naltrexone (42). A pilot study of nalmefene 40 mg/d showed it to be superior to both 10 mg/d of the medication and placebo in the prevention of relapse to heavy drinking in patients with alcohol dependence (43). A subsequent study showed no difference between nalmefene 20 mg/d or 80 mg/d. However, when combined, the nalmefene-treated subjects reported significantly less heavy drinking than did the placebo group (44). A 12-week, multisite, dose-ranging study compared placebo with 5, 20, or 40 mg of nalmefene in a sample of recently abstinent outpatients with alcohol dependence (45). In this study, all subjects showed a reduction in self-reported heavy drinking days and on biological measures of drinking, with no difference between the active medication and placebo groups on these measures. Recently, targeted nalmefene (where subjects were encouraged to use 10-40 mg of the medication when they believed drinking to be imminent) was combined with a minimal psychosocial intervention in a multicenter, placebo-controlled, randomized trial (46). Nalmefene was superior to placebo in reducing heavy drinking days, very heavy drinking days, and drinks per drinking day and in increasing abstinent days. Further, after 28 weeks of treatment, when a subgroup of nalmefene-treated subjects was randomized to a withdrawal extension, patients assigned to receive placebo were more likely to return to heavier drinking. Nalmefene was approved for reduction of alcohol use by the European Medicines Agency in 2013 at a dosage of 18 mg/d as needed when the patient perceives a risk of alcohol consumption.

Summary There now exists abundant evidence of the efficacy of opioid antagonists (particularly naltrexone) for the treatment of alcohol use disorder. In unselected samples of patients, these medications exert a modest overall effect. Targeted administration of naltrexone and the long-acting injectable formulation may enhance the clinical utility of this medication. The optimal dosage and duration of treatment and the relative benefit accruing to combining the medication with different types and intensities of psychosocial treatment are important clinical questions that have not yet been adequately addressed.

Acamprosate Acamprosate (calcium acetyl homotaurinate) is an amino acid derivative that increases gamma-aminobutyric acid (GABA) neurotransmission and also has complex effects on excitatory amino acid (ie, glutamate) neurotransmission, which is most likely the effect that is important for its therapeutic effects in alcohol use disorder. Acamprosate was first shown in a single-site study to be twice as effective as placebo in reducing the rate at which patients with alcohol dependence returned to drinking (47). The medication has been studied extensively in Europe, and three of the European studies provided the basis for the approval of acamprosate by the FDA for clinical use in the United States (48). Meta-analyses from the European studies provide consistent evidence of the efficacy of acamprosate in the treatment of alcohol use disorder (26,28,49–51). The magnitude of the advantage accruing to treatment with acamprosate over placebo in those studies varied as a function of the outcomes examined but was in the small range of effect sizes. A meta-analysis of continuous abstinence showed a significant advantage for acamprosate over placebo, and although the effects were modest, they increased progressively as treatment duration increased from 3 to 6 and then to 12 months (50). Chick et al. (50) sought to determine whether treatment with acamprosate reduces the severity of relapse for patients in abstinence-oriented treatment who fail to abstain completely. Among patients who relapsed to drinking, acamprosate treatment was significantly associated with less quantity and frequency of drinking than was placebo at follow-up periods as long as 1 year. Acamprosate also reduced the risk of heavy drinking (ie, 5 or more drinks per day).

In a study that has implications for the use of acamprosate in combination with disulfiram, a multicenter trial was conducted in which patients were randomly assigned to receive acamprosate or placebo, with stratification for those who voluntarily were using disulfiram. Acamprosate was found to be superior to placebo on measures of total abstinence and on cumulative abstinent days (52). The group treated with acamprosate and disulfiram showed a significantly greater percentage of abstinent days than did any of the other three groups. However, because the design was not fully randomized, more rigorous studies of this combination therapy are needed to evaluate the validity of these findings. In summary, studies in more than 4000 patients in Europe provide evidence of a beneficial effect of acamprosate in the prevention of relapse to drinking and in the reduction of drinking among patients who relapse. Based on the evidence of its efficacy, the FDA approved the medication for clinical use in the United States (48). However, two multicenter trials conducted in the United States, the first being a multicenter trial of two active dosages of acamprosate (53) and the second being the COMBINE (Combining Medications and Behavioral Interventions for Alcoholism) study (30), the largest alcohol treatment trial to date (described in the following section), failed to show an advantage of acamprosate over placebo on an intent-to-treat basis. This raises the question of the factors that distinguish alcohol pharmacotherapy trials in Europe from those in the United States. Differences in features of study design (eg, European studies required a lengthier period of abstinence) and of the samples studied (eg, European subjects were heavier drinkers) may explain these discrepant findings.

Clinical Considerations in the Use of Acamprosate Acamprosate is FDA approved at a dosage of 1998 mg/d (ie, two 333-mg capsules three times per day) in patients who are abstinent from alcohol and receiving psychosocial treatment. The most common adverse effects of the drug are generally mild and transient and include gastrointestinal (eg, diarrhea, bloating) and dermatological (eg, pruritus) complaints. In contrast to disulfiram and naltrexone, which are metabolized in the liver, acamprosate is excreted unmetabolized, so that renal function is the rate-limiting factor in the drug’s elimination. Evaluation of renal function prior to initiation of the drug is warranted, particularly in individuals who have a history or are otherwise at risk of renal disease and in the elderly.

Studies Comparing Acamprosate With Naltrexone and the Two Medications Combined Two placebo-controlled studies have directly compared treatment with acamprosate, naltrexone, and acamprosate and naltrexone combined. In the first study, a 12-week trial in 160 patients, all three active medication groups (naltrexone, acamprosate, and the two medications combined) were significantly more efficacious than was placebo (54). In that study, although the rate of relapse of participants in the combined medication group was significantly lower than that in either the placebo or acamprosate groups, it was not statistically better than naltrexone alone. The COMBINE study, a 4-month, multicenter, placebo-controlled study conducted at 11 sites in the United States, compared naltrexone, acamprosate, and their combination in a sample of nearly 1400 abstinent alcohol-dependent subjects. The design of the study was complex, insofar as two different behavioral interventions (medical management or an intensive behavioral treatment) were combined with naltrexone (100 mg/d), acamprosate (3 g/d), naltrexone and acamprosate, or placebo, so that eight groups received study medication. Further, to evaluate the effects of placebo treatment, a ninth group, which received an intensive behavioral treatment but no medication, was also included. Overall, when on study treatment, subjects significantly increased the percentage of abstinent days. Groups receiving naltrexone and medical management; intensive behavioral treatment, medical management, and placebo; and naltrexone, intensive behavioral treatment, and medical management had a significantly greater percentage of days abstinent than the group receiving placebo and medical management. Naltrexone also reduced the risk of a heavy drinking day in the group receiving medical management but not intensive psychotherapy. In addition to showing a modest advantage for the use of either naltrexone or intensive behavioral treatment, it is noteworthy that the study failed to show an advantage for acamprosate over placebo, either alone or when added to naltrexone on any of the drinking outcomes. The study also showed evidence of a placebo response among individuals receiving the intensive behavioral intervention, in that those that received neither an active nor a placebo medication showed significantly less improvement than those who were treated with placebo. It should be noted that, with one exception (26), published meta-analyses do not include data from the COMBINE study, of clear relevance

because it is among the largest studies of either naltrexone or acamprosate.

Anticonvulsants Of growing interest is the use of anticonvulsants for the treatment of alcohol use disorder, although currently none are FDA approved for this indication. The efficacy of this class of medications for the treatment of alcohol use disorder was initially demonstrated in placebo-controlled studies of carbamazepine (55), divalproex (56), and topiramate (57), with a multicenter study (58) confirming the efficacy of topiramate for this indication. Although these medications have different mechanisms of action, it is likely that they exert beneficial effects in alcohol use disorder through their actions as glutamate antagonists and GABA agonists, helping to normalize the abnormal activity in these neurotransmitter systems seen following chronic heavy drinking. In a 12-month pilot study, Mueller et al. (55) found carbamazepine to be superior to placebo in increasing the time to the first heavy drinking day and in reducing drinks/drinking day and the number of consecutive days of heavy drinking. In a 12-week, double-blind pilot study, Brady et al. (56) found that a significantly lower percentage of patients receiving divalproex than placebo relapsed to heavy drinking. There was also a significantly greater decrease in irritability in the divalproex-treated group. Johnson et al. (57) initially conducted a single-site, 12-week, placebocontrolled study of topiramate, with the dosage gradually increased over 8 weeks to a maximum of 300 mg. Topiramate-treated patients showed significantly greater reductions than did placebo-treated patients in drinks per day, drinks per drinking day, drinking days, heavy drinking days, and γ-glutamyl transpeptidase levels. Based on these findings, a subsequent multicenter study was conducted (58), which showed many of the same effects on drinking as the single-site study, though topiramate was not as well tolerated as it was in the initial trial. The authors interpreted these findings to reflect the more rapid dose titration (to a maximum of 300 mg, but over 6 weeks). The most common adverse effect of topiramate compared to placebo is numbness and tingling (which is secondary to the commonly observed metabolic acidosis produced by the antagonism by topiramate of carbonic anhydrase), with other common side effects including a change in the sense of taste, tiredness/sleepiness, fatigue, dizziness, loss of appetite, nausea, diarrhea, weight decrease, and difficulty concentrating, with memory, and in word finding. Of clinical concern also are suicidal thoughts or actions, which have been reported

uncommonly but at a frequency greater than that seen with placebo treatment. Other adverse effects of topiramate that are less likely to occur but potentially serious are renal calculi and acute secondary glaucoma. These findings provide clear support for the efficacy of this anticonvulsant for the treatment of alcohol use disorder and suggest that the use of topiramate for this purpose should include a slowly increasing dosage. Additional research focusing on the optimal rate of dosage increase and the minimal dosage that is efficacious in alcohol use disorder is warranted. In regard to personalized medicine, a randomized, controlled, double-blind trial of topiramate 200 mg/d versus placebo showed a robust effect of topiramate on number of heavy drinking days, but in a subsample of European Americans, this effect was accounted for almost entirely by a single nucleotide polymorphism in the gene coding for one of the subunits of the kainate type of glutamate receptor (59). This finding requires replication in a larger prospective study before it would be clinically applicable. Mason and colleagues (60) conducted a 12-week, double-blind trial (n = 150) of two different doses of gabapentin (900 mg, 1800 mg) versus placebo in patients with alcohol dependence. Significant linear dose effects were reported with abstinence rate, no heavy drinking, cravings, mood and sleep. These effects were more pronounced in the gabapentin 1800 mg group (abstinence: NNT = 8; no heavy drinking: NNT 5). These finding add to the literature suggesting gabapentin may reduce heavy drinking, increase abstinence, improve sleep, and reduce acute/protracted withdrawal syndromes (61,62). Larger trials are warranted.

Baclofen This GABA-B receptor agonist has been approved as an antispasmodic for more than 30 years and has recently been studied as a treatment for alcohol use disorder, although not FDA approved for such treatment. In a small trial, Addolorato et al. (63) randomly assigned recently abstinent individuals with alcohol dependence to receive up to 30 mg/d of the medication or placebo divided into three daily doses. The medication was well tolerated, and the baclofen-treated group was more likely to remain abstinent over the 1-month treatment period (also showing a greater number of cumulative abstinence days) than was the placebo group. More recently, these investigators (64) evaluated the efficacy of baclofen in a sample of 84 patients with alcohol dependence with liver cirrhosis. Baclofen-treated patients were significantly more likely than were

placebo-treated patients to maintain abstinence (71% vs. 29%), with a concomitant doubling of abstinence days in the baclofen group. The medication was well tolerated, and the baclofen group showed a nonsignificantly lower rate of study dropout than did the placebo group (14% vs. 31%). More recent studies have shown contradictory findings. A flexible dosing double-blind randomized trial with 56 participants found significantly higher total abstinence rates and abstinence duration among participant who received active medication (mean dose in the active baclofen group = 180 mg [SD = 86.9]/day) (65). However, a larger multicenter randomized, double-blind trial with 151 participants compared a high-dose baclofen group (mean = 93.6 [SD = 40.3]/day) to 30 mg/d and placebo groups and saw no differences between groups in any measure of alcohol use while also noting frequent adverse events in the high-dose group (66). Another multicenter randomized, double-blind trial among 180 U.S. military Veterans similarly found no effect of baclofen 30 mg/d compared to placebo on any alcohol use outcomes (67). Overall, there is insufficient evidence for efficacy of baclofen in treatment of alcohol use disorder at the present time.

Serotonergic Agents in Alcohol Use Disorder Subtypes Although there is no evidence overall that serotonergic agents act as effective treatments for alcohol use disorder, they may have benefit in certain subtypes. Adapting an approach first used by Kranzler et al. (68), Pettinati et al. (69) found that low-risk/low-severity patients with alcohol dependence (ie, those with later age of onset) drank on fewer days and were more likely to be completely abstinent in the 12-week treatment trial when treated with sertraline compared with placebo. In a 6-month posttreatment follow-up of these patients (70), the beneficial effects of sertraline treatment persisted in this subgroup. Chick et al. (71) also found an effect with fluvoxamine that was similar to that observed with fluoxetine (68). Specifically, among early-onset drinkers, fluvoxamine was associated with worse outcome than placebo. Using a subtyping approach, Johnson et al. (72) found that ondansetron (a 5HT receptor antagonist) selectively reduced drinking among patients with early onset of problem drinking (ie, before age 25; early-onset patients with alcohol dependence). Specifically, ondansetron was superior to placebo on the proportion of days abstinent and on the intensity of alcohol intake. In contrast,

late-onset patients with alcohol dependence showed effects of ondansetron on drinking behavior that were comparable to those of placebo. In a subsequent 8week, open-label study of ondansetron, early-onset patients with alcohol dependence had a significantly greater decrease in drinks per day, drinks per drinking day, and alcohol-related problems than did late-onset patients with alcohol dependence (73). Furthermore, a prospective double-blind trial of ondansetron in which participants were randomized based upon polymorphisms in the gene coding for the serotonin transporter showed a positive response in participants with the polymorphisms (74). A retrospective analysis of the same data showed that polymorphisms in the genes coding for serotonin 5-HT3 receptor subtypes also predicted outcome (75). Additional prospective and replication studies are needed to evaluate whether there is a clearer role for the serotonergic medications in the treatment of heavy drinking or alcohol use disorder in individuals differentiated by alcohol use disorder subtype or genotype.

MEDICATIONS TO TREAT COOCCURRING PSYCHIATRIC SYMPTOMS OR DISORDERS IN PATIENTS WITH ALCOHOL USE DISORDER Although most patients with alcohol use disorders report a reduction in mood or anxiety symptoms following acute withdrawal, for some, these symptoms may persist for months. Even among patients without substantial symptoms of alcohol withdrawal, persistent, low-level mood or anxiety symptoms may develop, a condition that has been called “subacute withdrawal.” In a substantial minority of patients, these symptoms may reflect diagnosable psychiatric disorders. Although medications (eg, serotonin reuptake inhibitors) are often prescribed during the postwithdrawal period in hopes of relieving these symptoms, there is not good evidence that the treatment of persistent or subacute withdrawal symptoms that do not meet diagnostic criteria for a co-occurring psychiatric disorder results in better outcome in patients with alcohol use disorder. Many of the early studies of the efficacy of medications to treat mood

disturbances targeted symptoms of depression and anxiety in unselected groups of patients with alcohol use disorder after withdrawal. These and other methodological limitations in these studies make the failure to demonstrate an advantage over control conditions through reductions in either psychiatric symptoms or drinking behavior difficult to interpret (76). Over the past 10-15 years, there has been renewed interest in the incidence and prevalence of cooccurring psychiatric disturbances among patients with alcohol use disorder (77). Community studies have shown high rates of co-occurrence of psychiatric disorders in individuals with alcohol use disorder (78,79). Further, the majority of such individuals who seek treatment meet lifetime criteria for one or more psychiatric disorders in addition to alcohol use disorder, most commonly mood disorders, drug dependence, antisocial personality disorder, and anxiety disorders (80,81). Antidepressants, benzodiazepines and other anxiolytics, antipsychotics, and lithium have been used to treat anxiety and depression in the postwithdrawal state. Although, in general, the indications for use of these medications in patients with alcohol use disorder are similar to those for patients with psychiatric illness who do not have alcohol use disorder, careful differential diagnosis is warranted to identify patients for whom the symptoms can be ascribed to substance use. Further, the choice of medications should take into account the increased potential for adverse effects when prescribed to individuals who are actively drinking heavily. Adverse effects can result from pharmacodynamic interactions with medical disorders that commonly occur in the course of alcohol use disorder, as well as from pharmacokinetic interactions with medications prescribed to treat these disorders (82).

Antidepressant Treatment of Unipolar Depression and Alcohol Use Disorder A majority of the studies in a meta-analysis that included 14 prospective, parallel-group, double-blind, randomized, placebo-controlled trials of antidepressants for a co-occurring substance use disorder and unipolar depression focused on alcohol dependence (83). Eight studies (six of which were in patients with alcohol dependence) showed a significant or near-significant advantage for the active medication over placebo in reducing symptoms of depression. The pooled effect size on the standardized difference between means on the Hamilton Depression Rating Scale was 0.38 (95% CI 0.18 to 0.58), a small to moderate effect. Studies with a placebo response rate > 25% showed no

advantage for the active medication, whereas those with a smaller placebo response rate yielded effects in the moderate to large range. Allowing a week of abstinence to transpire before making a diagnosis of depression predicted a better antidepressant response. In contrast, a larger proportion of women in the study sample, the use of serotonin reuptake inhibitors (vs. tricyclic or other antidepressants), and a concurrent psychosocial intervention were associated with a poorer medication response. Studies that showed a moderate effect of the medication on depression scores also showed moderate reductions in substance use, whereas smaller effects on depressive symptoms were associated with no beneficial effects on substance use. Subsequent to the analysis by Nunes and Levin (83), there have been studies of pharmacotherapy for co-occurring alcohol dependence and depression. Hernandez-Avila et al. (84) compared nefazodone with placebo in subjects with alcohol dependence with current major depression. Although there were greater reductions in anxiety and depressive symptoms in the nefazodone group, the effects did not reach statistical significance, potentially because of the small sample size. Nonetheless, nefazodone-treated subjects reduced the frequency of heavy drinking days and total number of drinks more than did placebo-treated subjects. The occurrence of a limited number of reported cases of idiosyncratic hepatic failure during nefazodone treatment limits the drug’s clinical utility. Kranzler et al. (85) conducted a multicenter trial of sertraline in 328 patients with co-occurring major depressive disorder and alcohol dependence. After a 1week, single-blind, placebo lead-in period, patients were randomly assigned to receive 10 weeks of treatment with sertraline or placebo. Randomization was stratified, based on whether initially elevated depression scores declined with the cessation of heavy drinking. Both depressive symptoms and alcohol consumption decreased substantially over time in both groups, with no reliable medication group differences on depressive symptoms or drinking behavior in either group. The high placebo response rate may have contributed to the null findings. Pettinati et al. (86) performed an elegant clinical trial in which participants with co-occurring major depression and alcohol dependence were randomly assigned in double-blind fashion to one of four treatment conditions: (a) sertraline 200 mg/d (n = 40), (b) naltrexone 100 mg/d (n = 49), (c) the combination of sertraline 200 mg/d and naltrexone 100 mg/d (n = 42), and (d) double placebo (n = 39). Over 14 weeks, the combination treatment group had a significantly higher abstinence rate and a significantly longer mean time to relapse to heavy drinking than did the other three groups. The combination

group also had higher, though not statistically significantly higher, rates of depression remission with fewer serious adverse events than did the other three groups. The impressive findings from this study, absent any contraindications, strongly encourage the combination of naltrexone and sertraline for the treatment of patients with co-occurring alcohol use disorder and depression. In summary, there is evidence that most episodes of postwithdrawal depression will remit without specific treatment if abstinence from alcohol is maintained for a period of days or weeks (87,88). However, persistent depression requires treatment. Serotonin reuptake inhibitors and newer generation antidepressants have become the first-line treatment of depression because they have a favorable adverse event profile. These medications do not have the anticholinergic, hypotensive, or sedative effects of the tricyclic antidepressants, nor do they, with the possible exception of citalopram, have the adverse cardiovascular effects, which in overdose can be lethal. However, serotonin reuptake inhibitors can exacerbate the tremor, anxiety, and insomnia often experienced by patients with physiological dependence on alcohol who have been recently withdrawn from alcohol and may slightly increase the risk of gastrointestinal bleeding (particularly in combination with nonsteroidal antiinflammatory drugs or aspirin). Furthermore, the findings of Nunes and Levin (83) suggest that for the treatment of depression among patients with a substance use disorder, serotonin reuptake inhibitors may be less efficacious than tricyclic or other types of antidepressants.

Mood Stabilizer Treatment of Bipolar Disorder and Alcohol Use Disorder Bipolar disorder co-occurs commonly with alcohol use disorder. The presence of comorbid alcohol use disorder is associated with an increased rate of mixed or dysphoric mania and rapid cycling, as well as greater bipolar symptom severity, suicidality, and aggression (89). However, controlled trials of medication to treat these comorbid disorders are difficult to conduct. A placebo-controlled trial of divalproex sodium in bipolar patients with DSM-IV alcohol dependence taking lithium showed that the drug significantly decreased the proportion of heavy drinking days (corroborated by a decrease in the concentration of gammaglutamyl transpeptidase), whereas manic and depressive symptoms improved equally in both groups (90).

Treatment of Co-occurring Anxiety Disorders and Alcohol Use Disorder Benzodiazepines and Other Anxiolytics Benzodiazepines are widely used and generally considered to be acceptable treatment for acute alcohol withdrawal. In contrast, most nonmedical personnel involved in the treatment of alcohol use disorder oppose the use of medications that can induce physical dependence or even a substance use disorder, to treat the anxiety, depression, and sleep disturbances that can persist for months after withdrawal. The relative merits of the use of benzodiazepines in patients with alcohol and other substance use disorders during the postwithdrawal period for the management of anxiety or insomnia have also been debated in the medical literature (91,92). Despite the risks that the use of benzodiazepines may create in patients with alcohol use disorder beyond the period of acute withdrawal (eg, physical dependence or overdose), judicious use of the drugs in this setting may be justified. Early relapse, which commonly disrupts alcohol rehabilitation, can result from protracted withdrawal-related symptoms (eg, anxiety, depression, insomnia). To the extent that these symptoms can be suppressed by low doses of benzodiazepines, retention in treatment could be increased (93). Moreover, for some patients, benzodiazepine use disorder, if it does occur, may be more benign than alcohol use disorder. The controversy surrounding this approach to alcohol treatment stems from the fact that these potential benefits must be weighed against the risk both of overdose and of physical dependence on benzodiazepines. Although these drugs alone are comparatively safe, even in overdose, their combination with other brain depressants (including alcohol) can be lethal. Although there is little doubt that individuals with alcohol use disorder are more vulnerable to develop dependence on the benzodiazepines than is the average person, the potential for developing a use disorder may be lower than is generally believed (94,95). However, physiological dependence on both alcohol and benzodiazepines may increase depressive symptoms (87), and co-occurring alcohol and benzodiazepine use disorders may be more difficult to treat than is alcohol use disorder alone (96). The benzodiazepines currently available for clinical use vary by pharmacokinetics, in their acute euphoric effects, and the frequency with which

they are reported to cause physiological dependence. Diazepam, lorazepam, and alprazolam may have greater potential for a substance use disorder than does chlordiazepoxide or clorazepate (97). Similarly, oxazepam was reported to produce low levels of nonmedical use (94). Jaffe et al. (98) found that, when administered to recently withdrawn patients with alcohol dependence, halazepam produces minimal euphoria even at a supratherapeutic dosage. Partial agonist compounds at the benzodiazepine receptor complex may offer an advantage over approved benzodiazepines for use in individuals with alcohol use disorder, though there is no literature as yet that addresses this question. Buspirone, a nonbenzodiazepine anxiolytic, exerts its effects largely via its partial agonist activity at serotonergic autoreceptors. Although comparable in efficacy to diazepam in the relief of anxiety and associated depression in outpatients with moderate-to-severe anxiety (99,100), buspirone is less sedating than is diazepam or clorazepate, does not interact with alcohol to impair psychomotor skills, and does not have substance use disorder liability (101,102). This pharmacological profile makes buspirone more suitable than benzodiazepines to treat anxiety symptoms among patients with alcohol dependence. In contrast to benzodiazepines, however, buspirone does not have acute anxiolytic effects, is not useful in the treatment of alcohol withdrawal, and is not useful for treating the insomnia that is commonly reported by patients with alcohol use disorder during acute and protracted withdrawal. Results from three of four placebo-controlled, double-blind trials of buspirone to treat anxiety symptoms among patients with alcohol use disorder have shown the drug to be superior to placebo in increasing treatment retention and reducing anxiety symptoms and measures of drinking (103,104). Although buspirone appears to be useful in the treatment of anxiety symptoms in patients with alcohol use disorder, it has not been possible to identify clinical features that differentiate individuals for whom buspirone may be most efficacious from those who are not responsive to the medication.

THE USE OF PHARMACOTHERAPIES IN THE TREATMENT OF ALCOHOL USE DISORDER Despite data suggesting efficacy, the use of medications that have been approved for treatment of alcohol use disorder remains very limited. The lack of robust

utilization can be found in large organizations such as the Veterans Health Administration as well as other public and private entities (105,106). This limited use is evident even in clinicians who have been trained to treat alcohol use disorder—addiction physicians. A survey of nearly 1400 members of the American Society of Addiction Medicine and the American Academy of Addiction Psychiatry (107) showed that they prescribed disulfiram to only 9% of their patients with alcohol dependence, and naltrexone was prescribed only slightly more frequently (ie, to 13% of patients). In contrast, antidepressants were prescribed to 44% of patients with alcohol use disorder. Although nearly all of these physicians had heard of disulfiram and naltrexone, their self-reported level of knowledge of these medications was much lower than that for antidepressants and benzodiazepines. Additionally, primary care physicians, which represent the clinicians most likely to diagnose alcohol use disorder, were found in the not too distant past to be unfamiliar with approved pharmacotherapies (108). Clearly, additional education is needed to improve awareness among treatment professionals as well as patients.

SUMMARY AND CONCLUSIONS Although continuing developments in the United States, Europe, and Australia suggest that medications may eventually become a key element in alcohol treatment, many clinical questions must be considered before medications are likely to be widely employed for this indication. In addition to the issues discussed earlier in regard to specific agents (eg, What is the optimal duration of naltrexone treatment?), the safety and efficacy of medications to treat alcohol use disorder must be examined with adequate statistical power in women, in different ethnic/racial groups, and in adolescent and geriatric samples. The treatment of psychiatric symptoms that co-occur with alcohol use disorder, which can augment efforts at relapse prevention, has been studied in some detail (76). However, the literature remains mixed with respect to the efficacy of specific interventions. Anxiolytics that are low in nonmedical potential, such as buspirone, and antidepressants with benign side effect profiles, such as the newer generation drugs that may reduce ethanol intake, warrant careful evaluation in the treatment of anxious and depressed patients with alcohol use disorder. However, even if medications that are prescribed to patients with alcohol use disorder with persistent co-occurring mood and anxiety symptoms ameliorate

those symptoms, they will not necessarily reduce alcohol consumption after a significant degree of alcohol use disorder develops. This is likely to hold true even if pathological mood states were important in the initiation of heavy drinking (77,109). That is, the neuroadaptive changes and the complex learning that characterize alcohol use disorder (110) are not likely to resolve because one major contributing factor is brought under control. The challenge for practitioners treating alcohol use disorder is to combine efficacious medications with empirically based psychological interventions and self-help group participation for those patients willing and able to incorporate these elements into their treatment. The medications that have been most widely studied in alcohol treatment are disulfiram, naltrexone, and acamprosate. Results from the COMBINE study and trials of depot naltrexone formulations, topiramate, and gabapentin have provided important new information on the use of these medications in alcohol treatment. As the research literature on the use of medications to treat alcohol use disorder grows, it will be possible to assess the utility of different medication combinations and a variety of psychotherapies. There are also ongoing efforts to match medications with specific subgroups of patients with alcohol use disorder, based on clinical or genetic characteristics, and these are beginning to bear fruit. The use of medications in patients who are actively participating in self-help groups may be particularly challenging. Although members of abstinenceoriented groups such as Alcoholics Anonymous may be willing to work with physicians when they prescribe disulfiram, the use of which is supportive of their goal of total abstinence, they may be less supportive of other medications that aim to reduce drinking and its associated medical, psychological, and social harm. As evidence has accumulated showing that a growing number of medications are efficacious for the treatment of alcohol use disorder, the therapeutic options available to physicians in treating these patients have increased. Nonetheless, many of these developments have not been translated to widespread changes in treatment. The major challenge to medications development will be to identify new medications that are efficacious and well tolerated, as well as the patient and treatment factors that can be used to optimize effectiveness. Because all three medications that are FDA approved for the treatment of alcohol use disorder have demonstrated efficacy in some patients, these medications should be considered a first-line treatment in patients with alcohol use disorder, to be used in combination with behavioral treatment. Given limited data on how to choose which of the efficacious medications is

appropriate for any given patient, the choice can be made based on physician and patient preference.

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CHAPTER 56

Pharmacological Interventions Sedative–Hypnotic Use Disorder Jeffrey S. Cluver, Tara M. Wright and Hugh Myrick

for

CHAPTER OUTLINE Introduction Pharmacology Definitions Use of Sedative–Hypnotic Medications Indications for Pharmacological Interventions Management of Intoxication and Overdose Withdrawal Management of Withdrawal Treatment Setting Treatment of Co-occurring Disorders Conclusions and Future Directions

INTRODUCTION Sedative–hypnotic agents have long been popular in medicine because of their ability to mitigate anxiety and induce sleep. Most of the drugs in this class of medications have a mechanism of action in the central nervous system (CNS) that leads to their anxiolytic and sleep-inducing properties. Prior to 1900, agents such as chloral hydrate, bromide, paraldehyde, and sulfur were used. The first barbiturate (barbital, a derivative of barbituric acid) was introduced in 1903 and soon became popular because of its predictable ability to induce sleep and decrease anxiety. Phenobarbital was introduced in 1912, and in addition to the effects seen with barbital, this medication was also shown to have anticonvulsant properties. Despite safety and non-medical use issues, such as its narrow therapeutic index, tolerance, and drug interactions, phenobarbital proved to be a popular medication, and thousands of derivative compounds were developed. While there are still a number of barbiturates available, their clinical use has been largely supplanted by benzodiazepines. The first benzodiazepine was synthesized in 1957. Chlordiazepoxide (Librium) and the other benzodiazepines that followed, were found to be useful in the treatment of anxiety and sleep disorders. While the properties of benzodiazepines and barbiturates are similar, the relative safety and tolerability of the benzodiazepines has led to their widespread and lasting use. Medications in the benzodiazepine class all share a similar structure and bind to the same

receptor site on the gamma-aminobutyric acid (GABA) receptor. Barbiturates also act on the GABA receptor, by binding to a different subunit than the benzodiazepines. Other relatively new additions to this category of medications are the imidazopyridine derivatives (zolpidem and others), zaleplon, and eszopiclone. These medications are chemically distinct from benzodiazepines, but they also bind to the GABA receptor, at the omega subunit. In Table 56-1, currently available sedative–hypnotic agents are listed. It has been reported that the behavioral and subjective effects (including subject-rated measures related to addiction potential) of the newer compounds (zolpidem, zaleplon, and eszopiclone) are similar to those of the traditional benzodiazepines, in both individuals with and without a history of substance use disorders (1,2), and self-administration in laboratory animals has also been seen (3). Benzodiazepines and other sedative–hypnotics lend themselves to misuse, including use in conjunction with other substances (4). These medications can be used to enhance the effects of the other substances, or to help an individual cope with unpleasant side effects of other drug use or withdrawal. Additionally, alone or when used with other CNS depressants, benzodiazepines and sedative– hypnotics can lead to respiratory depression, coma, and death. In this chapter, we focus on the management of individuals with sedative, hypnotic, or anxiolytic use disorder, especially in the context of withdrawal.

TABLE 56-1 Classes of Sedative–Hypnotic Drugs: Drug Classes, Nonproprietary Names, and Trade Names

PHARMACOLOGY As mentioned previously, the effects of benzodiazepines and other sedative– hypnotics are mediated by their binding to the GABA receptor. GABA receptors are distributed widely throughout the brain and are so named because they bind

GABA, the major inhibitory neurotransmitter in the CNS. There are specific receptor subunits that are allosterically bound to the GABA receptor, and these medications act as agonists by increasing the ability of the inhibitory neurotransmitter GABA to bind to and activate the GABA-A receptor. When an agonist such as a benzodiazepine or barbiturate binds to the GABA receptor, the receptor opens its chloride channel, which then decreases neuronal excitability. Clinically, this leads to the effects of decreased anxiety, increased sedation, muscle relaxation, and increased seizure threshold. The toxic effects of these compounds are caused by excessive opening of chloride channels and can lead to respiratory depression. Barbiturates increase GABA-A activity by increasing the duration of chloride channel opening, which can lead to excessive activity of GABA-A receptor and respiratory depression. Benzodiazepines affect GABA-A activity by increasing the frequency of chloride channel opening, which can also lead to toxicity, but with a larger therapeutic index. The imidazopyridine derivatives zolpidem and zaleplon bind with high affinity at the type I benzodiazepine recognition site, on the GABA-A receptor omega subunit. Among the sedative–hypnotic agents, there are important differences in the onset of activity, half-life of the medication, presence of active metabolites, and specificity of the clinical effects. While benzodiazepines and other sedative–hypnotics are agonists at the GABA receptor, there are also inverse agonists (such as beta-carboline) that bind to the GABA receptor but cause the chloride channels to close. Such inverse agonists can cause increased anxiety and lower the seizure threshold. Flumazenil is an antagonist compound with a high affinity for the GABA receptor. This medication was developed and marketed to reverse the effects of benzodiazepines, including sedation and respiratory depression.

DEFINITIONS It is worth taking a moment to clarify several definitions, especially when discussing this class of medications. Physical dependence can be defined as an altered homeostasis at several levels of drug effect and activity. Examples of physical dependence include tolerance and withdrawal. Discontinuation of the drug in this state leads to symptoms resulting from a disruption of this homeostasis. Tolerance can be defined as a decreased pharmacological effect after repeated or prolonged exposure to the drug so that higher doses are needed to achieve the same initial clinical effects. Both physical dependence and tolerance are inevitable with prolonged and regular use of medications in the

class of benzodiazepines and other sedative–hypnotics. Non-medical use generally refers to inappropriate use of a medication such as the use of a higher dose than prescribed. Substance use disorder is defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria as a maladaptive pattern of substance use leading to clinically significant impairment or distress, defined by meeting multiple specified criteria within a 12-month period. Drugs with reinforcing properties, such as the ability to produce euphoria, reduce unpleasant sensations, or induce other positive subjective experiences, are more likely to lead to a substance use disorder. The onset of physical dependence should not be equated with, or imply, the presence of a substance use disorder, although the two often coexist. Similarly, the misuse of a medication does not directly imply a substance use disorder, as may be the case in patients with severe anxiety disorders who do not achieve relief with their initially prescribed doses.

USE OF MEDICATIONS

SEDATIVE–HYPNOTIC

Benzodiazepines have largely replaced barbiturates and other sedative–hypnotics in clinical settings, due to their preferred pharmacological profile. According to IMS Health, there were 49.0 million alprazolam, 27.6 million lorazepam, 26.9 million clonazepam, 15.0 million diazepam, and 8.5 million temazepam prescriptions dispensed in the USA in 2011 (5). An estimated 1.9 million people aged 12 or older in 2015 reported nonmedical use of tranquilizers, and an estimated 446 000 people aged 12 or older reported non-medical use of sedatives in** 2015 (6). These medications are often initially prescribed for the treatment of anxiety disorders and insomnia, but their non-medical use (use at high doses or more frequent intervals) often leads to euphoria and disinhibition. Laboratory studies involving rats and nonhuman primates demonstrate that many sedative–hypnotics are self-administered, although the benzodiazepines appear to be less reinforcing than barbiturates (7). While there have been human studies that have demonstrated the reinforcing effects of the benzodiazepines, there are notable differences among the compounds, which correlate with the agents’ onset of action. Lorazepam, alprazolam, and diazepam all appear to have a greater potential for non-medical use, likely based on their inherent lipophilic properties, and therefore more rapid onset of action. It is also important to note that other human studies have demonstrated that benzodiazepines do not have

reinforcing effects in a majority of individuals (8), thus suggesting that some individuals may have a vulnerability that leads to non-medical use. The non-medical use of benzodiazepines and sedative–hypnotics is commonly seen in individuals with other substance use disorders (9). In this context, sedative–hypnotics are often used to enhance the effects of other drugs and alleviate unpleasant side effects from use or withdrawal of other substances. Benzodiazepines and other sedative–hypnotics may also be used when individuals who use many substances cannot obtain their substance of choice. Many patients who develop benzodiazepine and sedative–hypnotic use disorders were initially being treated for problems with sleep and anxiety disorders. Individuals seeking treatment for anxiety disorders, sleep disorders, and depression are at higher risk for developing sedative–hypnotic use disorder if they have a history of substance use disorders. A family history of substance use disorders also places an individual at higher risk for developing a substance use disorder. The issue of alcohol use disorder warrants special caution because of the potential for dangerous interactions. The assumption that all individuals with alcohol use disorder have a propensity for non-medical use of benzodiazepines or invariably developing a use disorder has been challenged (10), but the use of these medications should be closely monitored in this population.

INDICATIONS FOR PHARMACOLOGICAL INTERVENTIONS In general, there are two clear indications for pharmacological intervention in individuals who are taking benzodiazepines and other sedative–hypnotics. In a state of intoxication, a patient may require monitoring and even intervention to ensure a safe recovery. In patients experiencing acute withdrawal, pharmacological management is often recommended because of the risk of dangerous sequelae, including seizures and sedative withdrawal delirium. Deciding whether or not a benzodiazepine or other sedative–hypnotic should be used on a long-term basis is important to consider early on in the treatment course. In general, if there is a clear diagnosis, benefit from the treatment, minimal side effects, and no evidence of non-medical use or substance use disorder, then the medication could be continued (11). Sedative–hypnotics are commonly recommended for the shortest period of time possible, and these medications are often seen as short-term therapies that should be discontinued as soon as the clinical situation permits. The American Psychiatric Association

published guidelines in a 1991 task force report (12), and while these have not been updated, there continues to be increased scrutiny on the effectiveness of these medications, especially in long-term use, and in the elderly (13,14).

MANAGEMENT OF AND OVERDOSE

INTOXICATION

The signs and symptoms of benzodiazepine and sedative–hypnotic intoxication are very similar to those of alcohol intoxication. Severe intoxication can lead to respiratory depression, coma, and death. Benzodiazepine intoxication, even in the context of intentional overdose, rarely leads to death, unless the benzodiazepines are combined with other CNS depressants. The management of acute intoxication is mostly supportive, with special attention to airway management, as respiratory depression is the most likely cause of death in overdose. In overdose, it is also critical to know what other psychoactive agents (especially CNS depressants) may have been acutely or chronically ingested. Flumazenil can be used in the case of benzodiazepine intoxication and overdose, but its use is limited by the risk of precipitating withdrawal symptoms, including seizures, if this is not used with caution. Flumazenil can be considered in patients who have confirmed or suspected benzodiazepine toxicity, who have lost consciousness or are at risk of losing consciousness, and who may require intubation. Flumazenil should be avoided in patients who have also recently ingested medications or substances that lower the seizure threshold, in patients with known or suspected epilepsy, and in patients who have developed physiological dependence on benzodiazepines. Because of the risk of adverse events related to the administration of flumazenil, it should be administered in the lowest possible doses for the shortest period of time required and in a medical setting where resuscitation equipment and appropriately trained health care personnel are present (15–18).

WITHDRAWAL Withdrawal symptoms are most often seen in patients with physiological dependence after abruptly discontinuing benzodiazepines or other sedative– hypnotics (19). Withdrawal may be precipitated unintentionally when an individual stops taking a prescribed medication or is unable to obtain the

sedative–hypnotic from illicit sources. Withdrawal may also be inadvertently initiated by a provider due to concerns of misuse, psychological dependence, or other substance use disorders. In some cases, the decision is made to stop benzodiazepines because of side effects, such as memory impairment or behavioral problems. Individuals are more likely to develop withdrawal symptoms when they have been taking high doses of sedative–hypnotics, and if they have been taking even low or moderate doses for a prolonged period of time (7,20). While withdrawal symptoms are similar to those seen in alcohol withdrawal (Table 56-2), the signs and symptoms of withdrawal manifest in a somewhat idiosyncratic manner in each patient. Individual traits such as age and medical conditions and the unique pharmacological properties of each medication (21) all impact the types and severity of the withdrawal symptoms that are experienced. The onset and duration of withdrawal symptoms depend on the intrinsic pharmacokinetic properties (ie, half-life) of the agent itself as well as extrinsic factors that impact the metabolism and effective half-life of the agent, such as the inhibition or induction of cytochrome P-450 enzymes, patient age, and preexisting liver disease. The half-life of the medication, and its active metabolites, is of particular importance, especially when discussing the onset of withdrawal symptoms. Withdrawal from medications with short half-lives usually begins within 12-24 hours, and reaches peak intensity within 1-3 days. With longer-acting agents, withdrawal symptoms may begin later and not peak until 4-7 days after discontinuation. Symptoms may then continue for several more days or even weeks, depending on the half-life of drug. Advanced liver disease may lead to significantly prolonged half-lives and reduced elimination rates for benzodiazepines requiring oxidative metabolism prior to glucuronidation (ie, diazepam, clonazepam, chlordiazepoxide, and alprazolam) due to the impairment of the oxidative process. Impairment of the oxidative process and resulting prolongation of the half-lives of these benzodiazepines may also occur due to advanced age (22,23). As one example of cytochrome P450 enzyme effects, norfluoxetine (a metabolite of fluoxetine) may lead to the inhibition of the liver microsomal system responsible for alprazolam metabolism, resulting in clinically significant changes in the half-life and clearance of this benzodiazepine (22). Lorazepam, oxazepam, and temazepam avoid phase I metabolism via cytochrome P-450 enzymes and are conjugated directly in phase II metabolism; as such they are often the preferred agents in situations where there are concerns about liver function, age, and medication interactions.

TABLE 56-2 Sedative–Hypnotic Withdrawal Symptoms

Another common occurrence during withdrawal is the reemergence of symptoms of anxiety and insomnia, which has been found to occur in 60–80% of benzodiazepine-dependent patients who were initially treated for these disorders (24–28). Initially, these reemergence symptoms are perceived to be more severe and intense than the original symptoms, but within several weeks return to pretreatment levels. Although there is some debate as to the validity of the “protracted abstinence syndrome,” these residual symptoms are thought to persist for weeks to months and in some cases even years. Smith and Wesson (29) suggest that receptor-mediated changes lead to worsening of withdrawal symptoms when patients are tapered from the remaining, low-dose, medication. Prolonged or protracted withdrawal symptoms may include anxiety, sensitivity to light, sound, and touch (30), and tinnitus (31). In contrast to symptom reemergence, protracted withdrawal symptoms often wax and wane and slowly resolve with continued abstinence. It has been estimated that up to 50% of those who use benzodiazepine on a regular basis will experience clinically significant signs of withdrawal with sudden discontinuation (32). The duration and intensity of use necessary to cause withdrawal symptoms is unclear. Some sources suggest that it may take as little

as 4-6 weeks (25), while rebound insomnia has been seen after just 2 weeks of daily drug use (33).

MANAGEMENT OF WITHDRAWAL The decision to discontinue or taper sedative–hypnotic medications should be discussed at length with patients, with education provided about the reasons for discontinuation, the signs and symptoms that are likely to be experienced, and the risks and benefits of the available withdrawal strategies. There are several strategies that may be employed in the management of sedative–hypnotic withdrawal. The approach with the most data to support its safety and efficacy includes slowly tapering a medication over a prolonged period of time, in an effort to minimize the withdrawal symptoms. One benefit of this strategy is that it can be safely completed in an outpatient setting. Modest evidence exists to support more acute and rapid medically supervised withdrawals, similar to the approach taken in alcohol withdrawal treatment, though this is generally not as well tolerated as a prolonged taper (34). The later approach also requires close observation and monitoring and thus should only be undertaken in a closely supervised setting. Emerging evidence supports the use of certain anticonvulsants for the treatment of alcohol withdrawal, indicating there may be a role for the use of similar agents in the treatment of sedative–hypnotic withdrawal (34–36). However, there is little to no evidence that their use will prevent more a severe withdrawal course, including seizures and delirium tremens, especially in higher risk patients. The use of phenobarbital in the setting of an acute medically supervised withdrawal has also been studied, though the evidence to support this treatment is limited and somewhat dated. Flumazenil has also been studied for use in the management of benzodiazepine withdrawal.

Benzodiazepine Taper The approach with the most data to support its safety and efficacy is a taper that uses decreasing doses of the currently used medication over the course of 4-12 weeks (37–39). This is most often used in settings of long-term use and physical dependence when there is not an urgent need to abruptly discontinue the current medication. While this method could be used in settings where there are issues of non-medical use and use disorder, this approach is not recommended in such a context because it would provide the patient with continued doses of the medication for a period of weeks to months—creating risk for worsening of

substance use disorder, or diversion. In order for this strategy to be effective, the patient must be able to follow complex dosing regimens, adhere to regular follow-up appointments, and be free of other active substance use disorders. It is recommended that as lower doses are achieved, the dose reduction at each stage be more modest, especially if short half-life drugs are being prescribed. More frequent dosing intervals can also be used in the later stages to help prevent the emergence of any withdrawal symptoms. There is an increased likelihood of withdrawal symptoms with medications with a short half-life, even during prolonged tapers. Another withdrawal management strategy involves conversion of the therapeutic agent to an equivalent dose of a longer acting medication, and then a gradual reduction in the dose of the latter, using the principles described above. Agents such as clonazepam (40) and chlordiazepoxide are especially good choices given their long half-lives and their slower onset of action and therefore relatively lower addiction and diversion potential. Short-acting benzodiazepines, like the triazolobenzodiazepines alprazolam and triazolam, warrant special consideration as they can be particularly difficult to taper. Traditionally, these medications have been thought to have a higher binding affinity at a subpopulation of benzodiazepine GABA receptors that are not targeted by other benzodiazepines (41). There is limited evidence to support this, or the notion that other, longer acting, benzodiazepines may not have fully effective cross-tolerance and may be less effective when they are used for tapering and withdrawal management. There are case reports that suggest that clonazepam can be used effectively for the treatment of triazolobenzodiazepine withdrawal (40), while others have reported distinct withdrawal symptoms with alprazolam (21,42). A recent Cochrane review found that cognitive behavioral therapy interventions provided some short-term benefit when combined with a medication taper, though this benefit did not extend past 3 months, and motivational interviewing combined with a taper did not provide any additional benefit (43).

Anticonvulsants Another strategy for the treatment of withdrawal is the use of anticonvulsants, with an emphasis on the data that supports the use of carbamazepine. This anticonvulsant has been shown to be as effective as oxazepam in the treatment of alcohol withdrawal (44), and two open-label studies also demonstrated the

effectiveness of this agent in the management of complicated benzodiazepine withdrawal (45,46). One multisite, placebo-controlled study suggested that carbamazepine could also be effective for the treatment of alprazolam withdrawal, but the findings were limited by a high dropout rate. Based on these initial studies, the suggested dosing of carbamazepine is in the range of 200 mg three times a day for 7-10 days. Clinical experience suggests that this strategy is effective, but because of the potential for serious adverse events during sedative– hypnotic withdrawal, patients should be monitored closely, and benzodiazepines should be used as needed, especially for elevated vital signs or other uncontrolled symptoms. Carbamazepine has the distinct advantage of having low misuse potential and limited cognitive side effects, especially during short-term use. These properties make carbamazepine an attractive option in patients who are beginning a treatment program while also undergoing medically supervised withdrawal. Studies have also shown gabapentin and divalproex to be effective in the treatment of alcohol withdrawal in patients who experience mild to moderate symptoms (35), and gabapentin has some limited initial data that supports its use in the treatment of benzodiazepine use disorders in a specific patient population (47). While these medications have not been directly studied in the context of sedative–hypnotic withdrawal, there is reason to suggest that these agents could be used in this context, but further research is needed. Another medication that warrants further investigation is pregabalin. There is some evidence to support its efficacy in the treatment of benzodiazepine and alcohol withdrawal, but additional research is needed to better understand its safety and efficacy in this context (48). Many of these studies excluded patients at risk for severe withdrawal, including seizures and DTs, and as such these agents should be used with caution in more complicated populations at risk.

Phenobarbital Smith and Wesson (49,50) elucidated a protocol for utilizing phenobarbital for medically supervised withdrawal by converting patients from other sedative– hypnotics to equivalent phenobarbital doses. The starting daily dose of phenobarbital should be based on the patient’s drug use during the previous month. In cases when this is not known, a pentobarbital challenge test (51) can be used to determine the starting dose. (The maximum starting dose is 500 mg daily.) The daily dose should be administered in divided doses, three times a day,

and then tapered by 30 mg a day. Signs of phenobarbital intoxication are similar to those seen with other sedative–hypnotics and include slurred speech, ataxia, and nystagmus. If signs and symptoms of intoxication are present, then the total daily dose should be decreased by 50% or more and the patient reassessed at frequent intervals until the intoxication resolves. This strategy has limitations due to the aforementioned narrow therapeutic index of phenobarbital compared to benzodiazepines.

Flumazenil Another treatment strategy for managing benzodiazepine withdrawal that is being studied involves the use of flumazenil (52–57). The data on the use of flumazenil are limited and still emerging, but published reports and studies suggest that parenteral and subcutaneous flumazenil may be effective in the management of benzodiazepine withdrawal. As described above, flumazenil is used to counteract benzodiazepine toxicity and can precipitate severe withdrawal, so the use of this agent to manage withdrawal is not intuitive and warrants explanation. While flumazenil is generally thought of as a pure antagonist, it acts as a partial agonist with weak affinity at the benzodiazepine receptor site. Explanations for flumazenil’s potential efficacy in the treatment of withdrawal symptoms include flumazenil-induced changes in receptor sensitivity and binding affinity, though the exact mechanism of action in ameliorating withdrawal symptoms is not clear (58,59). The evidence supporting the use of flumazenil is preliminary at this point—there is not a consensus on the efficacy of this treatment and therefore not generally agreed upon strategy for dosing. Factors that may limit the use of this strategy include the method of administration of the medication and the treatment setting, as intravenous infusion would necessitate an appropriately monitored environment such as an inpatient unit.

Protracted Withdrawal Symptoms One additional consideration is the treatment of residual symptoms of withdrawal in the days and weeks following the discontinuation of the medication used to manage the withdrawal. The phenomenon of prolonged or protracted withdrawal has been commented on and studied in a limited way to date, but parallels could be drawn with the work done on understanding the nature and effective treatment of protracted alcohol withdrawal symptoms. There are no definitive pharmacological options for the treatment of protracted

benzodiazepine withdrawal symptoms, and this is a subject that is in need of further investigation and understanding. Pharmacological strategies with antidepressants, antihistamines, alpha adrenergic agents, anticonvulsants, buspirone, melatonin, and others have been described, but there is not an evidence base to support the use of a particular agent or strategy (60–64).

TREATMENT SETTING While discussing with the patient the pharmacological strategy for the treatment of withdrawal, a decision must also be made regarding the setting in which the withdrawal will be treated. While inpatient treatment is often optimal because of the close observation and controlled environment, this is often not feasible due to limited accessibility to inpatient resources and cost considerations. Therefore, inpatient treatment of withdrawal should be limited to cases in which the patient is medically compromised, or a high risk of the patient developing severe symptoms, such as seizures, exists. This may be the case in patients who have been taking high doses of sedative–hypnotics for a long period of time and who require a rapid withdrawal, or abrupt discontinuation, of the medication. Medically supervised withdrawal on an inpatient basis may also be appropriate if the patient has been taking multiple sedative–hypnotics or is alcohol dependent. Patients who have a history of experiencing severe withdrawal when they have previously stopped using sedative–hypnotics are also at high risk for having their withdrawal complicated by serious side effects. Medically supervised outpatient withdrawal is reasonable if the patient does not appear to be at risk for severe withdrawal, especially if the method of slowly reducing the sedative–hypnotic dose can be utilized. If outpatient management is undertaken, the patient should be given clear instructions and close follow-up appointments. If a gradual dose reduction approach is employed, it is recommended that the patient be seen each time there is a dose reduction, and if this is not possible, then there should be a mechanism by which the patient can access the provider to address any questions or concerns. It is preferable for the patient to have some level of supervision by friends or family, but this is not always possible. Urine drug screens and clinical and laboratory assessments for the use of alcohol should be utilized to monitor for complications that could arise from the concomitant use of other substances.

TREATMENT

OF

CO-OCCURRING

DISORDERS Medically supervised withdrawal should not be seen as definitive treatment in the case of sedative–hypnotic use disorder. This is the first step in the management of patients who often have other substance use disorders, anxiety and sleep disorders, and other co-occurring medical and psychiatric disorders. In the case of other substance use disorders, a treatment plan should include cooccurring medically supervised withdrawal from other substances, and substance use disorder treatment in an appropriate setting. When treating patients with underlying anxiety and sleep disorders, other pharmacological and psychotherapeutic treatments, particularly cognitive–behavioral therapy, should be initiated to counter any reemerging symptoms that may be experienced following withdrawal, which may help to reduce the risk of relapse (64–67). Other co-occurring psychiatric disorders should also be addressed during, or soon after, withdrawal. Failure to stabilize anxiety, sleep, or other co-occurring conditions will likely lead to higher rates of relapse due to patient discomfort, limited compliance, and inability to effectively engage in the early stages of rehabilitative treatment.

CONCLUSIONS DIRECTIONS

AND

FUTURE

Sedative–hypnotic medications have been used for many years for a variety of disorders and symptoms. Today, benzodiazepines are by far the most commonly used sedative–hypnotics, and their use is widespread. The appropriate use of benzodiazepines requires a clear understanding of the medications, an accurate diagnosis and treatment plan, and close monitoring. Most individuals who use sedative–hypnotic medications take their medications as prescribed and do not manifest non-medical use or develop a substance use disorder. Physical dependence may be unavoidable in cases of prolonged use; therefore, benzodiazepines should be prescribed for the shortest period of time that is clinically reasonable. Potential withdrawal signs and symptoms should be initially discussed with patients before treatment with this class of medications is initiated. Prescribers must be aware of the risks inherent in prescribing benzodiazepines and other sedative–hypnotics, but they should be careful not to withhold treatment when appropriate. If providers and patients are well informed and openly discuss the risks and benefits of these medications, and they are

prescribed at reasonable doses, sedative–hypnotics can be used safely and effectively for the treatment of a number of otherwise disabling conditions. Sedative–hypnotics continue to be widely prescribed, and while these medications are relatively safe when taken alone, their use in conjunction with opioids is receiving increased attention. The risk of death in the context of concurrent sedative–hypnotic and opioid use has led to renewed debate and discussion about the overall efficacy and safety of the sedative–hypnotic medications, and in many cases, it precipitates a more urgent need to address issues related to overdose and withdrawal. Pharmacological strategies to manage intoxication and withdrawal are limited in their scope and the evidence base to support newer strategies, and manage protracted withdrawal symptoms, needs to be expanded so that patients and prescribers have more options at their disposal.

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CHAPTER 57

Pharmacological and Psychosocial Treatment for Opioid Use Disorder David Kan, Joan Zweben, Susan M. Stine, Thomas R. Kosten, Elinore F. McCance-Katz, and John J. McCarthy

CHAPTER OUTLINE Introduction History and context of opioid agonist treatment Modern historical understanding of OUD Overview of pharmacologic interventions Abstinence syndromes and medically supervised withdrawal Long-term treatments for OUD Special issues in ongoing medication treatment Patients with co-occurring psychiatric disorders Psychosocial interventions Oversight and regulatory challenges

INTRODUCTION In 2016, 1.9 million American adults had an opioid use disorder (OUD) related to prescription pain relievers, and 586,000 related to heroin. According to the Centers for Disease Control and Prevention (CDC), sales for prescription opioids nearly quadrupled between 1999 and 2014, while deaths rose to over 165,000. Approximately three out of four heroin initiates used prescription opioids before switching to heroin (1,2). As of September 2017, synthetic opioids such as fentanyl were responsible for more overdose deaths than prescription pain relievers or heroin (3). Of the estimated two million persons with OUD in the United States in 2016, ~360,000 are enrolled in federally licensed programs offering opioid agonist treatment (OAT) in 49 states except for Wyoming (4,5). The 1460 specially licensed opioid treatment programs (OTPs) in the United States offer counseling, testing, and pharmacotherapy using methadone (and buprenorphine in certain facilities), with daily dispensing or strictly regulated take-home medication for selected patients (5). There are currently 24,767 prescribers authorized to prescribe buprenorphine for OUD under the DATA 2000 act (6). Of those prescribers, 24 hours). 3. They have minimal side effects during chronic administration. 4. They are safe (ie, they lack true toxic or serious adverse effects). 5. They are efficacious for a substantial proportion of persons with the disorder. Methadone and buprenorphine are agonists, and naltrexone is an antagonist generally exhibiting these characteristics.

Opioid Physical Dependence and Protracted Abstinence Himmelsbach (80), reporting on 21 prisoners dependent on morphine, observed that “physical recovery requires not < 6 months of total abstinence.” Martin and Jasinski (46) reported in a subsequent study that the period of protracted abstinence (PA) persisted for 6 months or more after withdrawal and that it was associated with “altered physiologic function.” They found decreased blood pressure, decreased heart rate and body temperature, miosis, and a decreased sensitivity of the respiratory center to carbon dioxide, beginning about 6 weeks after withdrawal and persisting for 26-30 or more weeks. They also found increased sedimentation rates (which persisted for months) and electroencephalograph (EEG) changes. Martin and Jasinski (46) postulated a relationship between the PA syndrome and relapse. In another study, Shi et al. (82) also studied PA symptoms in individuals who formerly used heroin,

comparing those who were not receiving medication and those receiving methadone after similar lengths of heroin abstinence. Seventy individuals who had formerly used heroin were included in one of four groups: in days 15-45 of short-term methadone treatment (MT), in months 5-6 of MT (long-term MT), no opioids for 15-45 days after methadone-assisted heroin withdrawal (short-term post methadone), and no opioids for 5-6 months after methadone-assisted heroin withdrawal (long-term post methadone). Analysis of PA symptoms during the study allowed the investigators to conclude that long-term methadone treatment reduces PA symptoms of heroin abstinence and cue-induced craving. The concept of PA has been controversial (83) but remains a useful model for scientific hypothesis testing and development of new therapeutic approaches (84). As Dole pointed out, since methadone continues physical dependence, PA may remain a problem later if medically supervised withdrawal from methadone is undertaken. In addition to biologic considerations, psychosocial concomitants of OUD also necessitate longer, more specialized adjunct treatments for these and additional problems.

Treatment Using Methadone Continued Illicit Opioid Use Versus Methadone Treatment The person with OUD who is actively using heroin or other short-acting opioids typically experiences rapid and wide swings from a brief pleasure usually characterized by relief of withdrawal symptoms, sedation, fading into a period of normalcy and alertness, which can be described as the “comfort zone.” This period is uniformly followed by the beginnings of subjective withdrawal, which soon develops into the full objective withdrawal syndrome typical of OUD. This cycle is particularly evident in the patient who engages in injection or inhalation of potent short-acting opioids such as heroin. A full cycle from “sick” (withdrawal) to “high” (intoxication) to “normal” (alert, comfortable) to “sick” (withdrawal) can occur repeatedly throughout the day (Fig. 57-1). The sensation of the “rush” is associated with a very rapid increase in blood levels. The pleasure is experienced during the time that drug levels remain above the therapeutic window (Fig. 57-2). OATs, such as methadone or buprenorphine regularly administered at steady state, are present at levels sufficient to maintain alertness without craving or drug preoccupation (comfort zone or therapeutic window) throughout the dosing interval—usually 24 hours.

Figure 57-1 Heroin-simulated 24-hour dose–response.

Figure 57-2 Methadone 24 hours at steady state. With each administration of methadone, there is a gradual rise in blood level,

reaching a peak at 3-4 hours. Typically, the peak level is less than two times the trough level. There is a gradual decline over the rest of the 24-hour period, back to the trough level. When the patient is on the correct dose at steady state and with development of sufficient tolerance, at no time does the rate or extent of change in blood levels cause a sensation of being intoxicated or result in withdrawal symptoms.

Methadone Induction Although most patients eventually will need 80-120 mg/d of methadone to achieve stability (19), and although adequate doses are needed to provide stability and retention in treatment (85),the starting dose must be much lower, and the eventual steady state is reached slowly over many days to weeks. The first several doses require careful evaluation and adjustment. This phase is called induction. Even though methadone treatment has been shown to reduce mortality, including overdose mortality (86,87), several studies have reported deaths during the first 10-14 days of treatment, particularly when induction doses are high and particularly if the patient is also ingesting sedatives (88–92). About 42% of drug-related deaths during treatment occurred during the first week of OAT (93). In one study, patients were reported to be 6.7 times more likely to die during induction as compared to untreated individuals using heroin (90). The mean induction dose was more than 50 mg among those who had died. All cause mortality dropped sharply over the first 4 weeks of methadone treatment, but the induction phase onto methadone treatment and the time immediately after leaving treatment are periods of particularly increased mortality risk (21). Variability in methadone metabolism, discussed later in the section on drug interactions, may also be a factor.

Initial Dose In most cases, patients being evaluated for admission to OAT have developed significant tolerance to opioids and therefore demonstrate objective signs of withdrawal as evidence of current opioid physical dependence. The response to the initial dose of agonist medication provides valuable information about tolerance levels and the target “therapeutic window.” Significant relief during peak methadone effect (2-4 hours) indicates that the dose is in the range of the established level of tolerance and may not require further escalation. The absence of relief suggests that the dose is well short of the therapeutic window. Additional methadone can be provided when significant objective withdrawal

persists during peak methadone levels. Patients who come in 24 hours after their very first dose can be expected to be uncomfortable as tissue store accumulation is still incomplete. If they were comfortable during the first 4-12 hours after their dose, they probably need more time at the same dose and not a higher daily dose. Under federal regulations, the initial dose of methadone is no more than 30 mg and may be lower in patients in whom low tolerance might be expected (eg, recent relapse after a significant period of abstinence, or addiction to lowerpotency opioids such as hydrocodone or codeine, or in opium smokers). Identification of low tolerance is the principal task of the initial medical assessment after confirming the diagnosis of OUD. An additional dose of 10mg of methadone may be administered on day one of dosing if documentation is present that withdrawal is inadequately suppressed with the initial 30-mg dose. A total dose of no more than 40 mg may be given on the first treatment day unless the program physician documents in the patient’s record that 40 mg did not suppress opioid abstinence symptoms.

Stabilization and Steady State After the initial dose, the induction phase allows for subsequent careful adjustments of the dose to achieve elimination of drug craving and prevention of withdrawal while avoiding the risk of intoxication or overdose associated with accumulation of methadone (94,95). The induction phase can be considered to last until the patient has attained a methadone dose that meets the four goals outlined above. The safe and effective introduction of methadone requires an understanding of steady-state pharmacologic principles. In general, steady-state levels are reached after a drug is administered for four to five half-lives (methadone has an average half-life of 24-36 hours). The clinical significance is that, with daily dosing, a significant portion of the previous dose remains in tissue stores, resulting in increased peak-and-trough methadone levels after the second and subsequent doses. Thus, the blood levels of methadone increase daily, even without an increase in dose. The rate of increase levels off as steady state is achieved at four to five half-lives, that is, 3-7 days (Fig. 57-3). Further dose changes every 3-7 days may be needed to achieve the maintenance dose. Dose adjustments can be done in 5- to 10-mg increments for highly tolerant patients. Liquid medication allows dose adjustments by smaller increments for less tolerant patients.

Figure 57-3 Steady-state simulation—maintenance pharmacology attained after four to five half-times, 1 dose/half-life.

Duration and Dose Dose level and duration of treatment are individualized clinical decisions. There is no scientific or clinical basis for an arbitrary dose ceiling on methadone, although QT prolongation has been seen in the electrocardiograms of patients receiving high doses of methadone (95). Methadone doses of 80-100 mg have greater benefits than doses below 50 in heroin-dependent patients (96–98). For most patients receiving methadone, a long-term approach is most appropriate. Based on an extensive review of the research literature on the prognosis of patients who have been withdrawn from methadone, as well as the safety of continued treatment, the American Society of Addiction Medicine supports the principle that methadone treatment is most effective as a long-term modality (99). The known risks of discontinuing methadone treatment, with predictable return to use to injected heroin or fentanyl use, become increasingly critical when viewed in the context of overdose and the HIV and Hepatitis C Virus (HCV) prevalence among people who inject drugs. These risks, when combined with the proven safety and efficacy of long-term methadone treatment, suggest that long-term—even indefinite—methadone treatment is appropriate and even

essential for a significant proportion of eligible patients. Methadone treatment is therefore a treatment of a chronic medical disorder, with the goal of achieving control of the opioid addiction and avoiding the ravages of the untreated disease (100). Treatment should be continued as long as the patient continues to benefit, wishes to continue, remains at risk of relapse to opioid or other substance use, and suffers no significant adverse effects and as long as continued treatment is indicated in the professional judgment of the physician (101). Patients receiving methadone do at times seek to discontinue maintenance for nonmedical but very real and practical reasons (eg, transportation or scheduling difficulties) and to escape continued disruption of their lives associated with the burdensome restrictions, regulations, and structure of the treatment delivery system. Regulations permit clinic attendance just once a month with take-home doses for the other days for long-term, stable patients. For patients who attempt withdrawal, it is important for practitioners to provide encouragement along with the best medical and supportive treatment available, without fostering unrealistic expectations or unnecessary guilt, and to provide a means for rapid readmission to methadone treatment in the event of relapse or impending relapse to the use of illicit opiates (99).

Techniques to Ensure Adequacy of Dose In most cases, clinical observation and patient reporting are adequate to make appropriate dose determinations. In rare cases in which patients fail to stabilize on methadone and continue to complain of withdrawal symptoms and craving even at daily dose of 120 mg or greater, evaluation of methadone blood levels may be indicated.

Procedure for Obtaining Blood Levels Peak blood levels should be drawn at 3 (2-4) hours after a dose and trough levels at 24 hours, once said dose has been stable for at least 5 days, to allow tissue store equilibration. Patients already on a divided dose, such as every 12 hours, should have 2- to 3-hour and 12-hour specimens. A trough level alone is of little clinical value unless it is extremely low or very high. Blood levels are interpreted in the context of a clinical presentation for which the laboratory values can supplement clinical judgment. The peak level at 2-4 hours should be no more than twice the trough level. A peak-to-trough ratio of 2 or less is ideal (peak/trough = ratio). Ratios >2 suggest rapid metabolism. The rate of change is of greater clinical significance than the actual levels. For example, a patient with

a 24-hour level of 350 ng/mL after a peak of 1225 ng/mL (1225/350 = 3.5, indicating rapid metabolism) may be experiencing early opioid withdrawal, whereas a patient with a trough of 150 ng/mL and a peak of 250 ng/mL (250/150 = 1.7, indicating a normal metabolism) may be quite comfortable. No particular blood level should be considered “therapeutic” outside of the clinical context.

Observed Doses and Take-Home Medication in OAT Patient stability reduces need for daily visits. Patients who do well and who improve per specified criteria set out in US federal regulations can receive takehome medications. The criteria include adherence to treatment, stability of home environment, involvement in productive activity, abstinence from illicit substance use, and resolution of any legal problems. As of March 2017, the guidelines governing methadone treatment allow patients to take home up to six doses a week after 9 months, 2 weeks of medication after the first year, and 30day doses after the second year of treatment (42 CFR 8.12). Monthly observed dosing at the OTP, with take home doses for the month, is as close as most patients receiving methadone come to receiving their medication in a fashion like that in other well-controlled medical conditions. Methadone medical maintenance (MMM) and office-based opioid treatment (OBOT) with methadone remain a rarity in the United States.

Methadone Medical Maintenance MMM, designed for “stable, recovered” patients on methadone, is an effort to release the patient from attendance in an OTP by allowing a physician who is affiliated with the clinic, but in office practice, to prescribe or administer methadone. In April 2000, the CSAT circulated draft guidelines describing medical maintenance. These guidelines were developed after more than 10 years of pilot projects and showed that this approach to care works and that it improves the quality of life for patients (102). A 2001 study randomly assigning patients to either office- or OTP-based methadone showed no difference in clinical outcomes and improved patient and physician satisfaction (103). For those who are attempting to receive ongoing treatment in a different setting rather than from the effects of daily medication, medical maintenance could be an acceptable solution. Current regulations require a federal waiver for medical maintenance; however, as of 2018, MMM is still rarely used.

Methadone–Medication Interactions Clinical experience suggests that concomitant medications can either induce or inhibit cytochrome (CY) CYP450 activity on methadone metabolism (104). Drugs that stimulate or induce CYP450 activity can precipitate opioid withdrawal by accelerating metabolism, thus shortening duration and diminishing intensity of the effect of methadone. For example, addition of ethyl alcohol, rifampicin, phenytoin, carbamazepine, phenobarbital, nevirapine, or efavirenz may result in the onset of withdrawal symptoms and require dose adjustments of methadone. Considerable flexibility in dosing may be required to stabilize some patients whose metabolism has been altered by medication interactions or have increased rates of metabolism due to other causes. Other medications such as cimetidine, ciprofloxacin, fluconazole, erythromycin, and fluvoxamine may inhibit this enzyme activity, slowing the metabolism and extending the duration of the medication effect. Metabolism of methadone is largely a function of enzyme activity in the liver, and intestinal enzymatic activity has also been observed to be clinically relevant. Multiple CYP450 isoenzymes may affect methadone metabolism in vivo (105). Liver 3A4 activity in vitro is shown to influence methadone metabolism (106). Methadone exists as a racemic mixture of R and S isomers. Genetic variability in CYP2D6 activity may affect clinical status by affecting metabolism of the R-methadone isomer (107–109) and may also affect toxicity (110). Enzymatic activity of intestinal CYP2B6 is stereoselective and may be important in clinical effects and drug interactions (111). A 17-fold variability between patients in their methadone metabolism is shown, mostly due to activity of various CYP450 enzymes (112). Due to variability in methadone metabolism, it is important for clinicians to focus on functional outcomes rather than absolute dose amounts when determining the appropriateness of treatment.

Methadone and QT Interval Several case series have been published showing that methadone treatment is associated with prolongation of the QT interval on the electrocardiogram and possible consequent cardiac arrhythmia (Torsade des Pointes or TdP) (113,114). In 2006, the FDA published a boxed warning that included QT interval prolongation and the risk of arrhythmia. In vitro study of human ether-à-go-go–related gene potassium channels (hERG K+) confirms that methadone at therapeutic doses can affect cardiac conduction (115). Genomics of CYP2B6 were shown to be associated with QT

interval, and in vitro studies suggest that most of this prolongation is due to the nontherapeutic S-methadone enantiomer (116). Interviews of patients receiving methadone treatment found an association between longer QT and retrospective self-report of syncopal episodes (117). Several studies look at QT interval in the methadone clinic setting (118–120). However, there are no clear data to guide any intervention. Some clinics are offering cardiograms and are screening patients for cardiac risk. Risk–benefit discussion with patients includes a review of other medications that might contribute additional cardiac risk, eliciting a history of structural heart disease, unexplained syncopal episodes, or familial prolonged QT syndrome. All of these conditions may heighten the risk for TdP and may warrant ECG screening. In general, it is considered that almost certain relapse to uncontrolled opioid use is more risky than the rare occurrence of an arrhythmia. However, coordination of care with outside physicians to monitor the use of other medications or transfer to buprenorphine treatment might in some cases be indicated (121). Hospitalized patients receiving methadone may have particularly high risk of TdP (121). The Center for Substance Abuse Treatment (CSAT) convened a consensus panel on this topic, and the final iteration of the consensus panel’s recommendations include risk assessment and ECG screening, patient and staff education about cardiac risk, and informed consent (122,123). However, this advice was not based upon solid evidence of preventing deaths and did not include a cost-benefit assessment. Thus, the support of the panel for this viewpoint was not unanimous. Feasibility of offering QT screening on-site in the OTP has been shown in several studies (122,124), but substantial barriers remain including cost, staff time, and access to cardiologists to read the tracings. It has not become standard of care to do routine ECG screening in licensed OTPs.

Benzodiazepines and OAT Including Methadone The potentially lethal combination of benzodiazepines with OAT is important to address in patients who have concomitant benzodiazepine use or benzodiazepine use disorder. For patients with therapeutic sources of benzodiazepines, careful coordination with prescribing physicians is indicated. Alternate treatments for insomnia or anxiety may be possible. Abrupt cessation of high doses of benzodiazepines may require medically supervised withdrawal due to the risk of withdrawal seizures. Reported rates of benzodiazepine misuse among methadone-treated patients are between 24.9% and 50.6% (125). Benzodiazepine testing should be a routine in OTPs (126). A recent retrospective chart review of 278 OAT patients showed patients prescribed benzodiazepines

had longer treatment retention and lower mortality than patients who never received benzodiazepine prescriptions. However mortality significantly increased once patients receiving benzodiazepines left treatment (127).

Medical Monitoring of Methadone The initial pharmacologic rationale for long-term methadone maintenance was its ability to relieve the PA syndrome and to block heroin euphoria (48,128). No serious side effects are associated with continued methadone use (129) with the exception of hypogonadism in men, sleep apnea (130), and risk of QT prolongation with exceedingly rare but potential subsequent progression to TdP (122). Minor side effects, such as constipation, excess sweating, peripheral edema, drowsiness, and decreased sexual interest and performance, have been noted. In addition, neuroendocrine studies have shown normalization of stress hormone responses and reproductive functioning after several months of stabilization on methadone (131).

Buprenorphine Treatment In October 2002, the FDA approved two sublingual formulations of buprenorphine for treatment of DSM-IV opioid dependence. In the initial FDAapproved formulation, a combination of buprenorphine and naloxone in a 4:1 ratio was designed to discourage injected diversion and misuse. There are now four FDA-approved buprenorphine/naloxone products for the treatment of OUD that are administered sublingually or through buccal administration. The originally approved formulation had a buprenorphine:naloxone ratio of 4:1. Current formulations range from buprenorphine:naloxone from 7:1 to 3.88 to 1. Newer formulations were approved based upon demonstrating the production of equivalent serum levels of buprenorphine compared with the 4:1 product. Technologies deployed to allow for lower doses of buprenorphine include saliva pH modification to enhance buprenorphine absorption as well as the development of bioerodible mucoadhesives (BEMA). Naloxone is an opioid antagonist that is not significantly bioavailable when taken sublingually or when swallowed. When injected into individuals actively using opioids who are blinded, the buprenorphine/naloxone combination was not judged to be desirable or to be different from the antagonist in the first hour after injection (132,133). This buprenorphine/naloxone combination is the preferred formulation for outpatient use as an effort to minimize diversion. The other sublingual formulation contains only buprenorphine and is used in controlled settings, such

as inpatient medically supervised withdrawal, or in pregnancy.

Pharmacology of Sublingual/Buccal Buprenorphine Buprenorphine has slow onset and long duration of action, conferring similar benefits as discussed earlier for methadone. As a partial mu agonist, buprenorphine has a maximal dose–effect ceiling that is well below significant respiratory depression for most patients. This safety profile led to its DEA Schedule III, allowing office-based use under the restrictions of the Drug Addiction Treatment Act of 2000 (134).

Pharmacology of Implantable Buprenorphine An implantable buprenorphine matrix was FDA approved in 2016. Implantable buprenorphine binds buprenorphine with ethylene vinyl acetate polymer. Each rod contains 74.2 mg of buprenorphine. Four rods are implanted into subdermal tissue in the upper arm. This formulation is indicated for patients who are stable for a minimum of 3 months on buprenorphine/naloxone 8 mg/2 mg or an equivalent dose. The implants last 24 weeks and must be removed after 24 weeks. In one study, 114 subjects received buprenorphine implants, 54 subjects received placebo implants, and 119 subjects received open-label buprenorphine– naloxone combination product at doses of 12 to 16 mg sublingual daily (135). Buprenorphine implant subjects had a mean proportion of opioid-negative urine drugs screens of 31.2% compared with 13.4% of patients with the placebo implant. Sixty four percent of patients with the buprenorphine implant completed the study compared with 26% of placebo implant patients. The buprenorphine implant also results in a lower rate of cocaine use. The rate of opioid-negative urine drug screens was not significantly different between buprenorphine–naloxone sublingual products and buprenorphine implant. Side effect profiles were similar between buprenorphine implant and buprenorphine– naloxone sublingual medication except for implant site reactions in 27% of buprenorphine implants. Commonly reported implant side reactions include hematomas and pain. A second phase III trial was conducted with 177 participants who were already stable on buprenorphine 8 mg daily or less. Subjects receiving the buprenorphine implant had a statistically significant improvement in achieving continuous opioid use remission (85.7% vs. 71.9%) during the 6-month study period (136).

Both of these studies demonstrated the efficacy and safety of buprenorphine implants, but neither study has had long-term outcome follow-ups. Buprenorphine implant recipients currently are counted under a provider’s cap in the DATA 2000 waiver.

Pharmacology of Injectable Buprenorphine Sustained-release injectable (SR) buprenorphine was approved and released in the United States in March of 2018. SR buprenorphine is a buprenorphine-only product administered subcutanously in abdominal tissue. SR buprenorphine is available in 300 mg and 100 mg doses to be given once monthly. One 12 week study of SR buprenorphine showed blockade of drug liking effects of intramuscular hydromorphone after two injections of SR buprenorphine (137). A 24 week study with SR buprenorphine administered at 300mg on months one and two followed by administration of four 100 mg doses monthly demonstrated superiority to placebo producing more illicit opioid-free weeks (138). In both studies, patients receiving SR buprenorphine were stabilized on eight to 24 mg of sublingual buprenorphine prior to receiving SR buprenorphine. Serum levels of SR buprenorphine were comparable to sublingual buprenorphine doses usually used to treat OUD. SR buprenorphine has detectable serum levels for up to one year after six injections.

Induction and Precipitated Withdrawal Buprenorphine has strong receptor affinity. Relative to a displaced full agonist, its activity can be felt as the rapid onset of (relative) opioid withdrawal by the patient unless the first dose is clinically well timed. The first dose should be given when the patient is already in mild to moderate opioid withdrawal. When opioid withdrawal is present, the onset of activity will be felt as agonist, with relief of withdrawal. In contrast to methadone, induction doses are not set by regulation, though clinical guidelines and physician training courses recommend 2-4 mg of sublingual buprenorphine/naloxone as a first dose, with first-day maximum of 8 mg (139). One study found that higher induction doses were associated with better engagement in ongoing care (140). There has been one case series showing the successful transition from high-dose full agonists using concomitant transdermal buprenorphine to allow for the initiation of sublingual buprenorphine without precipitated withdrawal (141). More research in this area is recommended to produce protocols that limit patient discomfort between transitions from full agonists to partial agonist therapy.

Induction Setting The majority of published studies have conducted buprenorphine inductions with supervised dosing. The advantages of supervised dosing include attenuation of withdrawal symptoms under medical supervision. However, observed inductions require significant staff time and monitoring. Observed induction logistics are seen as a barrier to buprenorphine prescribing (142). There is a growing practice and body of evidence that supports the feasibility and safety of unobserved or “home” inductions particularly from office-based practices (143).

Buprenorphine Dose Adjustment The dose of buprenorphine can be titrated over the first 3 days to control withdrawal. Average daily doses are 16-20 mg. One labeled imaging study showed mu opioid receptors to be ~90% occupied depending upon the brain region at doses of 16 mg/d of sublingual solution (144). Because of the partial agonist ceiling effect, no additional benefit is expected in doses above 32 mg/d. Sublingual buprenorphine/naloxone is usually prescribed as a single daily dose.

Buprenorphine–Medication Interactions Compared to methadone, buprenorphine may confer advantages when certain HIV medications are used (145) and in cases of QT prolongation with methadone (120,146). The presence of an active metabolite—norbuprenorphine —and strong affinity for the mu opioid receptor make this medication less dependent than methadone on blood level and tissue stores.

Federal Regulations and Sublingual Buprenorphine When dispensed in the OTP, sublingual buprenorphine/naloxone is subject to the same regulations as methadone, except for the observed dosing requirements, as explained below. When prescribed in the office-based setting, there are certain restrictions set forth in the Drug Addiction Treatment Act of 2000. This law provides for a waiver to the 1914 Harrison Act that forbids prescription of a “narcotic” to a person with an addiction. The qualifying prescriber notifies the Secretary of Health and Human Services of his or her intent to prescribe, after which the DEA assigns to the prescriber a second DEA registration number that is specifically for use under DATA 2000. There are restrictions on census and type of medication and rules on storage and record keeping. Physicians, nurse practitioners, and physician assistants can receive the DATA 2000 waiver. The

DATA 2000 restrictions do not apply when buprenorphine or buprenorphine/naloxone are dispensed at clinics under their OTP license. In those cases, the same federal regulatory restrictions apply to both buprenorphine and methadone except that the time-in-treatment regulations that apply to takehome doses of methadone no longer apply for buprenorphine so that decisions about the number of buprenorphine take-home doses given are determined purely based on patient stability and not on how long the patient has been in treatment. Alternate-day or thrice-weekly dosing is an option for the buprenorphine-maintained patient who is not stable enough to have take-home doses (147,148).

Diversion and Nonmedical Use of Buprenorphine An early and limited investigation of the effects of DATA 2000 was carried out in 2005. No serious adverse events were found by the introduction of sublingual buprenorphine/naloxone in the office-based setting. That study showed that most of the patients treated with buprenorphine listed prescription pain relievers as their primary opioid of misuse (149). In view of the increase in nonmedical use of prescription opioids, it is hoped that buprenorphine/naloxone may provide a timely treatment for those who become addicted and who might not otherwise seek out a methadone clinic. Wherever buprenorphine treatment has been introduced, there has been diversion and nonmedical use of the medication, including injected use (150,151). As the clinical use of buprenorphine has increased since 2002, so have reports of diversion. One study in the United States showed that diverted buprenorphine/naloxone is being used mostly for relief of withdrawal and rarely as a primary drug of misuse (152). A more recent study found that diversion increased as treatment with buprenorphine became more available, though not as steeply as full agonists (153). In areas of higher prescribing of buprenorphine, most treatment seekers have already tried the medication, having used it illicitly for relief of withdrawal or during times when the preferred opioid of misuse is not available (154). Buprenorphine diversion suggests a lack of OUD treatment availability (155). An Australian study that interviewed patients who were found to be diverting doses given under observation at pharmacies found that discarding it, saving it for another time, or giving the dose to someone else were cited as reasons for not taking an observed dose (156,157). Buprenorphine has two- to threefold lower rates of drug diversion reports compared with methadone and other full agonist opioids (155,158,159). Guidelines for agonist treatment recommend monitoring for diversion with urine testing or pill counts and adding

observed dosing or shortening time span between prescriptions when diversion is suspected. Long-acting buprenorphine formulations such as the implant or sustained release injection are options as well.

SPECIAL ISSUES IN MEDICATION TREATMENT

ONGOING

Comparative Efficacy of Buprenorphine Versus Methadone: Choice Between Methadone and Buprenorphine The clinical issue of choosing between pharmacotherapy options or matching patients to buprenorphine versus methadone maintenance continues to be an open question that is actively investigated. Early studies offered few head-tohead comparisons, and those available had limited dose comparisons. Treatment retention is higher with LAAM, high-dose methadone (80 mg/d), and buprenorphine than low-dose methadone (30 mg/d) (160,161). A meta-analysis published in 2014 (20) found that buprenorphine is an effective intervention for use in the treatment of OUD, and it is as effective as methadone delivered at adequate dosages. A study by Ridge et al. (162) demonstrated that buprenorphine was more likely to be prescribed for short-term opioid withdrawal and methadone for maintenance treatment. A large longitudinal study of opioiddependent outpatients selected from 10 Italian Public Services for Addiction centers in Naples (Italy) (163) examined the use of treatment with the buprenorphine/naloxone combination and also compared these patients to patients receiving methadone. In patients treated with buprenorphine/naloxone, a significant improvement was reported in social life status, educational level, and urine toxicology outcomes compared with methadone treatment. Though both medications have been shown to be comparable in various outcomes (160,161) systematic reviews suggest that methadone and buprenorphine are roughly equivalent in reducing illicit opioid use with methadone demonstrating slightly better rates of treatment retention (164,165). In the United States, site of care and level of care, local availability, or cost may determine which medication is applicable for a given patient. A blinded study showed that a “stepped” approach of starting patients on buprenorphine and

transferring those who did not stabilize onto methadone had identical outcomes to directly admitting patients to methadone treatment (166). Buprenorphine may confer less cardiac risk (117,146), although no prospective studies have been carried out. A randomized prospective liver safety study showed no liver damage produced by either medication (167).

Opioid Agonist Treatment during Pregnancy Opioid misuse during pregnancy is a growing concern in the United States and internationally and is often associated with adverse consequences for both the mother and her infant, especially prematurity and low birth weight (168–176). From 1998 through 2011, there was a 127% increase in pregnant women with OUD presenting for delivery (177). The current literature suggests that children of women with OUD might be at risk for poor outcomes not only because of opioid drug exposure but also because of concomitant alcohol and tobacco exposure and numerous factors related to the caregiving environment (172,178). Treatment options studied include methadone or buprenorphine (179,180), antagonist maintenance (181) (ie, naltrexone), and medication-assisted withdrawal (182). Methadone has been the recommended standard of care over no treatment or medication-assisted withdrawal. This is based on longer durations of maternal drug abstinence, better obstetrical care compliance, avoidance of associated risk behaviors, reductions in fetal illicit drug exposure, and enhanced neonatal outcomes (179). Methadone is the oldest, most widely used medication prescribed during pregnancy (180), and in comparison to infants from mothers using heroin, infants from methadone-treated mothers have increased fetal growth, reduced fetal mortality, and decreased risk of HIV infection (171,183). Moreover, for pregnant women under conditions where nonmedication and methadone treatment were both available, methadone is associated with longer treatment retention (184,185) and less relapse (183). Studies examining the consequences of prenatal methadone exposure on later development have produced inconsistent results (186–192) that could be due to confounding factors and are complicated by study attrition (192). Overall, methadone treatment in pregnancy does not appear to be associated with developmental or cognitive impairments (186–192). Nevertheless, methadone use at effective clinical doses during pregnancy may be avoided by some practitioners due to concerns over the associated neonatal abstinence syndrome (NAS). Although newborns of women receiving methadone may experience NAS, these are readily treated without consequences

(192). Furthermore, dose is not a reliable proxy for fetal exposure since the fetus is not exposed to the maternal dose but to the maternal serum level, which is largely determined by individual patient pharmacogenomics and pharmacokinetics (193). (See discussion below in NAS subheading.) Hence, pregnant women should receive appropriate methadone doses to treat their addiction (194). Large, definitive randomized controlled trials of buprenorphine in pregnant women have not been conducted. There have been 31 published reports of buprenorphine exposure during pregnancy that were reviewed and summarized by Jones et al. (194) Overall, the pregnancies were uneventful, without physical teratogenic effects and with low rates of prematurity, suggesting that buprenorphine is relatively safe and effective in this population. Conclusions from data on the prenatal exposure to buprenorphine are limited by methodologic challenges (eg, varied dose ranges, lengths of exposure, care settings). Many reports omitted information regarding concomitant substance use and prescribed medications that could impact the expression of NAS. However, there is a lack of detailed studies of fetal physiology during buprenorphine induction, which could cause acute maternal/fetal withdrawal and pose potential hypoxic problems for the fetus (195). The Maternal Opioid Treatment: Human Experimental Research (MOTHER) study (165) was a large multisite clinical trial enrolling a diverse sample of pregnant opioid-dependent women into both methadone and buprenorphine treatment. The methadone group had better retention (the most important variable in drug treatment outcomes): treatment was discontinued by 18% of methadone patients and 33% of buprenorphine patients. However, infants born to mothers in the buprenorphine group required less morphine, had a shorter hospital stay, and had a shorter duration of treatment for the NAS. There were no differences between groups in other primary or secondary outcomes or in the rates of maternal or neonatal adverse events. The authors conclude that buprenorphine is an alternative to methadone for the treatment of OUD during pregnancy. While buprenorphine appears to be associated with reduced severity of NAS, methadone dosing was done as a single daily dose in the MOTHER study, rather than the divided dosing dictated by pharmacokinetic science and clinical studies (196). More research is needed into optimal dosing of both medications. Dosing that does not address the variability in drug elimination between mothers or that limits maternal dose to an arbitrary limit (the MOTHER study set a dose limit of 140 mg/d that is below the needs of many rapid metabolizing mothers) ignores the risk of protracted and/or episodic stressfulmaternal–fetal withdrawal and potential adverse effects on neonatal health (193).

Clinicians should also take into account the possibility of reduced adherence and the ceiling effect of buprenorphine compared with methadone. It is unknown how many buprenorphine practices provide the intensity of medical monitoring needed by pregnant women. Methadone regulations require intensive clinic attendance, monitored dosing, a counselor, and an actively involved physician who meets regularly with the patient. The higher rate of treatment discontinuation in the buprenorphine group raises issues of optimal induction onto buprenorphine and retention as an issue for future exploration. Comparison studies have been done in specific clinical areas. Prospective, randomized, and blinded studies during pregnancy and the perinatal period show that both methadone and buprenorphine are safe, with methadone associated with more severe NAS (165,197–199).

Neonatal Abstinence Syndrome NAS is an important outcome for OAT in pregnancy. Nevertheless, across studies, there is often insufficient detail regarding medication used to treat ensuing NAS as well as the criteria for initiation, maintenance, and weaning of NAS medication. Sublingual buprenorphine shows promise in one placebocontrolled trial in significantly reducing length of hospitalization for NAS when compared to oral morphine (200). Although the scoring systems used to assess NAS treatment efficacy vary across reports (eg, Finnegan et al. (201) or modifications of this scale and Lipsitz (202)), the literature suggests that buprenorphine is associated with NAS, half the cases of which require pharmacotherapy. The pregnancy, birth, and NAS outcomes are confounded by other drug use in 86% of the reports. Although considerable individual variability exists, the NAS timing observed to date has an apparent onset within the first 12-48 hours, peaks within ~66-96 hours, and lasts ~120-168 hours. The exception to this has been the few infants who were reported to exhibit withdrawal signs for 6-10 weeks after delivery (203,204). These cases may represent protracted abstinence, as seen with adults, or neonatal ill health related to adverse pregnancy events beyond simple opioid exposure, such as illicit drug use and long-term effects of chronic intrauterine withdrawal stress. To date, only one report has found a correlation between buprenorphine dose and the severity of the NAS (205). Other reports (197,206,207) have reported no correlation. Research has demonstrated that NAS is not managed consistently after delivery (208). There is likely major overuse of Neonatal Intensive Care Units for uncomplicated withdrawal leading to unnecessary maternal/fetal separations

at a time critical for bonding. A rooming-in model of care where the mother and fetus are not separated and where the mother is an active part of NAS management has been shown to reduce NAS symptoms and length of hospitalization (209). The OTP physician should explain the advantage of rooming-in to the mother and encourage her to discuss this option with her doctors.

Intrauterine Abstinence Syndrome Intrauterine abstinence syndrome (IAS) has received little attention until recently (195). Maternal and fetal withdrawal usually coincide, and the fetus is at risk of seizures, hyperactivity, and catecholamine excess. This increases fetal oxygen consumption and risk for asphyxia. Because of these risks, medically supervised withdrawal from opioids during pregnancy is not recommended (210). Increasing evidence shows unfavorable intrauterine conditions affect developing systems and produce epigenetic changes associated with adult disease and longterm behavioral abnormalities (211,212). While fetal demise is not a common outcome with maternal opioid withdrawal during pregnancy (213), relapse exposes the fetus to erratic drug levels and to episodic withdrawal. The ASAM and the American College of Gynecology jointly recommend against the practice of medically supervised withdrawal because of the high risk of relapse (214). OAT with partial or full agonists should be offered to all female patients with OUD when pregnancy is discovered for the health of the mother and developing fetus no matter the determination to continue or terminate the pregnancy. Methadone dosing in pregnancy is complicated by the clinical need to respond to the altered metabolism caused by pregnancy-related induction of the key metabolic enzymes, which convert the active medication to an inactive metabolite (215). The variable timing and rate of enzyme induction during gestation dictates that dose increases are likely to be required at any stage of pregnancy to minimize maternal/fetal withdrawal symptoms and divided doses are routinely needed to manage the reduced half-life of the medication (196). Further, divided dosing eliminates or minimizes fetal physiologic abnormalities seen with single-dose methadone treatment (216,217). Pharmacokinetic science should be the basis for dosing to minimize withdrawal stress by maintaining a stable level of mu receptor occupancy in both maternal and fetal brain (193). Methadone trough serum levels provide an objective window on both maternal metabolism and fetal exposure. This information can document the need for dose increases and reduce anxiety about adverse effects of increased

doses on the fetus. It is not uncommon to see the methadone dose go up and the serum level go down or remain constant (196). Further, serum levels postpartum are necessary for clinical safety to monitor the reversal of enzyme induction and a rise in serum levels, which can pose problems of oversedation, higher than normal amounts of methadone entering breast milk, and maternal dependence on unnecessarily high serum levels (193). Most women will need dose decreases in the early postpartum period. Buprenorphine is converted to three active metabolites: norbuprenorphine and the glucuronide conjugates of the parent and norbuprenorphine (193,218). Therefore, serum levels are likely to remain more constant than methadone and require less frequent dose adjustments. However, accelerated metabolic effects can also affect buprenorphine metabolite levels, and dose increases and divided dosing are likely needed for optimal maternal/fetal mu receptor occupancy, as with methadone (219). The treating clinician should partner with an obstetrician and neonatologist in the management of a pregnancy in the context of OUD. Consultants may lack understanding of the nature of addiction and the special issues related to maternal/fetal OUD, leading to negative physician–patient interactions and maternal stress and shame (193). Pregnant women are especially reassured to know that their physicians communicate and agree on a treatment plan.

Interactions of Opioid Agonist Treatment and Human Immunodeficiency Virus and Acquired Immunodeficiency Syndrome Pharmacotherapy The introduction of new antiretroviral agents and antiretroviral therapy (ART) created a new therapeutic era for HIV-infected patients but also has introduced new complexities related to potential toxicities and interactions. Preclinical studies of ART and opioids indicate that drug interactions may occur as methadone and buprenorphine are both primarily metabolized by hepatic cytochrome CYP4503A4 (106,220). A number of antiretroviral medications have been shown in preclinical studies to inhibit or induce the activity of this same enzyme. Methadone has been associated with several clinically important adverse drug interactions with ART. Significant drug–drug interactions between methadone and antiretroviral medications include potential for opiate withdrawal symptoms with efavirenz, nevirapine, lopinavir/ritonavir, and rilpivirine while

methadone levels may be increased as a result of inhibition of methadone metabolism with delavirdine, although this medication is rarely used for the treatment of HIV infection at this time. Medications known to inhibit CYP3A4 have been used as a means of enhancing the plasma concentrations of other HIV medications. These include ritonavir and cobicistat, but neither has a clinically significant effect on methadone metabolism. Antiviral medications for the treatment of hepatitis C including, boceprevir, sofosbuvir, and telaprevir have no significant drug interactions with methadone (221). Antiretroviral medications that induce methadone metabolism present a risk for methadone toxicity if discontinued without concurrent tapering of methadone dose that had been increased to assure therapeutic effect of methadone while treatment with the inducing medication occurred (155). It has been recommended that after the medication that is inducing CYP4503A enzymes is stopped, the methadone dose should be tapered over 1-2 weeks to reestablish the previous therapeutic dose of methadone (ie, that dose on which the patient was stable before starting the antiretroviral medication that induced methadone metabolism) (5). Buprenorphine has been studied in combination with antiretroviral medications more recently. To date, reductions in buprenorphine concentrations resulting from drug interactions have not been associated with opioid withdrawal. Further, a recent review (145) regarding specific interactions between buprenorphine and ART found that drug interactions between buprenorphine/naloxone and HIV medications are less likely than with methadone.

Methadone-to-Buprenorphine Transfer Some patients will be transferred from methadone to buprenorphine. This clinical decision may be driven by several possible factors. First, there is the unique pharmacology of buprenorphine, leading to its more favorable safety profile and longer duration of action (thus permitting thrice-weekly dosing) relative to methadone (61,222–224). Second buprenorphine may engender less fear of stigma than methadone (225). Third, owing to its availability in officebased primary care—outside standard OTPs (52,73,226)—buprenorphine is more accessible over a wide geographic area. It also may be more appropriate as an early intervention strategy for those with short OUD histories (eg, adolescents) or with less physical dependence. However, if a patient is stable on methadone, the advisability of transfer to buprenorphine requires careful scrutiny

of the factors motivating the request. Furthermore, transferring patients from a long-acting agonist such as methadone to buprenorphine without producing significant withdrawal discomfort, attrition, or relapse to drug use has been shown to be more challenging than transfer from a short-acting opioid. Research on transfer from methadone to buprenorphine is limited. These studies support an important role for methadone dose and interval between methadone and buprenorphine administration in determining precipitated withdrawal symptoms. Four studies examined the effect of time interval between the last methadone dose and the initial buprenorphine dose (227–230). Most subjects received methadone at 30 mg/d. Buprenorphine has a lower risk of precipitating withdrawal the greater the time between the last methadone dose and the first buprenorphine dose (227,228,230–233). Buprenorphine transitions from methadone doses of 30 mg/d are generally well tolerated (234). Buprenorphine induction from methadone doses of 60 mg/d risks increasing opioid withdrawal symptom (230). Two additional studies (231,233) showed mild withdrawal with buprenorphine initiation from methadone, but withdrawal severity was not correlated with methadone dose. Five studies have directly examined a full medication transfer (231,233,235,236). Precipitated withdrawal was not consistently seen with the transition from methadone to buprenorphine. Some patients were not adequately treated with buprenorphine. If a patient experiences precipitated withdrawal with the initial buprenorphine dose, additional doses of buprenorphine are not likely to worsen withdrawal and may produce greater comfort (237). Lofexidine may assist in the transition from methadone doses of 30-70 mg to buprenorphine (238). Owing to variable designs and individual differences among volunteers, a single recommended protocol is not currently available. In the absence of large clinical trials, the Provider Clinical Support System (PCSS) guidance (PCSS 2013) recommends tapering to 20 or 30 mg of methadone, waiting a minimum of 48 to 72 hours after last methadone dose, obtaining a COWS of 15 to quantify withdrawal, and starting buprenorphine at 2 mg, continuing to dose until the patient is comfortable at up to 32 mg on day 1. If withdrawal is precipitated, management with ancillary medications is advised. Discomfort may persist for up to 96 hours, but usually after 3-5 days, the patient will be stable and comfortable. In addition to clarifying the best strategy for minimizing symptoms during the transfer, clinical trials are needed to answer questions concerning short- and long-term clinical outcomes after methadone-to-buprenorphine transfer. A related relevant clinical need is identification of profiles and genetics of patients

responding differentially to methadone versus buprenorphine (pharmacotherapy treatment matching).

Buprenorphine in Agonist-to-Antagonist Treatment A number of strategies have been tried to transition patients from buprenorphine to treatment with the antagonist naltrexone. No specific protocol has emerged as the optimal way to affect the transfer. This procedure can be accomplished within the span of a few days, but precipitated withdrawal can occur. Often, α2 adrenergic and other ancillary medications are needed to manage precipitated withdrawal. There should be good justification, even if just patient preference, for using naltrexone in this situation when patients could be stabilized on buprenorphine or methadone much more easily.

Naltrexone Treatment The theoretical value of the opioid antagonist, naltrexone, is tempered by clinical reality, as reflected in retention rates of only 20% to 30% over 6 months. Multiple factors account for such poor retention (129). Opioid antagonists, unlike methadone and buprenorphine, do not provide cross-tolerance. Therefore, if antagonists are stopped, there is no immediate reminder in the form of withdrawal. In addition, craving for opioids may continue during naltrexone treatment. A meta-analysis did not provide strong support for oral naltrexone treatment of OUD (239). Nevertheless, for certain highly motivated subsamples of patients with OUD (such as healthcare professionals, business executives, or probation referrals) for whom there is an external incentive to comply with oral naltrexone therapy and to remain opioid abstinent, oral naltrexone has been very effective (240–243). Improved adherence has also been reported in programs that include psychosocial therapy (244,245), including contingency management (246,247). Clinically, oral naltrexone is initiated after withdrawal from opioids. There should be at least a 5- to 7-day opioid-free period for the short-acting opioids and a 7- to 10-day period for the long-acting agents. This does not apply to withdrawal treatments using the naltrexone–clonidine combination. The first dosage of naltrexone may be preceded by a naloxone challenge test to assure the absence of precipitated withdrawal prior to administering naltrexone. The initial dose of naltrexone used generally is 25 mg on the first day, followed by 50 mg daily or an equivalent of 350 mg weekly, divided into three doses (100, 100, and 150 mg). The principal reason for the reduced dose on day 1 is the potential for

gastrointestinal side effects, such as nausea and vomiting. This occurs in about 10% of patients taking naltrexone. In most cases, gastrointestinal upset is relatively mild and transient, but in some cases, it may be so severe as to cause discontinuation of the naltrexone. Oral naltrexone also has infrequent potential to cause transaminitis; however, 50 mg daily has been given safely to individuals with OUD (248). Transaminitis, in the rare instances it occurs, appears to be limited in extent in that it resolves when naltrexone is discontinued and does not progress to liver failure. The enzyme dihydrodiol dehydrogenase appears to catalyze the metabolism of naltrexone to the active metabolite, 6β-naltrexol. When administered orally, naltrexone has an average plasma half-life of 4 hours, whereas 6β-naltrexol has an average half-life of 13 hours after oral administration of the parent drug. In summary, though oral naltrexone has not lived up to expectations, for selected, motivated patients with OUD, it may represent a very effective form of maintenance pharmacotherapy. Extended-release formulations of naltrexone (by implant and by depot injection) have been investigated. An extended-release formulation of naltrexone (XR-NTX) injected once monthly (every 4 weeks), found safe and well tolerated by participants in studies of treatment for alcohol use disorder (249–251), was approved for OUD by the FDA in 2010. The medication has peak drug concentrations occurring at 2 hours and again at 2-3 days, remaining at therapeutic levels through 30 days. The recommended dose of 380 mg of extended-release naltrexone resulted in minimal and mild adverse events. The most common adverse events associated with XR-NTX in clinical trials were nausea, vomiting, headache, dizziness, and injection site reactions. It can also reduce opioid tolerance, which can increase the potential for overdose if opioids are used following cessation of long-term naltrexone treatment. In preliminary studies of sustained-release naltrexone in opioid-dependent subjects, Comer et al. (252–254) found that 384-mg XR-NTX was able to block the reinforcing, subjective, and physiologic effects of up to 25-mg heroin and provided therapeutic plasma levels for ~30 days (252–254). At this dose, naltrexone also resulted in better than 80% retention in treatment at 6 weeks versus 40% for placebo (254). Adverse events were minimal and limited to local injection site responses (255). A trial of XR-NTX in patients with DSM-IV opioid dependence was reported by Krupitsky (256,257). This randomized, placebo-controlled, double-blind trial of XR-NTX was conducted in Russia, where agonist therapy is not available (256,257). Participants received monthly intramuscular injections of XR-NTX 380 mg (n = 126) or placebo (n = 124) for 4 months with 12 biweekly counseling. The number of weeks of confirmed abstinence (based on

rate of opioid-negative urine drug tests and self-report during weeks 5-24) was the primary outcome. In the XR-NTX group, 90% were abstinent versus 35% for placebo (p = 0.0002). The XR-NTX participants also had more opioid-free days, greater retention, and reduced craving compared to no change in the placebo group. No XR-NTX participants died, overdosed, or ended participation due to severe adverse events associated with the study protocol. A more recent openlabel randomized trial in the United States among criminal justice–involved individuals with OUD showed that XR-NTX was superior to treatment as usual in preventing relapse to opioid use (257a). Ongoing research will need to address the effectiveness of XR-NTX compared to methadone and buprenorphine and which patients may differentially respond to this medication. XR-NTX was compared to daily sublingual buprenorphine in two studies (258,259). A 12-week open-label randomized clinical trial of 159 subjects showed XR-NTX was non-inferior to daily sublingual BUP-NLX in measures of treatment retention, total number of opioid negative urine drug screens, and use of heroin and other illicit opioids (259). A 24-week open-label randomized controlled comparative effectiveness study of 570 subjects showed that XR-NTX was not successfully initiated in 28% of subjects compared with non-successful initiation in 6% of BUP-NLX subjects. Once both medications were started, opioid negative urine samples and opioid abstinent days favored BUP-NLX in an intent to treat analysis but were similar in the per-protocol population. Selfreported opioid cravings was less with XR-NTX than with BUP-NLX initially but these converged by week 24. Five fatal overdoses occurred with two in the XR-NTX group and three in the BUP-NLX group. These studies demonstrate that XR-NTX has a role in the treatment of OUD but the high rate of initial dropout with XR-NTX is of concern. Other implant formulations of depot naltrexone are being studied; several international implant studies are reviewed by Krupitsky and Blokhina (256). The most studied is a single-dose Australian naltrexone implant. A double-blind, placebo-controlled, randomized clinical trial showed the effectiveness of this formulation in comparison with oral naltrexone (75). In comparison with the oral formulation, naltrexone implants (not XR-NTX) showed significantly higher abstinence rates and better treatment outcomes at 12 months (260–263). A large clinical trial is currently underway to compare the efficacy of XR-NTX versus buprenorphine for OUD (264). One author (DK) is aware of several opioid overdose deaths after the cessation of XR-NTX. According to unpublished data from a registry trial of XR-NTX for OUD (265), 30% of patients dropped out before receiving their

first XR-NTX injection. Seventy six percent of 403 patients treated with XRNTX dropped out in the first 6 months. Over 90% of patients were treatment failures during the duration of the study itself. Three patients died from overdose within 21, 55, and 115 days of their last dose of XR-NTX. Only 8.5% of patients discontinued XR-NTX because treatment goals were met. Naturalistic studies raise serious questions about the safety and long-term efficacy of XR-NTX for OUD.

Pain Management in Patients Receiving Opioid Agonist Treatment Patients on OAT require special consideration because of their baseline maintenance opioid. They will be tolerant to additional opioids, and if nonopioid approaches are not effective, they may need higher and more frequent doses of opioids to manage their pain.

Methadone and Acute Pain Management In cases of acute pain associated with surgery, trauma, or dental work, the physicians or dentists involved often—incorrectly—assume that usual daily dose of methadone will relieve any ensuing pain from the injury or procedure. Several points should be kept in mind. First, single daily doses of methadone may be effective in controlling addiction, but multiple daily doses may be required for analgesia. Second, long-term use of methadone and possibly buprenorphine as well is associated with hyperalgesia (266,267). Tolerance and hyperalgesia combined means that patients in OAT who require opioids for acute pain management may need very high doses of opioids. However, high-potency NSAIDs and nonopioid analgesics can also be considered as primary or adjunctive medications in the management for acute pain. Mixed agonist– antagonists (pentazocine, butorphanol, nalbuphine) and partial agonists (buprenorphine) must not be used in patients receiving methadone as they will precipitate an opioid withdrawal syndrome. Meperidine should be avoided because of the risk of seizures at the higher doses required to produce analgesia in patients receiving methadone. In summary, for patients receiving methadone who require opioids for acute pain management, (a) continue methadone without interruption and use nonopioid pain treatments whenever possible; (b) provide adequate individualized doses of opioid agonists, which must be titrated to the desired analgesic or functional effect; and (c) doses should be given more frequently and

on a fixed schedule rather than “as needed for pain.” Although not thoroughly documented, it is probably best to choose agonists different from those previously misused.

Buprenorphine and Acute Pain Management Buprenorphine has a ceiling on respiratory depression. The ceiling on analgesia is controversial. Management of acute pain (eg, postsurgical pain) on the patient taking buprenorphine is poorly understood. Clinical guidelines recommend increased doses of buprenorphine or tapering or stopping buprenorphine to allow full opioid agonists access to opioid receptors to manage postsurgical acute pain syndromes. However, these guidelines lack any scientific evidence and are primarily based upon the known pharmacology of buprenorphine and clinical experience. A small case series reported on five patients receiving buprenorphine through seven major surgeries. Postoperative pain was adequately controlled using full agonist opioids by patient report and physician assessment while maintaining buprenorphine (268). More research is required in this important issue as fear of unmanaged pain is often a barrier to patients accepting partial agonist therapy for OUD.

Chronic Pain in Patients Receiving OAT More than 30% of patients receiving OAT report chronic, severe pain (269). Compared to those who primarily misuse heroin, patients admitted to the OTP for prescription opioid addiction may have higher prevalence of pain (159,270). The historical separation of pain treatment from addiction treatment in American medicine gets in the way of properly caring for patients with chronic pain who are receiving OAT. The OTP and office-based clinician can sometimes bridge this gap by coordinating care with the patient’s primary care or pain specialist. For example, in a patient with chronic noncancer pain who is able to comply with the regulatory criteria for take-home medication, the OTP physician can order a divided dose of methadone, and the outside physician can prescribe short-acting rescue medication. This might improve baseline pain control without the need for multiple sources of long-acting medication. Nonopioid pharmacologic strategies and nonpharmacologic interventions for chronic pain should typically be attempted before or in addition to relying solely on opioid medications to manage chronic pain.

Improving Treatment Access Through Emergency

Departments A randomized clinical trial tested the efficacy of various treatments for emergency department (ED) care for the treatment of OUD. Three hundred and twenty-nine opioid-dependent patients were enrolled. One hundred and four patients were randomized to a referral only, 111 patients were assigned to a brief intervention group, and 114 were assigned to receive buprenorphine and connection with a buprenorphine prescriber. Doses of buprenorphine were 8 mg on day 1 and 16 mg on days 2 and 3. Thirty four percent of all subjects were seeking treatment for OUD, and 8.8% presented with an overdose. The primary outcome at 30 days showed that 78% of patients who received buprenorphine were receiving formal addiction treatment, while only 37% in the referral group and 45% of patients in the brief intervention group were receiving such treatment (271). The DEA allows for daily dispensing (not prescription) of any opioid medication for up to 72 hours to treat OUD while arranging for more definitive treatment.

Overdose Education and Naloxone Distribution Overdose education and naloxone distribution (OEND) is a service that has demonstrated efficacy and is addressed in detail in the chapter on harm reduction. OEND traditionally has been relegated to needle exchange programs. OEND in programs that serve high-risk individuals have served to reduce overdose death rates in heroin-using populations. In a study of 2500 injection drug using participants from 2010 to 2013, 702 overdose reversals were reported (272). All individuals using opioids and some who are prescribed opioids are at risk for accidental overdose. Federal, state, and local governments have made efforts to increase the distribution of naloxone. It is recommended that all patients who are using opioids have access to FDA-approved parenteral or intranasal naloxone reversal devices. It is further recommended that peers and family members of persons using opioids receive training on overdose identification and instruction on naloxone use. Many states have increased access to naloxone by removing physician prescribing requirements and allowing pharmacists to dispense naloxone.

PATIENTS WITH CO-OCCURRING PSYCHIATRIC DISORDERS

The high rate of co-occurring psychiatric and addictive disorders obligates treatment providers to equip themselves to address both problems. It can be difficult to differentiate substance-induced disorders from independent conditions at intake, but it is noteworthy that symptoms can diminish rapidly upon initiation of methadone, especially within the first month. Nonetheless, many patients will remain with psychiatric conditions that need to be addressed. In an important early study, Woody and colleagues (273) found that lowseverity patients benefited from both drug counseling (focused on current life problems) and psychotherapy (employing supportive–expressive and cognitive– behavioral approaches). Patients with high levels of psychiatric symptoms were lower in all areas of pretreatment functioning, but the addition of psychotherapy by professionally trained therapists did maximize their improvement in many areas. Major depression and persistent depressive disorder (dysthymia) are common co-occurring disorders in the treatment-seeking population (4,273a) especially for women (274). Psychosocial stress and the discomforts of withdrawal may contribute to temporarily low mood as well. Life crises and depressive symptoms posed a substantial risk of relapse, which lessened for those who remained in treatment (275). Anxiety disorders also are common, with symptoms abating with a combination of an adequate methadone dose and the provision of counseling or psychotherapy over a period of time (276). Posttraumatic stress disorder (PTSD) is common in patients receiving methadone, and though it may be associated with greater drug use disorder severity, PTSD does not necessarily worsen the outcome of substance use disorder treatment (277). However, both traumatic events and a resurgence of PTSD symptoms are associated with increased risk of treatment interruption, despite the fact that patients left treatment (278). Sleep disorders are often overlooked and appear to be common in those with psychiatric disorders, chronic pain, and benzodiazepine misuse and in those whose methadone dose is high (279). Schizophrenia is relatively uncommon in OUD treatment patients (280), though most programs have some patients with the disorder. Based on historical references and clinical observations, some clinicians have proposed that opioids have antipsychotic properties (281), Clinicians have described a subgroup of patients, who appear calmed and stabilized by the medication; when their doses drop, they become disorganized. It is common to find reports of personality disorders, particularly antisocial personality disorder, in the heroin-using population. Effective treatments are

being developed, even for this difficult group. Ball studied methadone patients with at least one personality disorder who were receiving two different forms of psychotherapy and who showed significant reductions in various severity indicators, including psychiatric symptoms and psychosocial impairment (282). Although neither heroin nor methadone has been found to be neurotoxic, several factors among some patients with OUD can increase the likelihood of cognitive impairment. These include overdose, concomitant hazardous alcohol use, and traumatic brain injury. Deficits in information processing may also result in difficulty following instructions and problem solving (283). However, significant improvement in concentration and executive functions after 8 to 10 weeks of treatment have been reported in both methadone and buprenorphine groups (284). A 2016 systematic review of medication use and the risk of vehicle collisions concluded that both methadone and buprenorphine are among 15 medications associated with increased risk (285). However, a 2014 comprehensive review indicated that although opioids induced some impairment of driving ability, this is less than other psychotropic agents or drugs of misuse. These authors note that impulsivity, sensation seeking, low-risk perception, antisocial behavior, and comorbid psychiatric and neurologic disorders also play a role. They suggest that the risk for impaired driving is likely less for patients stabilized on opioid medications (286).

PSYCHOSOCIAL INTERVENTIONS Psychosocial interventions are considered integral to good treatment in an OTP, and requirements for this are written into regulations for methadone and buprenorphine. A 2016 review of psychosocial interventions highlighted the need for guidelines in matching therapy combinations for individual patients (287), beyond noting that psychotherapy is useful for patients with moderate psychiatric severity (288) and that interim or minimal psychosocial treatments can still benefit patients (289–291). Counseling in OAT has variable availability, accountability, and quality, although psychosocial care reduces drug use and improves retention. Counselors act as case managers and may not be prepared for it, because they range widely in educational level and professional training. Materials from both the SAMHSA/CSAT and National Institute on Drug Abuse (NIDA) websites have tried to upgrade counselor training (www.ncbi.nlm.nih.gov/books) and include motivational enhancement strategies

(292,293) and contingency management (294,295). Buprenorphine-specific training for counselors is also available (http://www.danyalearningcenter.org). Matching patients to therapies such as multifamily and parenting therapy have some guidelines (296) for producing clinically significant improvements across a variety of domains (297). Overall, a good therapeutic alliance can continue patient improvement over a period of years (298). Comprehensive services are also needed (299–305) with monitoring of a close fit between the patient’s needs and the services delivered (302,306). This system’s level management (https://www.niatx.net) is essential for agency managers and staff to solve deficiencies step by step.

OVERSIGHT CHALLENGES

AND

REGULATORY

The opioid epidemic will likely continue to be a challenge for at least another decade. Fortunately, there are new treatment options and beneficial regulatory changes to bring to bear on the problem. Unfortunately, there are major gaps in data with no visible prospect of remediation. Buprenorphine was released for clinical use with the goal of making it widely available. This has been achieved; however, the absence of requirements for data collection makes it difficult to know how effective it is in the manner it is currently utilized. Office-based physicians are not required to create a firm structure for addressing psychosocial needs or to track progress through regular drug screens or other methods. In the absence of gathering data on a large scale, we know little about the characteristics of those taking various medications, whether they are using illicit drugs of any kind, whether they remain in treatment, and what happens to those who drop out. Five years is a common standard for evaluating many forms of treatment, but there appears to be no commitment on the part of the federal agencies to conducting such studies. Without such research, it is difficult to advocate for Congress to fund treatment efforts. In one study, claims data indicate that ~43% of buprenorphine recipients filled prescriptions for other opioids during their treatment, and 67% filled other opioids after their treatment. Consistent with other studies, retention was poor; only 33% continued to fill their prescriptions after 3 months. The data did not permit analysis of whether other opioids were prescribed for pain, highlighting the challenge of developing coordination strategies to manage OUD while managing chronic pain (307).

People who use drugs and dealers are creating new challenges for law enforcement and public health officials. New preparations, such as fentanyllaced heroin, play an increasing role in overdose deaths. It is estimated that 41% of the heroin-related deaths from 2012 to 2014 involved fentanyl (308). Adding fentanyl to white powder heroin allows suppliers to cut costs and the price while creating a serious overdose risk because of the added potency. Since many people who use drugs who die from a fentanyl overdose do not know they are ingesting it, surveillance systems and dissemination of information to people who use drugs are critically important. Fentanyl is found as a drug of deception in cocaine, methamphetamine, and counterfeit pills. Education has the potential to deter distribution, sale, and use. Naloxone may require more rapid administration and perhaps multiple doses than is needed for heroin or other opioids. Maintaining and expanding access to treatment are crucial to meet this challenging public health threat.

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2017;376(7):605-607.

CHAPTER 58

Special Issues in Office-Based Opioid Treatment Andrew J. Saxon

CHAPTER OUTLINE Introduction Epidemiological and Regulatory Issues Research Issues Clinical Issues Conclusions

INTRODUCTION Current interest in office-based approaches to the treatment of opioid use disorder springs from a recognition that the numbers and needs of individuals with this disorder continue to overwhelm the capacity of the traditional, program-based treatment system. Many such individuals cannot gain access to opioid maintenance therapy, which is the most effective intervention yet devised for this disorder (1). Meanwhile, indicators of opioid-related healthcare costs and criminal justice contacts continue to surge (2,3), as do the number of opioidrelated deaths (4). Many individuals with opioid use disorder also have unique and serious medical and psychiatric problems that the program-based treatment system cannot always address and that contribute to morbidity and mortality (1). Office-based opioid therapy (OBOT) offers one potential avenue and has made substantial inroads in the drive to ameliorate this unsatisfactory situation. In addition to referencing research on office-based treatment from France and the United Kingdom, this chapter reviews some of the historic and regulatory events that shaped the current treatment system in the United States and account for some of the ongoing gaps in services for individuals with opioid use disorder. Office-based treatment effectively fills some of these gaps, in part because office-based treatment encompasses two distinct treatment paradigms. First, OBOT offers a less structured, more flexible, and more personalized form of intervention for patients with opioid use disorder who have succeeded in the traditional treatment system of opioid agonist clinics licensed by the Center for Substance Abuse Treatment of the Substance Abuse and Mental Health Services Administration but who need to continue in pharmacotherapy. Second, OBOT provides an alternative route of entry into treatment for individuals with opioid use disorder who, for a variety of reasons, have not had access to adequate treatment or to reengagement in treatment for individuals who have not achieved

their goals in the traditional treatment system. A summary of the evidence for the benefits of transferring selected, stable methadone-treated patients into office-based settings precedes a synopsis of efforts to apply and evaluate the office-based approach for less stable patients newly entering treatment. Results of these investigations of office-based treatment then guide a discussion of clinical issues pertinent to conducting office-based treatment with patients who have opioid use disorder.

EPIDEMIOLOGICAL REGULATORY ISSUES

AND

During the first few years of the 21st century, the purity of heroin sold in the United States continued to increase, while the price decreased (5). Heroin-related emergency department visits have increased from 33,900 in 1990 to 258,482 in 2011 (6). Heroin-related overdose deaths more than tripled between 2010 and 2014 rising to 3.4 per 100,000 individuals in the United States (4). Overdose accounts for only half the overall observed mortality in people who use heroin, who exhibit mortality rates 6-20 times greater than those of age-matched populations (7,8). A subset of the heroin-using population engages in repeated criminal activity (9). The Arrestee Drug Abuse Monitoring Program (10) provides urine toxicology results of 4182 male arrestees in 10 counties around the country. These data show that, in 2010, rates of adult male arrestees testing positive for recent opioid use varied around the country from a low of 3% in Charlotte, NC, to a high of 22% in Portland, OR, and that rates of testing positive increased at most sites from 2007 to 2010. The past decades have also seen a surge in the illicit use of and problems with prescription opioid medications. Emergency department visits related to nonmedical use of opioid analgesics increased from 168,379 in 2005 to 366,181 in 2011 (11). Large numbers of overdoses on prescription opioids have also been noted (4). In 2015, 3.78 million people in the United States misused prescription opioids in the past month (12). Despite these trends, most individuals with opioid use disorder cannot access adequate treatment services. In 2014, 357,293 individuals entered treatment for heroin-related opioid use disorder, but only 28.3% received medication treatment. Similarly, 132,387 entered treatment for prescription opioid use

disorder, but only 20.7% received medication treatment (13). These data reflect a circumstance that has been prevalent throughout the past 100 years. However, these data do not reflect individuals receiving office-based opioid treatment, which is making medication treatment more widely available. The mobilization of office-based treatment as a response to this problem does not represent a true innovation but rather a return to a once commonly used strategy. Thousands of untreated individuals with opioid use disorder also worried society in the early part of the 20th century. Before the Harrison Narcotic Act was enacted in 1914 (see Chapter 26, “Addiction Medicine in America: Its Birth and Early History (1750-1935) with a Modern Postscript”), no legal restrictions limited the right of physicians to prescribe opioid medications for the care of patients considered addicted. Although controversy raged then, as it does now, about how best to handle individuals with opioid use disorder, many experts of that generation already had recognized the high likelihood that patients with opioid use disorder would resume opioid use after enforced withdrawal. Physicians in many areas of the country thus viewed opioid addiction as a medical disorder; they advocated and practiced the ongoing prescribing of opioids from their offices as a reasonable and apparently useful way to manage the problem. Most of these physicians conducted this part of their work in a responsible way. A minority may have allowed their practices to become conduits for controlled substances out of a profit motive without always providing adequate medical care. On the basis of a small number of reports of this type of inappropriate prescribing, concern about the safety and wisdom of prescribing opioids to individuals with opioid use disorder increased in the medical profession itself as well as among regulators and the general public. In 1919, the U.S. Supreme Court ruled that the Harrison Act disallowed such physician prescribing to individuals with opioid use disorder for “maintenance” purposes (14). This decision effectively ended the first era of office-based treatment for opioid addiction. Such a wholesale shift in policy left patients without access to the opioids on which they depended. Many municipalities responded by creating publicly funded and administered opioid maintenance clinics (15). For example, when New York City experienced one of its waves of heroin addiction after World War I, a clinic under the auspices of the city health department treated 8000 heroinaddicted patients with prescribed heroin (16). These pioneer efforts at agonist pharmacotherapy ended within a few years when the Narcotic Division of the Federal Prohibition Unit shut down these maintenance clinics as violators of the

Harrison Act (15). Thus, from the 1920s onward, physicians were actively discouraged from treating heroin-addicted individuals, and indeed, medical school curricula provided no training to physicians in this regard. In essence, opioid addiction was reconceptualized as a criminal justice rather than a medical problem. Convicted violators of federal narcotics laws caused an overload in the federal penal system, so the Congress established federal narcotics hospitals at Lexington, KY, and Forth Worth, TX, in the 1930s. Despite high recidivism rates, these isolated facilities remained the only treatment option for opioidaddicted individuals until the advent of methadone maintenance 30 years later (15). In some respects, the severance of opioid addiction treatment from the general practice of medicine actually was exaggerated in the 1970s when opioid agonist therapy, in the form of methadone maintenance, once again was permitted and, to some extent, promulgated. Federal methadone regulations (21 CFR Part 291) promulgated in 1972, and the Narcotic Addict Treatment Act of 1974 mandated a closed distribution system for methadone, with special licensing by both federal and state authorities. These regulations effectively made it illegal for physicians not associated with a licensed program to treat patients with opioid use disorder with agonist pharmacotherapy in an office setting. Until 2003, a private physician would have to obtain an additional registration from the U.S. Drug Enforcement Administration, annual certification by the U.S. Department of Health and Human Services, and approval by state drug authorities to provide opioid agonist therapy (16). Only a small number of physicians around the country have been willing to negotiate this bureaucratic maze. As a result, the only option for patients who desired opioid agonist pharmacotherapy was to enroll in a specialized, licensed methadone treatment program. Once again, most practicing physicians were deprived of exposure to and experience in treating patients with opioid use disorder. The divergence between mainstream medicine and opioid addiction treatment has had some unfortunate consequences. Opioid addiction causes considerable medical morbidity as a consequence of drug effects and injection routes of administration (17). Medical problems common in people who use illicit opioids include infectious diseases such as pneumonia, tuberculosis, endocarditis, as well as sexually transmitted diseases (18); soft tissue infections (19); bone and joint infections (20); central nervous system infections (21); and viral hepatitis (22), particularly hepatitis C (23). In addition, HIV infection poses a considerable problem among people who inject drugs (22,24). Noninfectious

problems also typically occur in the lungs (25), the central and peripheral nervous systems (21), the vascular system (19), and the musculoskeletal system (19). Licensed opioid agonist treatment programs often lack the resources to provide comprehensive medical care (16), with the result that comorbid medical disorders may be unattended, delaying care and driving up its ultimate cost. The economic burden to society in the United States from prescription opioid misuse alone was $78.5 billion in 2013 with $28.9 billion of that total consumed by healthcare costs (2). Similarly, a high prevalence of psychiatric comorbidity, particularly mood and anxiety disorders, is seen among patients who are addicted to opioids (26,27), and licensed programs typically cannot provide the treatment these conditions require (16). As the divide between general medical practice and opioid maintenance treatment is bridged, patients have improved access to simultaneous care for these serious comorbid medical and psychiatric conditions. Many potential patients who need and desire opioid maintenance treatment and are willing to enroll in licensed programs cannot overcome the barriers to entry. Geography creates an impossible hurdle for some. Two states (North Dakota and Wyoming) do not offer licensed opioid agonist treatment programs. In states that do offer such programs, the licensed clinics, by virtue of economic necessity and neighborhood acceptance, tend to be sited primarily in urban locations (16,28). Even within larger metropolitan areas, specific neighborhoods or communities can bar licensed clinics (16,29). A few patients who reside in states or communities without opioid agonist clinics or in rural areas invest considerable effort in traveling to other states or cities to obtain treatment; most who cannot afford the time or cost simply must forgo it (28). Inadequate treatment capacity creates another barrier for potential patients who do live in reasonable proximity to a licensed clinic (30). Many clinics have waiting lists that discourage potential patients from even attempting entry (31). Many more potential patients lack the financial resources to pay for their treatment (31). Although OBOT does not necessarily cost less than treatment in a licensed clinic, insurance companies and managed care organizations frequently reimburse at least some of the expense of physician office visits, particularly if comorbid conditions are addressed (30). Finally, the very nature of licensed opioid maintenance treatment clinics, with the potential to be recognized and stigmatized by passersby, waiting lines for medication administration, rigid attendance policies, and lack of privacy,

deters some potential patients (32). Many of the latter concerns pertain most directly to long-term, stable patients who have achieved a measure of rehabilitation in opioid maintenance treatment. Such patients have ceased illicit drug use and, in most cases, have employment and family responsibilities (30,33). To make their schedules accommodate frequent clinic visits with waits for medication, to hold up their travel plans to obtain regulatory approval, and to bring them to a locale where unstable patients with residual drug use congregate may undermine rather than support their rehabilitation (30,33). In addition, many of these rehabilitated patients already have derived maximum benefit from counseling and other services available at licensed clinics. Moving stable patients out of the restrictive clinic setting while continuing their maintenance pharmacotherapy would permit reallocation of clinic resources to patients who most need them. Three important developments altered the landscape. Since 2001, stable, long-term patients in licensed opioid treatment programs can have visits to obtain medication less frequently than once per week. The Children’s Health Act of 2000, signed into law in October 2000, included a provision waiving the requirements of the Narcotic Addict Treatment Act to permit qualified physicians to dispense or prescribe schedule III, IV, or V narcotic drugs or combinations of such drugs that are approved by the Food and Drug Administration (FDA) for the treatment of opioid addiction. This change, termed the Drug Addiction Treatment Act, allows qualified physicians to prescribe certain opioid agonist medications in an office-based setting. In October 2002, the FDA approved buprenorphine and buprenorphine + naloxone for the treatment of Diagnostic and Statistical Manual-IV (DSM-IV) opioid dependence (now called opioid use disorder in DSM-5). These medications were placed in schedule III and so are available for use in OBOT. Clearly, the current U.S. treatment system cannot accommodate all the individuals with opioid use disorder who want or need treatment. A century ago, office-based treatment met with some success in the United States. The current resurrection of office-based treatment has helped to remove geographic, social, and regulatory barriers for both new and rehabilitated patients and thus make opioid maintenance treatment more widely available. Because of the divide between opioid maintenance treatment and general medical practice, some physician education and training in management of pharmacotherapy for opioid use disorder have been necessary, have been delivered, and will continue to occur. Considerable data, described in detail in the subsequent text, offer instruction to physicians.

RESEARCH ISSUES Research Related to Stable, Long-Term Patients in Office-Based Practice Several investigations have demonstrated the general safety and utility of transferring patients who have achieved specified degrees of stability through initial treatment in a licensed methadone clinic into an office-based setting (Table 58-1). The concept of transferring stable methadone patients to officebased practice originated with Novick et al. (33–35) of New York City, who have used this procedure since 1983 and have documented their findings in several reports over the years.

TABLE 58-1 Studies of Stable Methadone-Treated Patients Transferred to OBOT

A summary of their work describes outcomes for 158 total patients (36). Stringent standards were set for patients to participate in the program. Until 1996, patients were required to have completed 5 years of methadone treatment; this requirement subsequently was reduced to 4 years, though all patients actually accepted had at least 6 years of methadone treatment. At the time of

entry, all participants had to have at least 3 years without illicit drug use, excessive alcohol use, or criminal activity. All had to verify employment or other productive activity. Additional criteria addressed the need for financial, emotional, and social stability. Patients who met the criteria were transferred from their methadone programs to the care of internists or family physicians in a hospital-based practice. The physicians, most of whom had little familiarity with treating opioid addiction, received specific training from physicians with experience in methadone agonist treatment. The average methadone dose at entry was 60 mg/d. Patients attended two office visits in the first month and then advanced to a monthly reporting and dosing schedule. At each office visit, they provided a specimen for urine toxicology screening and took a dose of methadone under observation to confirm tolerance. They received annual physical examinations from their office-based provider along with routine medical care as needed. To remain in compliance with the office-based program, patients had to avoid methadone misuse or loss, avoid illicit drug use, attend all appointments, pay fees, and maintain acceptable office comportment. Only 26 patients (16.5%) ever failed to meet these standards, 15 for uncontrollable use of cocaine, and 11 for other violations. Eighteen of the “failed patients” returned to their clinics of origin. Patients had a projected median retention time of 13.8 years in officebased treatment. During the years of this investigation, 12 subjects voluntarily and successfully tapered off methadone. Of 99 active patients, 27 required dose increases, while 10 achieved dose reductions. A retrospective analysis detected several differences between patients for whom this office-based model was successful. Patients for whom the model of care was successful were more likely to be married or in stable relationships, were more likely to have had multiple prior treatment episodes in traditional methadone programs, and had more total years of treatment in traditional methadone programs before entering office-based treatment. A similar, though smaller, uncontrolled trial was conducted in Baltimore by Schwartz et al. (30). The sample consisted of 21 patients enrolled during a 4month period in 1985 and 1986. This program required that patients have at least 5 years’ documented abstinence from illicit drug use in a traditional methadone program and a record of no alcohol misuse. Patients also were required to have self-supporting employment and emotional and social stability. Those who used psychotropic medications for psychiatric disorders were excluded. All patients transferred to the private office practice were under the care of a single physician. For the first 6 months, patients visited the office every 2 weeks, at

which time they gave a urine specimen, had a brief interview with the physician, and received a 14-day supply of methadone. They subsequently advanced to visits every 28 days and a 28-day supply of medication. Only minor medical problems were addressed by the primary practitioner, with most healthcare services delivered by outside referral. Average methadone dose over the course of the project was 71.4 mg/d. To remain in compliance with the office-based program, patients had to avoid methadone misuse or loss, have accurate return of outstanding medication doses during a “callback” procedure, avoid illicit drug or alcohol use, attend all appointments, and avoid legal problems leading to arrest. During 12 years of follow-up, six patients (28.6%) failed to comply and were transferred back to their original methadone program: two for legal problems, three for positive urine tests, and one for a combination of problems. Of all urine specimens collected, only 0.5% showed any positive results. Not a single patient failed any of the 65 random medication callbacks conducted. A third uncontrolled trial of the transfer of stable clinic-treated patients to an office-based setting was conducted in Seattle (37). The two programs described earlier gained permission to provide methadone treatment outside the established guidelines by obtaining an Investigational New Drug approval by the FDA to conduct research. The Seattle program was the first to obtain extensive FDA waivers to establish a clinical program allowing stabilized patients to receive methadone in a medical setting, with extended take-home privileges. Thirty-one patients who attended the licensed methadone clinic no more often than three times a week and who had 12 months of clinical stability (demonstrating responsibility with take-home medication, no urine drug tests positive for illicit drugs, consistent clinic attendance, and psychiatric stability) were transferred to an internal medicine clinic in a public hospital for primary medical care and methadone treatment. General internal medicine specialists cared for the patients after attending several training sessions on opioid addiction and agonist therapy. Ongoing counseling beyond physician visits was not required but was available through the licensed clinic. Trained pharmacists dispensed the medication through a satellite hospital pharmacy in the medical clinic. Patients who demonstrated stability in office-based care could be advanced to monthly medication pickups. Subjects supplied monthly urine toxicology specimens and had to comply with periodic medication callbacks. Patients who required intensive monitoring or treatment could be returned immediately to the licensed methadone clinic. Twelve-month results showed that 28 of 30 patients were still in office-based treatment, with 2 patients choosing to leave the program voluntarily. Only two patients provided any drug-containing urine

toxicology specimens, and 99% of collected specimens were negative. An additional retrospective study of 127 patients receiving methadone transferred to an office-based setting had similar positive results (38). Although the investigations described certainly suggest that most highly stable patients receiving methadone can safely transfer to office-based care, the lack of control groups in these open trials precludes conclusions about whether fewer subjects would deteriorate if they remained in traditional methadone clinics. A few controlled investigations of stable methadone patients in officebased practice have been completed. The largest of these controlled trials, although a very worthwhile study that addressed many of the concerns pertinent to office-based practice, did not represent, in the strictest sense, a trial of officebased practice because of the methodology employed. In the study, Senay et al. (39) worked with a group of 130 patients who had received at least 1 year of methadone treatment, who had 6 months of negative urine toxicologies, steady employment or productive activity, no arrests, general program compliance, and no current legal involvement. Patients were assigned randomly to either an experimental (two of three subjects) or a control condition (one of three subjects). The experimental condition consisted of a monthly visit with a physician; observed ingestion of methadone every 14 days, with 13 take-home doses for use between visits; three random urine toxicology screens per year; and random medication callbacks. Patients were required to attend at least one counseling session and leave one nonrandom urine specimen per month in their clinic of origin. Thus, the experimental subjects did continue ongoing contact with their traditional methadone programs, a situation not typical of most officebased paradigms. The control subjects remained in their clinics of origin for 6 months and then entered the experimental program. The report of this study did not provide methadone dose levels. Subjects continued in either the experimental or control conditions if they provided negative urine specimens, paid their fees, and refrained from criminal activity or lateness. During the first 6 months, 89% of experimental and 85% of control subjects remained in the program. At 1 year, 73% of both groups remained. Of the patients removed from the program, 70% were for positive urine specimens, and 30% were for other causes. Removal rates did not differ by condition. The report of this study does not mention the results of the medication callbacks. The advantages of this study derive from its randomized, controlled methodology and from its enrollment of subjects who had far less time in traditional methadone programs and less stable time than did the subjects in the studies described earlier by Salsitz et al. (36) or Schwartz et al. (30). Obviously, subjects of the type in the Senay et al. (39) study comprise a

much larger proportion of typical methadone clinic populations than do the exceedingly stable patients in the other studies. The disadvantage of the Senay study resides in the fact that all subjects continued some attendance and counseling at their clinics of origin. Hence, the study really only demonstrates that most moderately stable patients receiving methadone can manage adequately with observed ingestion of medication only once every 14 days and monthly contact with a physician, but it conveys little about office-based practice independent of a traditional methadone program. Two small controlled studies have, however, assessed office-based practice for stable patients receiving methadone without confounds from ongoing clinic involvement. In one study (40), 46 patients already receiving methadone agonist therapy at a licensed treatment program were randomly assigned to be transferred to office-based treatment with an internal medicine physician (n = 22) or to remain in standard clinic treatment (n = 24). Eligibility requirements for participants included more than a year of methadone treatment; 1-year abstinence from use of illicit opiates, as reflected by negative monthly random urine specimens; no current evidence of dependence on other substances; no significant medical or psychiatric conditions that could be compromised by the transfer; a source of legal income; and stable housing. Of note is the fact that only slightly more than 10% of the clinic’s total population met these criteria, which clearly are less stringent than those employed in the studies by Salsitz et al. (36) and Schwartz et al. (30). The average methadone dose for the subjects assigned to the office-based treatment condition was 69 mg. The average dose for those assigned to remain in standard clinic treatment was 70 mg. The six physicians who provided the office-based treatment and their staff members received training in management of patients on opioid agonist therapy. Subjects assigned to office-based treatment received a weekly supply of methadone from the physician’s office. They had an initial 1-hour office visit in which a history and physical were performed. They subsequently met with their physician monthly. Subjects assigned to remain in standard clinic treatment came to the clinic one to three times a week to pick up their methadone. All subjects provided monthly urine specimens and quarterly hair specimens for toxicological analysis. If a patient’s urine was positive for opioids or cocaine or negative for methadone, a repeat urine specimen was obtained within 1 week. If this repeat specimen also tested positive for opioids or cocaine or negative for methadone, patients were considered out of compliance with the protocol, removed from the study, and transferred back to routine care. During a 6-month follow-up interval, 18% of the office-based subjects and 21% of the standard

clinic subjects violated the study criteria and were transferred back to routine care. By urinalysis, hair toxicology, or self-report, 55% of office-based and 42% of standard clinic subjects had evidence of illicit opioid use and 27% and 25%, respectively, had evidence of cocaine use. Hair toxicology testing at baseline in this study allowed for some valuable observations. Though all subjects had submitted 12 consecutive negative monthly urine specimens before entering the study, hair testing found evidence of illicit drug use in the preceding 90 days by 44% of the subjects. Though the failure of monthly urine testing to detect all substance use does not come as a surprise (41), positive hair testing at baseline did act as a predictor of substance use during follow-up. Among those with positive hair toxicology at baseline, 90% had evidence of illicit use during follow-up. In contrast, only 20% of those with negative baseline hair toxicology had such evidence at follow-up. In another controlled study (42,43), 98 subjects who were receiving methadone treatment were randomly assigned to one of three conditions: (a) medication pickup every 28 days in a physician’s office away from the licensed treatment program; (b) medication pickup every 28 days, with a monthly physician visit at the licensed treatment clinic; or (c) continued routine clinic care, with medication pickup once or twice a week at the clinic. Of those randomly assigned, six declined further participation after receiving their treatment assignment and were terminated from the study. Eligibility requirements for participants included continuous methadone treatment and absence of any positive monthly urine specimens over the preceding 12 months, full-time employment, and no failed medication recalls or problems handling medication over the preceding 24 months. About 25% of patients from two different clinics met these criteria. The average methadone dose was 65 mg/d. The four physicians who provided the office-based treatment had previous experience treating patients with methadone agonist therapy. All subjects received a single 20-minute counseling session per month. The 28-day pickup subjects received counseling from their physicians. The routine care subjects received counseling from clinic counselors. All subjects submitted to a monthly random medication recall procedure. All subjects gave two urine specimens per month. The 28-day pickup subjects provided a routine, nonrandom specimen at the time of their scheduled physician visits and also produced a random urine specimen at the time of the medication recall. The routine care patients gave a routine random urine specimen once a month, just as did the other clinic patients, and provided a second random specimen at the time of their medication recall. An innovative stepped-care counseling intensification procedure was used

so that subjects who exhibited problems such as a positive urine specimen or failed medication recall could be transferred back to the clinic for five weekly medication visits until they again attained stability. They would then resume treatment in their assigned research condition. Treatment retention at 12 months was 82% for routine clinic care, 79% for clinic-based medical maintenance, and 92% for office-based medical maintenance. Only 12 patients submitted positive urine specimens over 12 months (9 had one positive, 2 had two positives, and 1 had repeated positive specimens for cocaine and benzodiazepines), while nearly 30% of patients failed at least one medication recall. These problems resulted in 33 subjects (36%) entering intensified counseling. The three groups did not differ significantly in the likelihood that patients would experience any negative outcome. Consideration of the overall data obtained from patients who have achieved some measure of stability on methadone therapy delivered in a clinic setting shows fairly convincingly that most can transfer successfully to office-based care. In addition, in virtually all cases, patients who fail in office-based treatment because of substance relapse or rule violations can be returned to routine clinic care to receive intensified counseling and monitoring without undue harm. The controlled studies also suggest that relapse or other problems in previously stable patients in office-based practice occur at rates no greater than those of similarly stable patients who remain in routine clinic care.

Research Related to Patients Entering Directly into Office-Based Practice Although policies and attitudes in the United States had, until 2000, steered practitioners away from the idea of bringing unstable individuals with opioid use disorder directly into office-based treatment, other countries have, out of necessity and an innovative spirit, embraced this concept more quickly (Table 58-2).

TABLE 58-2 Studies of Patients Admitted Directly to Office-Based Opioid Treatment

For example, in Scotland, most patients who receive methadone have it prescribed in general practitioners’ offices and ingest it in community pharmacies (44–48). These general practitioners receive training specific to this endeavor (45). A 1-year follow-up of 204 patients with opioid use disorder who entered such a paradigm in 1996 has been reported by Hutchinson et al. (45). A total of 58 general practitioners provided treatment to these patients. The study report does not specify the frequency or content of office visits, so practitioners presumably arranged their interventions on an individualized basis. The report also does not explicitly mention the frequency with which methadone doses were taken under observation, but it implies that this occurred on a daily or neardaily basis. Methadone dose levels are reported only for the 50 subjects who remained in continuous treatment for 12 months and who completed follow-up interviews. These subjects began at an average dose of 43 mg and increased to an average dose of 65 mg at 12 months. Follow-up interviews at 12 months were completed with 119 subjects (58.3%). Predictors of failure at follow-up included prostitution, unstable living arrangements, higher proportion of drug-using associates, higher daily drug expenditures, a higher level of benzodiazepine use, and a higher proportion of income from illegal sources. Among the 119 subjects

followed up, 50 (42.4%) remained continuously on methadone for 12 months, 34 (28.8%) interrupted and then resumed methadone treatment, and 35 stopped methadone treatment. In the group who stopped treatment, 39% did so because of imprisonment, 33% did so because they were taking other drugs or misbehaving in the pharmacy, and 27% left voluntarily because they disliked the program. In one analysis, the researchers imputed missing data for follow-up failures by carrying forward their baseline values. In this analysis, daily opioid injecting for the entire cohort declined from 80% at baseline to 43% at 12 months, the mean daily amount spent on drugs declined from £63 to £38, and the mean number of acquisitive crimes in the preceding month declined from 18 to 11. Another analysis that examined subjects followed up at 12 months compared 50 subjects who remained continuously on methadone with 57 subjects who interrupted methadone treatment during the first 6 months. Only 2% of those who remained continuously on methadone reported daily opioid injecting at 12 months as compared with 21% of those with interrupted treatment. Continuous treatment subjects were spending a daily mean of £4 on drugs at 12 months, compared with £16 for those with interrupted treatment. Continuous treatment subjects committed a mean of three acquisitive crimes in the preceding month, compared with five for those with interrupted treatment. England also has had a policy since the 1980s of encouraging individuals with opioid use disorder to get methadone treatment through office-based treatment by general practitioners (49). A nonrandomized comparison study evaluated subjects who began methadone in 1995, either in a specialist drug clinic (n = 297) or with a general practitioner (n = 155). Training required for general practitioners was not specifically mentioned. At baseline, the two groups were similar in illicit drug use except that the specialist clinic group had greater use of amphetamines. The mean initial methadone dose was 51 mg (standard deviation [SD] = 18.7) for the general practitioner group and 48 mg (SD = 19.1) for the specialist clinic group. General practitioners prescribed less than daily dispensing for 43% of their patients, while specialist clinics allowed less than daily dispensing for only 25% of their patients. Only 14% of general practitioners required that methadone administration (at retail pharmacies) be supervised. Frequency of office visits with general practitioners was not specified. Follow-up at 6 months was achieved with 76% of the original sample. At 6 months, 66% of general practitioner patients and 60% of specialized clinic patients remained in treatment. In both groups, heroin use was reduced, on average, from more than 19 days per month at baseline to fewer than 10 days per month at follow-up; there was no significant difference between groups. All

other substance use was reduced significantly and similarly for both groups. Drug injecting decreased among the general practitioner group from 53% to 41% and among the specialist clinic group from 66% to 53%. Non–drug-related crime fell among both groups but significantly more so among the general practitioner group. France did not offer agonist pharmacotherapy to individuals with opioid use disorder until the introduction of methadone at specialist addiction centers in 1995 (50). Shortly thereafter, buprenorphine became available in France for the treatment of opioid use disorder, and general practitioners, regardless of their training, gained permission to prescribe it for this indication (50,51). General practitioners in France can prescribe up to 28 days’ supply of take-home medications and a maximum daily buprenorphine dose of 16 mg. As of 2004, about 65,000 patients per year had received buprenorphine in this office-based paradigm (52). A nonrandomized comparison study examined outcomes for patients with opioid use disorder in France who were treated with buprenorphine by general practitioners (n = 32), compared with patients treated with buprenorphine at specialized addiction centers (n = 37) (50). The general practitioners had a fixed frequency of consultations, although the report does not specify the frequency. General practitioners performed urine testing weekly, required cannabis abstinence, and could arrange psychosocial services but did not necessarily have such services available. The addiction centers had a variable frequency of consultations, had no systematic frequency of urine testing, did not require cannabis abstinence, but had psychosocial services directly available. Apparently, subjects self-selected their own treatment venues. The two groups differed at baseline on important variables. The patients treated in the addiction centers were older, less likely to be employed, had more polydrug use, experienced many more episodes of overdose, and were more likely to be injecting heroin. Doses of buprenorphine (5.9 mg/d for the general practitioner group vs. 6.6 mg/d in the addiction center group) were relatively low in both groups. Treatment retention at 180 days was ~70% in the general practitioner group and about 60% in the addiction center group. Addiction Severity Index scores improved similarly for both groups from baseline to 90 days. The first U.S. study to evaluate a quasi–office-based approach to individuals with opioid use disorder just entering treatment also used buprenorphine as an agonist pharmacotherapeutic agent (53). Potential subjects with other drug or alcohol addiction, recent cocaine use, or complex medical or psychiatric comorbidities were excluded. Subjects were assigned randomly to receive 12

weeks of buprenorphine pharmacotherapy, either in a primary care setting or in a drug treatment setting that typically provided methadone treatment. The primary care setting was housed in a clinic designed to handle the primary care needs of people who use substances and patients with psychiatric disorders. Physicians in the primary care setting relied on a manual-guided clinical management protocol. Subjects assigned to the primary care setting (n = 23) received an initial 1-hour visit with a primary care provider, who recorded a substance use and medical history, created a treatment plan, made a referral to group psychotherapy, and prescribed buprenorphine. The subjects then saw their primary care provider in weekly 20-minute sessions. Group therapy conducted by a primary care nurse practitioner occurred weekly for 50 minutes, with a selfhelp focus on promoting abstinence. Subjects assigned to the drug treatment setting (n = 23) received a standard set of services, including individualized substance use disorder counseling and weekly relapse prevention group therapy. In both settings, subjects attended 5 days during week 1, with a buprenorphine dose escalation beginning at 2 mg and doubling daily until the dose reached 32 mg on day 5. From weeks 2 through 12, subjects attended clinic three times a week and received observed buprenorphine doses of 22 mg on Mondays and Wednesdays and 40 mg on Fridays. Thus, this study avoided prescribing take-home medications. Subjects in both settings also gave urine specimens three times a week. Patients were terminated from the study for missing three consecutive medication doses or for failure to attend group therapy. Successful completion of 12 weeks of treatment was observed for 78% of the subjects in primary care, compared with 52% of the subjects in drug treatment. Urine specimens were positive for opioids in 63% of urine specimens provided by primary care subjects, compared with 85% of drug treatment subjects. Primary care subjects showed a decreasing trend of opioid-positive specimens over time, whereas drug treatment subjects did not. Roughly a third of urine specimens in both groups tested positive for cocaine (53). This study lends some support to the notion that treatment-seeking patients with opioid use disorder can derive as much benefit from treatment in an officebased setting as from a drug treatment setting. Nevertheless, the researchers themselves properly note several aspects of the study design that limit its applicability to a true office-based setting. The primary care setting in this study required many more visits and more observed medication administration than would be practical in a typical office-based practice. The clinic used for the primary care setting had much more familiarity and expertise with substanceusing patients than would most office-based settings. The study excluded

patients with the medical and psychiatric complications commonly seen in treatment seekers with opioid use disorder. Another, much larger U.S. study also examined a quasi–office-based approach for patients with opioid use disorder just entering treatment (54). This study differed from the others in that it did not compare an office-based with a clinic approach but rather compared different medication strategies within a quasi–office-based setting. In this randomized, double-blind, placebo-controlled, multicenter trial, 326 subjects were randomly assigned to receive (a) buprenorphine 16 mg/d, (b) buprenorphine 16 mg + naloxone 4 mg/d, or (c) placebo. Medication was administered in office-based settings affiliated with Veterans Affairs Medical Centers. Subjects received their doses 5 days a week, with take-home medications given for weekends and holidays. The trial was terminated early because of the demonstrated efficacy of buprenorphine + naloxone compared with placebo. Subjects treated with either buprenorphine alone or buprenorphine + naloxone had a greater proportion of urine specimens that were negative for opiates than did the subjects given placebo. The rate of adverse events was manageable and comparable between the two active treatments. The largest study yet conducted of office-based treatment, A Multicenter Safety Trial of Buprenorphine + Naloxone for the Treatment of Opiate Dependence, consisted of an uncontrolled, naturalistic investigation that examined outcomes for 582 individuals with opioid use disorder newly entering office-based treatment. Patients were not excluded for psychiatric or medical problems (other than pregnancy, because buprenorphine + naloxone is not approved for use in pregnant patients), as long as the treating physician could manage the problems on her or his own or by appropriate referral. Patients were treated by 38 physicians in seven states with buprenorphine + naloxone, in doses ranging from 2 mg/0.5 mg to 24 mg/6 mg/d. Medications were dispensed by institutional and community pharmacies. Physicians and pharmacists involved in the study received at least 8 hours of training in the pharmacology of buprenorphine + naloxone and issues pertinent to office-based treatment of opioid addiction. Treatment lasted up to a year. Patients were seen by the physicians at least twice in the first week of treatment, at least weekly during weeks 2 through 12 of treatment, at least biweekly from weeks 13 to 26, and monthly thereafter until week 52. For stable patients, medication dispensing followed a pattern similar to the office visits, so that in the final 6 months of treatment, patients could have monthly medication pickups. Urine toxicology screens were obtained onsite at each office visit. Relapse prevention counseling

was available and encouraged but not required. Patients who became stable early in treatment had the option to taper the dose of buprenorphine + naloxone between weeks 7 and 9 and to complete treatment at that time. The majority of patients (97.6%) were successfully inducted with the buprenorphine–naloxone combination. Most patients received 4 mg (22%), 8 mg (33%), or 16 mg (18%) on their first day. The most common maintenance doses prescribed to patients were 8 mg (11%), 16 mg (26%), and 24 mg (29%). The 16-week completion/retention rate was 362 (62%), with 189 patients (32.5%) completing either a supervised withdrawal or 52 full weeks of treatment. Patients demonstrated a significant decrease in percent of opioid-positive urines over time. There was significant improvement in composite scores for drug, legal, and family/social domains of the Addiction Severity Index. A significant reduction in HIV risk behavior was also seen (R. Walsh, personal communication, 2007). Four subsequent smaller uncontrolled studies of patients treated for opioid use disorder with buprenorphine + naloxone showed outcomes quite similar to those found in the multicenter safety study (55–58). As mandated by the Drug Addiction Treatment Act, the Substance Abuse and Mental Health Services Administration conducted a 3-year evaluation of the impact of buprenorphine availability between 2002 and 2005 (59). Among the data sources used for this evaluation were surveys of 959 addiction medicine specialists (80% response rate), surveys of 1837 physicians who had obtained a waiver to prescribe buprenorphine (86% response rate), and telephone interviews with 433 buprenorphine-treated patients recruited through prescribing physicians’ offices or clinics. The results showed that about half the patients receiving buprenorphine had never previously received opioid maintenance treatment. More than half the patients surveyed did not use heroin and were addicted to prescription opioids. Both the patients and the physicians overwhelmingly believed that buprenorphine was effective. At 6 months after treatment initiation, more than 70% of patients remained in treatment or had completed treatment, and 81% were abstinent from nonprescribed opioids. Increases in employment and decreases in criminal activity occurred among the patient group. Opioid maintenance treatment became available in geographic locations previously not served. All of these early evaluations of direct entry to office-based treatment for opioid addiction support its viability as a treatment option and show its acceptance by patients, physicians, and pharmacists. Treatment retention in these office-based investigations did not fall markedly below—nor did illicit opioid use rise strikingly above—rates reported in recent clinic-based investigations of

opioid maintenance treatment, even though the European studies discussed here used doses of agonist medications that currently would be considered less than optimal. Recent years have witnessed a considerable increase in reports in the literature regarding office-based treatment for opioid addiction with buprenorphine. Five will be highlighted here because of data they provide on longer-term outcomes, on effects of this intervention in impoverished populations, on individuals with co-occurring opioid use disorder and HIV infection, and on the impact of additional behavioral treatment given in addition to basic physician management. One study of longer-term outcomes arose as an extension of a randomized controlled trial (60). The controlled trial enrolled and randomized 166 patients to one of three treatments over 24 weeks: (a) standard medical management with once weekly buprenorphine + naloxone dispensing, (b) standard medical management with thrice weekly buprenorphine + naloxone dispensing, and (c) enhanced medical management with thrice weekly buprenorphine + naloxone dispensing. Standard medical management involved brief, manual-guided, medically focused counseling (20 minutes); enhanced management used similar techniques, but each session was extended (45 minutes). The mean maintenance buprenorphine dose was 17.5 mg. All three treatments had statistically indistinguishable outcomes and so showed no advantage for extended counseling or more frequent buprenorphine + naloxone dispensing. Of the 166 patients randomized in the trial, 53 (32%) achieved at least 9 consecutive weeks free of illicit opioid use. These patients were enrolled in a long-term study (61). Thirtyseven and a half percent of patients remained in treatment for at least 2 years beyond the original 24 weeks, and 24.5 remained 3 years or longer. Of 1106 urine toxicology specimens provided, 91% were negative for illicit opioids. A second study of longer-term outcomes included 176 patients with opioid use disorder from both high and low socioeconomic status started on buprenorphine + naloxone in the office setting with buprenorphine doses of 1216 mg/d, although all were also enrolled in intensive outpatient treatment (62). Data were collected via retrospective chart review and cross-sectional phone interviews conducted 18-42 months after starting the medication. Among the 110 patients (67%) who completed the interview, 77% remained continuously on buprenorphine + naloxone. Patients who continued buprenorphine + naloxone were significantly less likely to have used heroin or any substance and to be employed at both baseline and follow-up. High socioeconomic status patients were more likely to be employed at baseline but not at follow-up. Low

socioeconomic status patients were more likely to remain continuously on buprenorphine + naloxone but also more likely to have substance use at followup. An examination of 408 opioid-addicted patients treated with buprenorphine + naloxone at doses of 8 mg/2 mg/d or 16 mg/4 mg/d in a primary care setting using nurse care managers showed that of 382 who could be evaluated, 187 (49%) remained successfully in treatment for 1 year, and 9 (2.4%) were stable for at least 6 months and successfully tapered off medication (63). Among those who completed 1 year, 91% were no longer using opioids or cocaine based upon urine toxicology testing. Predictors of success in a multivariate analysis were white race, older age, and prior nonprescribed use of buprenorphine. Among 303 patients with opioid use disorder and HIV infection treated in HIV primary care clinics with buprenorphine + naloxone at a median dose (buprenorphine) of 16 mg/d over 1 year in a prospective, multisite, clinical demonstration project, 49% remained on buprenorphine + naloxone for the entire year (64). Rates of illicit drug use decreased from 84% at baseline to 42% among patients retained for the full year. This study demonstrates both the feasibility and effectiveness of integrating office-based opioid treatment into HIV care. A question often arises concerning how much behavioral or psychosocial intervention is needed in addition to basic physician office management for patients receiving buprenorphine for opioid use disorder. To address this point, 141 such patients treated in a primary care clinic were randomly assigned to receive either physician management alone or physician management with an added 12-week course of manual-guided cognitive–behavioral treatment for substance use disorders (65). Illicit opioid use decreased significantly and equivalently in both groups and both had equivalent study retention over 24 weeks. Two other studies, though not conducted in office-based settings, found similarly that the addition of drug counseling (66) or the addition of cognitive– behavioral therapy and/or contingency management (67) to physician management alone did not produce superior outcomes. Thus, current evidence suggests that while adding behavioral interventions to physician management of opioid use disorder with buprenorphine may have benefit for unmeasured outcomes such as interpersonal functioning or promoting productive activities, it is unlikely to have much additional effect on reduction of illicit opioid use or treatment retention. Whether patients in office-based treatment should be maintained on

medication or tapered is another issue that frequently comes up. A recent study examined this topic by randomly assigning 113 patients with DSM-IV prescription opioid dependence to 14 weeks of buprenorphine maintenance or 6 weeks of stabilization followed by a 3-week taper and the offer of naltrexone treatment. Patients in the maintenance condition had far less illicit opioid use and much greater rates of completing the 14-week study (68). Another study, not conducted in an office-based setting, also found very low success rates with a buprenorphine taper (66). Therefore, our best current evidence argues against initiating a buprenorphine taper at least in the first several months of the treatment process.

CLINICAL ISSUES The totality of clinical experience with office-based treatment has increased considerably in the past few years, and the body of evidence reviewed previously encourages some synthesis of relevant ideas and recommendations related to clinical practice in an office setting. Again, it makes sense to divide this discussion into two segments: one most pertinent to care of long-term, stable patients who are transferred from a licensed program to office-based care and one focused on management of patients who are admitted directly to an officebased setting. Patient assessment and appropriate selection of patients for transfer from clinic-based to office-based care obviously are key elements of this paradigm. A comparison of the various studies discussed earlier gives rise to the expected impression that more stringent selection criteria with more required time and stability in clinic-based treatment lead to better success after transfer to officebased treatment. When several years of treatment and stability are required (31,36), patients exhibit no illicit opioid use and minimal other substance use and most remain in the protocol for many years. Within the group of subjects in the study by Salsitz et al. (36), more episodes of methadone treatment and longer time in treatment were associated with a greater likelihood of a good outcome after transfer to office-based care. When less stringent selection criteria are used (40,69), illicit drug use is more likely to manifest in the office-based setting. The hair toxicology performed in the Connecticut study (40) also provides insights into this issue. Hair testing detected illicit substance use for some subjects who were believed by their program to be substance-free on the basis of monthly urine screens. Positive hair testing at baseline in that study clearly predicted substance use during the experimental paradigm for subjects in either office-

based or standard clinic care. Because hair testing remains unavailable in most clinical settings, an alternative might be to obtain weekly or more frequent urine screens for some period before the anticipated transfer of any apparently stable patient from a licensed clinic to office-based care. How thoroughly to assess and how stringently to screen patients for potential transfer to office-based care also depend on how much illicit substance use would be tolerated in the office-based setting. The programs thus far reported in the literature and reviewed here tolerated very little use before initiating protective transfer of the patient back to standard clinic care. In view of the fact that patients in office-based methadone treatment may have substantial quantities of take-home methadone doses in their possession, this conservative approach toward illicit drug use makes sense. Safety concerns would dictate that patients who are using illicit drugs should not have any (or have only a negligible supply of) take-home methadone to minimize the potential for overdose. Also, patients who use illicit drugs may pose a greater risk of diverting methadone to raise cash to buy drugs. Nevertheless, the controlled studies indicate that substance use did not differ on the basis of treatment in office-based versus standard clinic care (40). What remains unknown is whether patients transferred to office-based care who experience more than a few brief episodes of substance use will continue to deteriorate in office-based care and need protective transfer back to standard clinic care or whether such relapses could be contained as effectively within the office-based setting, presuming a practical mechanism exists to limit the number of take-home doses of methadone provided until stability is regained. The report by Salsitz et al. (36) described the need for termination of 15 patients with serious misuse of cocaine who could not be treated within private practice, but it does not specify what measures might be taken within an office-based setting to address this type of problem. The stepped care intensification procedure used in the study by King et al. (42) offered one model for handling instability in the office-based setting that does not preclude rapid return to office-based care. Future studies could help to answer this question through controlled trials that randomly assign office-based patients undergoing a substance use relapse either to stay in office-based care or to receive protective transfer back to standard clinic care. Further, office-based practitioners no doubt vary in their ability to tolerate and manage relapse. Some may feel very uncomfortable and immediately wish to transfer the patient back to standard clinical care, while others may prefer to intensify services in other ways, as through an increased number of office visits,

a referral to counseling or self-help groups, or an increase in the methadone dose. Concerns about relapse lead directly to a consideration of techniques for monitoring stable patients in office-based practice. All the studies described used urine testing, which would be a common practice in licensed agonist treatment clinics. With the exception of the study by Senay et al. (39), these studies typically tested urine specimens at least monthly, often in a nonrandom fashion. In the study by Fiellin et al. (40), subjects who provided a specimen that was positive for drugs were required to give another specimen within the following week. The study by King et al. (42) used a monthly, random medication callback schedule that also required subjects to give a random urine specimen. Rates of illicit drug use were lower in this study than in the study by Fiellin et al. (40), even though the subject populations appear to be relatively similar. Despite the dangers of comparing results across different studies, these observations lead to speculation that the random nature of the callback procedures in the King et al. (42) study may have deterred some illicit drug use. Although the regular and frequent callback procedure used in that study might prove somewhat cumbersome in a purely clinical setting, the data argue for physicians who provide opioid maintenance treatment in an office-based setting to institute some type of callback procedure. The office-based subjects in the King et al. (42) study were highly satisfied with their treatment, even though the callback procedures meant that they had to visit their physician’s office twice rather than once a month. A callback procedure obviously also helps to minimize the risk of inappropriate or excessive medication use or diversion. A monitoring plan that would be practical in an office-based setting would involve monthly nonrandom urine specimens at the time of scheduled office visits; a few unscheduled callbacks per year, with medication checks and provision of random urine specimens; and a very quick callback after any positive urine specimen to obtain a repeat specimen within a few days. The latter part of the plan dictates that the physician must use a toxicology laboratory with a rapid turnaround time and must remain vigilant and act on positive test results as soon as they are received from the lab. Alternatively, with the technology to conduct onsite urine testing now readily available, an office setting with that capacity could detect illicit drug use at the time of the office visit. A more frequent medication pickup schedule could be instituted immediately, along with plans to return for repeat urine monitoring. The clinical management of methadone pharmacotherapy clearly encompasses another major component of office-based treatment for transferred

patients. A substantial number of subjects in the investigation by Salsitz et al. (36) required methadone dose changes. Physicians who treat patients with methadone in office-based practice need to remain alert to the need for alterations in medication dose. Methadone plasma concentrations can change over time in response to a variety of somewhat unpredictable environmental factors, and such changes could lead to variations in clinical medication effects (69,70). Thus, physicians should frequently inquire about symptoms such as rhinorrhea, lacrimation, chills, nausea, diarrhea, muscle aches, and insomnia and assess whether these symptoms could be related to opioid withdrawal. They should query patients about thoughts of drug use or cravings. If such symptoms are occurring, an increase in the methadone dose should be given serious consideration. Similarly, physicians should ask about possible methadone side effects (such as constipation, excess sedation, or lowered libido) that may suggest the need for a reduction in methadone dose. In the absence of serious side effects or serious risk of relapse to drug use, the patient’s wishes about dose changes often serve as the best guide to clinical decision-making (71). Psychosocial interventions form another potentially valuable element of office-based treatment for transferred patients. It would be expected, in general, that such interventions would be brief and might be minimal or unnecessary for the highly stable, long-term patients seen in the studies by Salsitz et al. (36) and Schwartz et al. (30). In the context of an office visit, it would be desirable for the physician to ask about the patient’s drug and alcohol use and cravings; how the patient is doing at work and/or with family or child care responsibilities, financial and housing circumstances; about psychiatric and medical status; and about use of leisure time. In most cases, long-term patients will indicate in a few words that they have maintained stability in these areas of their lives. In the event that a patient acknowledges some problem or added stress, a few moments to delineate the scope of the difficulty, express concern and empathy, and provide support, advice, and encouragement may suffice to assist the patient in coping with mild or moderate distress. If the problem seems more severe, the office-based physician must either arrange more frequent sessions with the patient or have ready access to referral to counseling resources. Some of the office-based paradigms described earlier (37,42) had ongoing arrangements for temporary intensification of counseling services at the original licensed treatment program. The clinical management of unstable, patients with opioid use disorder newly entering office-based treatment poses some challenges that overlap those of already stabilized clinic patients but also some that are distinct. Patients who

enter directly into office-based care exhibit marked reductions in substance use, risk behavior, and criminality; also, they have higher rates of dropout and drug use than do stable patients. Even in the study by O’Connor et al. (53), which excluded subjects with recent cocaine use or serious psychiatric or medical problems, rates of dropout and substance use were substantial. With the exception of that study, most investigations of direct entry into office-based treatment have applied no exclusions to admission, so little direct scientific information exists to guide patient selection. To a great extent, then, patient selection for direct entry into office-based treatment must rely on the specific areas of expertise and clinical skills of the treating physician. Through thorough assessment, including a complete history and physical examination, the physician should ascertain whether he or she can comfortably manage—either by direct care or by adequate referral networks—the combination of substance use problems, general medical problems, psychiatric problems, and life crises likely to arise in the treatment of each patient. Physicians should exercise caution and refer patients who are not good candidates for their practice settings to licensed treatment programs. Although the current evidence suggests that many patients who enter directly into office-based opioid maintenance treatment have a smooth course, many certainly remain unstable for some time. Physicians who accept patients directly into office-based treatment will have to be able to tolerate and deal with some serious and unexpected clinical events. As with stable, transferred patients, appropriate monitoring strategies will help the physician to stabilize patients newly entering office-based treatment. Again, no solid scientific data are available to guide precise techniques or monitoring schedules. Urine toxicology testing and periodic medication callbacks, coupled with regular clinical evaluation, likely will continue to serve as the mainstays of monitoring. Medication-dispensing schedules allow another method of managing instability. For transferred, stable patients, weekly or more frequent dispensing schedules make no sense because such patients could obtain equivalent schedules at licensed clinics. For newly entering patients, conversely, tight control of medication dispensing, when practical, likely enhances the patient’s progress toward stability. Buprenorphine and buprenorphine + naloxone are the only opioid maintenance medications approved for the treatment of patients with opioid use disorder directly entering office-based care in the United States. Although daily observation of medication ingestion would not be practical in most office-based settings, buprenorphine can be administered effectively three times a week (53), a schedule that probably is feasible in some office-based

settings and/or their affiliated community pharmacies. Monitoring and dispensing schedules will vary much more for newly entering patients, with more intensity of services expected initially, later decreasing as indicators of stability appear. Such indicators would include generally compliant behavior; regular, timely attendance at scheduled office visits; successful compliance with medication callbacks; negative urine toxicology tests; productive use of time; supportive interpersonal relationships; and the absence of criminal justice involvement. As such signs of stability appear, medication dispensing can be liberalized from three times a week to once a week, biweekly, or monthly, with an appropriate number of take-home doses. The frequency of scheduled office visits, urine testing, and medication callbacks can be adjusted in a similar fashion. If signs of instability reappear, any or all of these monitoring techniques can be readjusted for greater frequency. As in the treatment of stable, transferred patients, careful pharmacotherapy of newly entering patients can contribute to their stability. The physician needs considerable skill to prescribe buprenorphine, particularly in view of its potential to precipitate opioid withdrawal during induction of patients with high levels of physical dependence (72–74). This characteristic of buprenorphine generally dictates initiation of pharmacotherapy at low doses, followed by dose escalation as soon as the patient demonstrates medication tolerance. Throughout the course of treatment, as in the care of transferred patients, the physician will need to be alert to the signs and symptoms described earlier and be ready to adjust the dose. The potential for medication diversion plays into decisions about medication dose and frequency of dispensing. Certainly, diversion poses a danger to the community by increasing the supply of illicit opioids. In addition, diversion by a patient undermines and endangers the patient’s efforts toward achieving a stable recovery from opioid use disorder. The presence of illicit methadone and buprenorphine in the community lets us know that some diversion is indeed occurring. Scant firm data exist on the frequency or the patient characteristics and behaviors associated with diversion, though self-reports suggest that 18%-28% of patients in treatment with methadone or buprenorphine have diverted or received diverted medications (75). Failing a medication callback or request for early refills because of purported lost or stolen medication offers some obvious warning signs. A negative urine test for methadone metabolite or buprenorphine or its metabolite norbuprenorphine also suggests possible diversion. Other more subtle but certainly not pathognomonic signs might be a sudden unexplained increase in disposable income or a sudden request for a dose increase in a previously stable patient without an apparent explanation for

instability. Physicians can deal with the risk of diversion first by exercising preventive measures. They should convey to patients at the outset of treatment, preferably in a written agreement, that being prescribed opioid medications entails a lot of responsibility and that diversion will not be tolerated. Loss of take-home medication or even discontinuation of treatment could be a consequence for diversion. Faced with these strictures, those patients who might actually consider diversion will desist for fear of losing their treatment. Medication callbacks, as noted earlier, also serve as a bulwark against diversion. If patients know that they will have to account for all outstanding medication, diversion will be deterred. If diversion is suspected, a callback should be implemented. If the patient fails the callback, appropriate interventions depend on the specific circumstances of the patient and the practice. At the very least, the amount of medication dispensed at any one time should be drastically reduced. Some physicians might want to consider discontinuation of officebased treatment and referral to a licensed opioid treatment program if available. Repeated episodes of diversion clearly indicate that office-based treatment is not an appropriate setting and argue for transfer to a more structured, licensed program. Psychosocial treatments may be even more important to patients who are newly entering office-based treatment than to stable patients who already have received regular counseling at a licensed program. Scant scientific data are available to provide reliable instruction as to the optimal modality or frequency of psychosocial treatments for these patients. The uncontrolled studies conducted in Britain did not evaluate the variety of psychosocial treatments prescribed by physicians. The study by O’Connor et al. (53) used weekly physician visits and weekly group therapy—an intensity of psychosocial services that might not be available or reimbursable in most clinical settings. Studies of various intensities of psychosocial services in licensed methadone programs (76–78) do offer some illumination on this point: patients who receive minimal psychosocial services do not fare as well as do those who receive moderate or high levels of services; however, the lower cost-effectiveness of more intensive services may nullify any slight advantage they hold over moderate services (78,79). One controlled study of the efficacy of weekly extended medical management counseling (45-minute sessions) compared to weekly standard medical management counseling (20minute sessions) added to buprenorphine + naloxone treatment, as noted above, found no advantage of the extended counseling (60). As noted above, recent evidence suggests that high-quality medical management may be sufficient for many newly entering patients (65–67). For patients who fail to achieve stability

additional psychosocial services then could be titrated to the response of each individual patient. One convenient way to provide free psychosocial services is by referral to mutual help groups in the community. Sometimes such groups are not supportive of pharmacotherapy for opioid use disorder, so it behooves the physician to assist patients in locating groups that will not stigmatize them for taking appropriately prescribed medications. Many of the studies summarized here used some form of brief physician training before the physician engaged in office-based care of opioid-dependent patients. As with many aspects of OBOT, little empirical evidence exists to specify the optimal training method. Practicing physicians have limited amounts of time in their schedules for training, so a brief course makes sense. At present, physicians in the United States are eligible to practice office-based treatment of opioid addiction on completion of 8 hours of formal training and physician assistants and nurse practitioners are eligible with 24 hours of formal training. Expert consensus suggests that appropriate training should consist of most of the following topics: (a) overview of opioid use disorder and rationale for agonist treatment; (b) legislation permitting office-based treatment; (c) general opioid pharmacology; (d) pharmacology of buprenorphine and buprenorphine + naloxone; (v) efficacy and safety of buprenorphine; (e) clinical use of buprenorphine, including induction, stabilization, and withdrawal; (f) patient assessment and selection; (g) office management, including treatment agreements, urine testing, record keeping, and confidentiality; (h) co-occurring psychiatric and medical disorders; (i) psychosocial treatments; and (j) special populations, including adolescents, pregnancy, and patients with pain.

CONCLUSIONS Patients with opioid use disorder clearly need medical treatment, which has not always been readily available. In recent decades, the system has tried to meet the challenge by providing opioid maintenance pharmacotherapy at licensed treatment programs. This approach has greatly improved the outcomes and lives of many patients but has failed to accommodate many others because of inadequate capacity and because, for some individuals, attendance at such a program creates undue hardships. Good scientific data now show that transfer of patients who have 1 or 2 years of demonstrated stability in a licensed methadone program to office-based care leads to outcomes comparable to those obtained if the patients had continued at a licensed clinic. If such patients become unstable in office-based care, they can be transferred safely back to clinic care.

Many such patients prefer office-based care and have more time for productive activities when receiving treatment in an office setting. Moreover, transferring such patients to office-based care opens treatment slots in licensed opioid treatment programs to previously untreated patients. Now that many thousands of patients have been treated in office settings, the appropriate management techniques (including patient selection, monitoring, and pharmacotherapy) have been reasonably well established. Studies of office-based care of patients with opioid use disorder newly entering treatment likewise suggest that such care is reasonable for many such patients and that their short-term outcomes appear nearly equivalent to those achieved with similar patients in traditional licensed programs. More can still be learned about optimal management techniques in office-based treatment via additional rigorous research. As more knowledge has accrued about office-based treatment of opioid addiction, and as it has become a more widespread practice, some positive “ripple effects” have ensued. The “treatment gap” has narrowed somewhat as more patients who live in a variety of locations and have varying needs have gained access to opioid agonist treatment. The medical and addiction treatment systems have taken small steps toward reintegration. With these efforts, ideally medical and psychiatric comorbidities will be attended to more fully, and physicians may become more willing to address substance use problems in addition to opioid use disorder. Society in general may benefit from reductions in crime and its associated costs, from an increased engagement in the workforce by previously unemployable individuals, and, possibly, from an overall decline in healthcare expenditures shifted from acute care for the medical sequelae of untreated opioid use disorder.

Sidebar Concerning Veterans and OfficeBased Treatment of Opioid Use Disorder Office-based treatment with buprenorphine has seen rapid uptake for veterans with opioid use disorder treated by the Department of Veterans Affairs. The number of veterans receiving buprenorphine increased from 300 at 27 facilities in 2004 to 6147 in 118 facilities in 2010 (80). Unfortunately, consistent with the nationwide epidemic of opioid use disorder described in this chapter, the number of veterans with opioid use disorder receiving care at the VA increased by 45% during that same interval so that the proportion of veterans with opioid

use disorder getting opioid agonist treatment had not gone above 27% (80). In 2016, the number of VA patients receiving buprenorphine rose again to 12,525 but still represented only 20.9% of those diagnosed with opioid use disorder. An additional 4045 (6.8% of those with opioid use disorder) received naltrexone. Thus, a treatment gap still exists in the VA, as it does elsewhere, pointing to the need for creating training opportunities and incentives for more widespread implementation of buprenorphine treatment, especially since VA data suggest that office-based treatment with buprenorphine may be one way to meet the treatment needs of the growing population of opioid use disorder patients (80).

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CHAPTER 59

Pharmacological Treatment Stimulant Use Disorders David A. Gorelick

of

CHAPTER OUTLINE Introduction Cocaine Use Disorder Choice of Medication Amphetamine Use Disorder Special Treatment Situations Future Prospects Conclusions

INTRODUCTION Stimulants such as cocaine and amphetamines are the second most widely used illegal drugs, surpassed only by cannabis. In 2014, an estimated 18.2 million people (15-64 years old) worldwide used cocaine, a prevalence of 0.38%; and an estimated 35.6 million people used amphetamines or prescription stimulants for nonmedical purposes, a prevalence of 0.8% (1). In the United States in 2015, an estimated 2.2 million people (12 years and older) met Diagnostic and Statistical Manual, Fifth Edition (DSM-5) criteria for stimulant use disorder (equivalent to abuse or dependence in DSM-IV) (2), a prevalence of 0.3% (3). About 40% used cocaine; the remainder used amphetamines or prescription stimulants for nonmedical purposes. In 2013, 242 000 patients reporting cocaine, amphetamines, or other stimulants as the primary drug that they used were admitted to publicly funded and/or licensed addiction treatment programs in the United States (4). Despite this clinical need, there is no well-established, broadly effective pharmacotherapy for stimulant use disorder. Both clinical interest and scientific interest in pharmacological treatment continue to be stimulated by the often disappointingly low success rates and short duration of efficacy of current psychosocial treatments (5). This chapter reviews the current state of pharmacological treatment for stimulant use disorder, including choice of medication and medications for use in special treatment situations, such as patients with mixed addiction or psychiatric comorbidities. Emphasis is given to the use of medications in clinical practice, rather than to laboratory studies or preclinical pharmacology. (For more information about the pharmacology of stimulants, see Section 2, Chapter 12 in this text.)

More of the clinical and clinical research literature deals with cocaine than with amphetamines, so these two classes of stimulants are considered separately. There is very little literature on the pharmacological treatment of other stimulant use disorders such as methylphenidate and synthetic cathinones (“bath salts”). The extent to which findings related to cocaine can be extrapolated to other stimulants remains unknown.

COCAINE USE DISORDER Goals of Treatment The goals of pharmacological treatment of cocaine use disorder are the same as for any other treatment modality, that is, to help patients abstain from cocaine use and regain control of their lives. The behavioral mechanisms by which medication achieves these goals are poorly understood and can vary across patients and medications. In theory, medication could shift the balance of reinforcement away from cocaine taking in favor of other behaviors through several mechanisms: By reducing or eliminating the positive reinforcement from using cocaine (eg, by reducing the euphoria or “high”) By reducing or eliminating a subjective state (such as “craving”) that predisposes to taking cocaine By reducing or eliminating negative reinforcement from cocaine withdrawal (as by reducing withdrawal-associated dysphoria) By making cocaine use aversive By increasing the positive reinforcement obtained from non–cocaine-taking behaviors Currently available medications are considered to act by one or more of the first three mechanisms, and these mechanisms are the focus of research in medication development. No current research addresses the fourth mechanism (which would be analogous to the use of disulfiram in treating alcohol use disorder). The fifth mechanism is crucial to successful treatment because it ensures that other behaviors are reinforced to replace cocaine use as the latter is extinguished, but such medications do not exist. In current practice, this mechanism is engaged by psychosocial interventions that address issues such as vocational rehabilitation, the patient’s social network, and use of leisure time.

Because of the importance of this mechanism, as well as other factors such as medication adherence, medication almost never is used without some psychosocial treatment component. Few controlled clinical trials explicitly compare the efficacy of medication use with varying (or no) psychosocial treatments (6,7), so the relative contributions of pharmacological and psychosocial treatments are largely unknown. The type, intensity, and duration of psychosocial treatment that should accompany pharmacological treatment are questions with little data to guide clinical decision-making. At a minimum, one would expect that addressing psychosocial factors that influence medication adherence would improve treatment outcome.

Pharmacological Mechanisms At least four pharmacological approaches are potentially useful in the treatment of cocaine use disorder (8). These approaches are (a) a cross-tolerant stimulant (analogous to methadone or buprenorphine treatment of opioid use disorder), (b) an antagonist medication that blocks the binding of cocaine at its site of action (true pharmacological antagonism, analogous to naltrexone treatment of opioid use disorder), (c) a medication that functionally antagonizes the effects of cocaine (as by reducing the reinforcing effects of or craving for cocaine), and (d) alteration of cocaine pharmacokinetics so that less drug reaches or remains at its site(s) of action in the brain. No medication currently is approved by the U.S. Food and Drug Administration (FDA) or any other national regulatory authority for the treatment of stimulant use disorder because no medication has met the scientifically rigorous standard of consistent, statistically significant efficacy in replicated, large controlled clinical trials. Most current clinical and research attention focuses on reducing or blocking cocaine’s actions, either directly at its neuronal binding site (true pharmacological antagonism) or indirectly by otherwise reducing its reinforcing effects. Treatment with a cross-tolerant stimulant has been evaluated in a small number of clinical trials, with mixed results. Alteration of cocaine pharmacokinetics has shown promise in animal studies and early phase II clinical trials (9). Cocaine has two major neuropharmacological actions: blockade of synaptic neurotransmitter reuptake pumps, resulting in psychomotor stimulant effects and blockade of sodium ion channels in nerve membranes, resulting in local anesthetic effects. Cocaine’s positively reinforcing effects derive from its blockade of the

dopamine reuptake pump, causing presynaptically released dopamine to remain in the synapse and enhancing dopaminergic neurotransmission (10). Cocaine’s local anesthetic effects are believed to contribute to cocaine-induced kindling, the phenomenon by which previous exposure to cocaine sensitizes the individual so that later exposure to low doses produces an enhanced response.

CHOICE OF MEDICATION Antidepressants A systematic review and meta-analysis of 28 published clinical trials (mean trial duration 10.7 weeks) involving 2547 participants found that antidepressants as a class (including tricyclics, selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine uptake inhibitors, and the monoamine oxidase (MAO) inhibitor selegiline) were no more effective than placebo in terms of drop-out from treatment (relative risk 1.03, 95% CI 0.92-1.16) or number of weeks of continuous abstinence (eight studies, 942 participants, mean difference 0.08, 95% CI −0.17-0.32) (11). However, there was some variation in efficacy across types of antidepressants.

Tricyclic Antidepressants Tricyclic antidepressants are the most widely used and best-studied class of medications for the treatment of cocaine use disorder. Their pharmacological mechanism of action is to increase biogenic amine neurotransmitter activity in synapses, primarily by inhibiting presynaptic neurotransmitter reuptake pumps. A systematic review and meta-analysis of 18 published clinical trials (17 with desipramine, 1 with imipramine) at antidepressant doses involving 1293 participants found no advantage over placebo for drop-out rate (15 studies involving 1141 participants, relative risk 1.00, 95% CI 0.85-1.18),but a significant advantage in proportion of participants achieving at least 3 weeks of continuous abstinence (5 studies involving 367 participants, relative risk 1.55, 95% CI 1.10-2.17) (11). This advantage over placebo disappeared when the analysis was limited to the three studies that involved participants with moderate-to-severe cocaine use disorder (234 participants, relative risk 1.41, 95% CI 0.93-2.14), suggesting that the therapeutic effect is not very robust. Differences in patient characteristics, concomitant treatment, and

desipramine plasma concentrations may account for some of the variability in the efficacy of desipramine. For example, patients with depression (12) and without antisocial personality disorder (13) may respond best to desipramine. Patients with cooccurring cocaine and opioid use disorders may do better on desipramine if their opioid use is treated with buprenorphine rather than methadone or if they receive contingency management treatment along with medication (14). There is weak evidence that patients with steady-state desipramine plasma concentrations above 200 ng/mL have poorer outcomes (15), with better outcomes at concentrations around 125 ng/mL (14). No unexpected or medically serious side effects have been reported in published clinical trials of tricyclic antidepressants (11). However, patients who relapse to cocaine use while still on antidepressant medications could, in theory, be at increased risk of cardiovascular side effects. Both cocaine and the tricyclics have quinidine-like membrane effects that, when superimposed, could lead to cardiac arrhythmias. The concurrent administration of cocaine and desipramine (blood levels above 100 ng/mL) to research volunteers has produced additive increases in heart rate and blood pressure (16).

Selective Serotonin Reuptake Inhibitors Antidepressants that selectively block the presynaptic serotonin reuptake pump have attracted interest because of the role of serotonin and its receptors in modulating dopaminergic brain reward circuits and the behavioral effects of cocaine (17,18) (see Chapter 12, Section 2). A systematic review and metaanalysis of eight published clinical trials (five with fluoxetine, one each with citalopram, paroxetine, and sertraline) involving 662 participants found no significant advantage over placebo in drop-out rate (6 studies involving 527 participants, relative risk 0.99, 95% CI 0.70-1.41) or craving for cocaine (3 studies involving 93 participants, standardized mean difference −0,22, 95% CI −0.52-0.54) (11).

Serotonin–Norepinephrine Reuptake Inhibitors Nefazodone (19,20) and venlafaxine (21), which block both serotonin and norepinephrine reuptake, were not effective in controlled clinical trials. Mirtazapine, which increases brain serotonin and norepinephrine activity by blocking autoregulatory α2-adrenergic and 5-HT2 receptors, showed some benefit in a small open-label trial (22).

Monoamine Oxidase Inhibitors The rationale for use of MAO inhibitors lies in their effect of increasing brain levels of biogenic amine neurotransmitters by inhibiting a major catabolic enzyme. Limited open-label experience with phenelzine, at antidepressant doses of 30-90 mg/d, suggests that this medication can reduce cocaine and other stimulant use (23–25). However, its clinical usefulness may be limited by the need for dietary and concomitant medication restrictions to avoid precipitating a hypertensive crisis, as well as by the theoretical possibility of potentiating cocaine-induced cardiovascular toxicity should the patient relapse to cocaine use while still taking the medication. Some researchers have argued that fear of such an aversive, potentially life-threatening reaction is what motivates abstinence while taking an MAO inhibitor (23), making the mechanism of action analogous to that of disulfiram for alcohol use disorder. Selective MAO inhibitors that act only on MAO type B, the predominant type in the brain, while sparing MAO type A, the predominant type in the gastrointestinal tract, might obviate this issue. It is inhibition of MAO in the gastrointestinal tract that produces a hypertensive crisis (“cheese reaction”) after ingestion of tyramine-containing foods or certain catecholaminergic medications. Selegiline, marketed for the treatment of parkinsonism and, in the transdermal form, for treatment of depression, is fairly selective for MAO type B at recommended doses (10 mg/d or 12 mg/d). A multisite, controlled clinical trial using selegiline administered via a skin patch found no evidence for efficacy in treatment of DSM-IV cocaine dependence (26).

Other Antidepressants The norepinephrine reuptake inhibitors reboxetine (27) and maprotiline (28) were effective in small open-label trials, while atomoxetine showed no efficacy in a small controlled clinical trial (29). Bupropion has attracted interest because it is a weak inhibitor of monoamine reuptake and has some stimulant-like behavioral effects in animals. A metaanalysis of two published controlled clinical trials involving 176 participants found bupropion significantly better than placebo in promoting at least 3 weeks of sustained abstinence in individuals with DSM-IV cocaine dependence (risk ratio 1.63, 95% CI 1.03, 2.59) (30).

Dopamine Agonists (Antiparkinson Agents)

A variety of direct and indirect dopamine agonist medications have been evaluated, based on the dopamine depletion hypothesis of cocaine addiction. Dopamine agonists, by stimulating synaptic dopamine activity, would ameliorate the effects of decreased dopamine activity caused by cessation of cocaine use; these include anhedonia, anergia, depression, and cocaine craving. A systematic review and meta-analysis of 24 published clinical trials involving 2147 participants that evaluated direct dopamine receptor agonists (bromocriptine, pergolide, pramipexole, cabergoline, hydergine), the indirect dopamine agonist amantadine, and the amino acid dopamine precursor L-dopa (sometimes combined with the peripheral dopa-decarboxylase inhibitor carbidopa) together as a class found no evidence of efficacy compared to placebo (31). An open-label trial of ropinirole in 39 patients with DSM-IV cocaine dependence found it well tolerated and showed a significant reduction in cocaine-positive urine specimens between baseline and week 6 of treatment (32). L-Tyrosine, the amino acid precursor of L-dopa, reduced cocaine craving in a small (12 patients) double-blind study of inpatients (33) but was not effective in reducing cocaine use in two outpatient clinical trials at 2 g every 8 hours (open label) (34) or 800 or 1600 mg twice a day (double blind) (35).

Disulfiram Disulfiram can be considered a functional dopamine agonist because it blocks the conversion of dopamine to norepinephrine by the enzyme dopamine-βhydroxylase, thereby increasing dopamine concentration (36). A systematic review of seven published clinical trials involving 492 participants identified several trials in which disulfiram (250 mg daily) was significantly better than placebo in reducing drop-out rate or cocaine use (37). The trials could not be combined for meta-analysis because of high heterogeneity and differences in outcome measures. Only one (38) of five recent, larger controlled clinical trials (39–42) found significant efficacy for disulfiram compared to placebo. Some of the heterogeneity in treatment response to disulfiram may be due to genetic factors. The recent positive clinical trial found no significant efficacy for disulfiram in the subgroup of patients with a dopamine-β-hydroxylase gene allele that results in low enzyme activity (38). Two other recent small controlled clinical trials in patients receiving methadone that found no disulfiram efficacy overall did find significant efficacy in subgroups with functional variants in the ankyrin repeat and kinase domain-containing 1 (ANKK1) and dopamine D2 receptor (DRD2) genes (43) and α1A-adrenoreceptor (ADRA1A) gene (44).

Gender may also influence the treatment response to disulfiram. A review of five published controlled clinical trials involving 434 participants found that disulfiram was less effective in reducing cocaine use in women than in men (45). There was no such gender difference in response to behavioral treatments. Although disulfiram is well tolerated in clinical trials, where subjects are carefully screened for medical and psychiatric comorbidity, questions have been raised about its safety in routine clinical practice (46). Several human laboratory studies give conflicting results on the safety of the cocaine–disulfiram interaction (47), although one study found no clinically significant adverse effects from even the triple interaction of cocaine–alcohol–disulfiram (48). These findings suggest that disulfiram may be a promising treatment for cocaine use disorder in some subgroups of patients, although raising a caution about potential adverse drug interactions should patients use cocaine while on the medication. However, preliminary findings from a recently completed 12-week, controlled clinical trial with nepicastat, a dopamine beta-hydroxylase inhibitor that does not have significant pharmacological interactions with cocaine (49), suggest that the medication has no significant benefit in reducing cocaine use (www.clinicaltrials.gov, trial number NCT01704196, accessed 06/18/2018) .

Serotonergic Agents Buspirone and gepirone are primarily 5-HT1A receptor agonists used to treat generalized anxiety disorder. Controlled clinical trials found neither effective in reducing cocaine use (50,51). Ritanserin, a 5-HT2 receptor antagonist developed as an antidepressant, was no better than placebo in reducing cocaine use in two controlled clinical trials (52,53). Ondansetron, a 5-HT3 receptor antagonist approved for the treatment of nausea and vomiting, significantly reduced cocaine use in a small controlled clinical trial, but only at the highest dose (4 mg twice daily) (54).

Cholinergic Agents Muscarinic cholinergic agents influence cocaine reward in animal models, both directly and by modulating dopaminergic neurotransmission (55). Biperiden (2 mg tid), a muscarinic cholinergic receptor antagonist used to treat movement disorders, significantly reduced cocaine use in a small controlled clinical trial

(55). Mecamylamine, a nicotinic cholinergic receptor antagonist, did not reduce cocaine use in a small controlled clinical trial (56). Varenicline, a partial agonist at α4β2 nicotinic acetylcholine receptors approved for smoking cessation, significantly reduced cocaine use in a small controlled clinical trial (57). Increasing brain cholinergic activity nonspecifically by inhibiting acetylcholinesterase activity with donepezil (58) or galantamine (59) had no effect on cocaine use in small controlled clinical trials.

Opioid Receptor Ligands μ-Opioid receptor (mOR) antagonists have been evaluated as treatments for cocaine use disorder because of the role of brain mORs in cocaine use. Those who use cocaine on a chronic basis have a decreased response to mOR agonists compared to those who do not use cocaine (60), and elevated mOR binding potential in brain regions associated with reward sensitivity is associated with increased cocaine craving (61), increased rate of relapse after enforced abstinence (62), and greater cocaine use during outpatient treatment (63). These findings suggest that blockade of μ-opioid receptors might reduce cocaine craving and use. Three small controlled clinical trials (two placebo-controlled) found that naltrexone (50 mg daily) significantly reduced cocaine use compared to placebo (64,65) or to cognitive–behavioral therapy without medication (66). Buprenorphine, a partial μ-opioid receptor agonist and κ-opioid receptor antagonist approved for the treatment of opioid use disorder, has been studied for the treatment of cocaine use disorder, in part because of its efficacy in treating patients with concurrent cocaine and opioid use disorders (see Concurrent Opioid Use Disorder below). A controlled clinical trial with buprenorphine (4 mg or 16 mg daily sublingually for 8 weeks) in 302 participants with current DSM-IV cocaine dependence and past or current opioid abuse or dependence found no significant group differences in treatment retention or cocaine use (by self-report and urine drug testing) (67). However, a longitudinal analysis of urine drug testing data within treatment groups found, compared to placebo, a significantly lower rate of cocaine-positive urine samples in the buprenorphine, 16 mg group (OR 1.71, p = 0.022), and no difference in the buprenorphine, 4 mg group (OR 1.05, p = 0.105).

Stimulants By analogy with methadone and buprenorphine treatment of opioid use disorder

or nicotine treatment of tobacco use disorder, treatment of patients with cocaine use disorder with stimulant medication might be beneficial in reducing cocaine craving and use. As with methadone and buprenorphine, advantages might include use of the less medically risky oral route of administration (vs. injected or smoked cocaine), use of pure medication of known potency (thus avoiding adulterant effects or inadvertent overdose), provision by a medical professional as part of a comprehensive treatment regimen, and use of a medication with slower onset (less euphoria) and longer duration (eg, daily dosing) of action (thus avoiding “rush”/“crash” cycling). A systematic review and meta-analysis of 14 published clinical trials involving 1549 participants found that stimulants as a class (including dexamphetamine, mixed amphetamine salts, methamphetamine, lisdexamfetamine, methylphenidate, modafinil, and mazindol) were significantly better than placebo in promoting at least 3 weeks of sustained abstinence (risk ratio 1.36, 95% CI 1.05-1.77), but did not increase proportion of cocaine-free urine samples among those who did not achieve sustained abstinence (8 studies involving 516 participants, standardized mean difference 0.16, 95% CI −0.020.33) nor improve study retention (12 studies involving 2205 participants, risk ratio 1.00, 95% CI 0.93-1.06) (30). Among specific stimulants, only dexamphetamine (3 studies involving 154 participants, risk ratio 1.98, 95% CI 1.12-3.52) and mixed amphetamine salts (1 study involving 176 participants, risk ratio 3.63, 95% CI 1.15-11.48) were significantly better than placebo in promoting at least 3 weeks of sustained abstinence. A recent controlled clinical trial involving 73 participants with cocaine use disorder who were receiving heroin treatment for opioid use disorder confirmed the efficacy of sustained release dexamphetamine, which was associated with a mean difference of 16.7 (95% CI 3.1-28.4) fewer days of cocaine use, compared to placebo, over the 12-week trial (68). In principle, cocaine itself, in a slow-onset formulation or route of administration, might be used for agonist treatment (69,70), in the same way that slow-onset transdermal or transbuccal nicotine is used to treat addiction to rapidonset smoked nicotine (cigarettes). Oral cocaine salt capsules (100 mg four times a day) significantly attenuated the response to an intravenous cocaine challenge (25 mg) (70) and reduced coca paste smoking in an open-label series of 18 patients in Lima, Peru (where oral cocaine products are legal) (71). A larger series of 200 patients treated with coca tea, also in Lima, reported that almost 80% reduced their cocaine smoking (71). A case series of 50 individuals who smoked coca paste in La Paz, Bolivia, reported that chewing 100-200 g of coca

leaf per week for a mean of 2 years substantially improved the mental health of one-third of the patients and improved the socioeconomic functioning of almost half (data on cocaine smoking were not reported) (72).

Antipsychotics The older (so-called first-generation or “typical”) antipsychotics, which are potent dopamine receptor antagonists (chiefly D2 [postsynaptic] subtype), do not significantly alter cocaine craving or use, as evidenced by clinical experience with patients with schizophrenia who use cocaine while receiving chronic antipsychotic treatment (73–75). Greater effectiveness was expected from the newer “second-generation” (so-called “atypical”) antipsychotics, in part because of their broader spectrum of receptor binding (including dopamine D1 and serotonin receptors). However, a systematic review and meta-analysis of 14 published clinical trials involving 719 participants found that anti-psychotics as a class (aripiprazole, olanzapine, quetiapine, risperidone, and one study each with haloperidol or reserpine) reduced study dropout (8 studies involving 397 participants, risk ratio 0.75, 95% CI 0.57-0.97) but did not significantly reduce proportion of subjects achieving at least 3 weeks of continuous abstinence (3 studies involving 139 participants, risk ratio 1.30, 95% CI 0.73-2.32) or number of participants using cocaine during treatment (2 studies involving 91 participants, risk ratio 1.02, 95% CI 0.65-1.62) (76). A recent controlled clinical trial of aripiprazole in individuals who use cocaine who had achieved 2 weeks of continuous abstinence with contingency management found no significant reduction in lapse or relapse rates but a significant increase in cocaine craving (77). Caution should be exercised when prescribing any antipsychotic medication to those who use cocaine because of their potential vulnerability to the neuroleptic malignant syndrome, based on their presumed cocaine-induced dopamine depletion (78). Individuals who use cocaine or amphetamine may also be at elevated risk of antipsychotic-induced movement disorders (79–82).

Anticonvulsants Anticonvulsants might be effective in the treatment of cocaine use disorder because they increase inhibitory GABA activity and/or decrease excitatory glutamate activity in the brain, both actions that would decrease the response to cocaine in the dopaminergic cortico-mesolimbic brain reward circuit (83–85).

A systematic review and meta-analysis of 20 published clinical trials involving 2068 participants found that anticonvulsants as a class (carbamazepine, gabapentin, lamotrigine, phenytoin, tiagabine, topiramate, and vigabatrin) had no significant effect on drop-out rate (17 studies involving 1695 participants, risk ratio 0.95, 95% CI 0.86-1.05), cocaine use (9 studies involving 867 participants, risk ratio 0.92, 95% CI 0.84-1.02), or cocaine craving (7 studies involving 428 participants, standardized mean difference −0.25, 95% CI −0.590.09) (86). When considered individually, no anticonvulsant showed any significant benefit over placebo. However, a separate meta-analysis including only the two topiramate trials (including 210 participants) that evaluated proportion of subjects maintaining continuous abstinence for at least 3 weeks found a significant benefit for topiramate over placebo (RR 2.43, 95% CI 1.314.53) (87). A recent controlled clinical trial (not included in either meta-analysis) involving 59 participants found topiramate (maximum dose 200 mg daily) significantly better than placebo in increasing cocaine-negative urine samples (odds ratio 8.69, p < 0.001) and reducing self-reported cocaine use (mean reduction −3.1 g [p < 0.001] for amount; mean reduction −0.78 times per week [p < 0.005] for frequency), but only during the first 4 weeks of the 12-week trial (88). A small controlled clinical trial found valproate ineffective (89). Baclofen, an antispasmodic rather than anticonvulsant, increases GABA activity by acting as an agonist at GABAB receptors. One controlled clinical trial found that baclofen (60 mg daily) did not significantly reduce cocaine use, except in the subgroup of individuals with heavier cocaine use (90).

Nutritional Products

Supplements

and

Herbal

Nutritional Supplements The use of amino acid mixtures, either alone or with other nutritional supplements (vitamins and minerals), has been widely publicized in the addiction treatment field, encouraged by their freedom from the regulations imposed on prescription medications and their perceived safety and absence of side effects. A double-blind, 28-day cross-over study found no significant effect of tyrosine and tryptophan (1 g of each daily) on cocaine craving or withdrawal symptoms (91). A more recent controlled clinical trial found L-tryptophan, even when coupled with contingency management treatment, no better than placebo

in reducing cocaine use (92). L-Carnitine (500 mg/d) plus coenzyme Q10 (200 mg/d) was no better than placebo in an 8-week controlled clinical trial (89). A small controlled clinical trial found magnesium L-aspartate (732 mg daily), an easily absorbed form of magnesium, no better than placebo (93).

Herbal Products Various herbal and plant-derived products have been touted as treatments for substance use disorders, but few have undergone controlled clinical evaluation. One that received substantial publicity, but not yet rigorous clinical evaluation, is ibogaine, an indole alkaloid found in the root bark of the West African shrub Tabernanthe iboga. This compound acts on several different neurotransmitter systems, including glutamate (N-methyl-D-aspartate [NMDA] type), κ- and μopioid, 5-HT2, 5-HT3, α3β4 nicotinic, and sigma-2 receptors; the 5-HT transporter; and alters the brain expression of substance P and brain-derived neurotrophic factor [BDNF] (94,95). Those who have used ibogaine report stimulant-like effects at lower doses and a hallucinatory, dream-like state at higher doses, although a recent phase I open-label trial involving 21 healthy men found no significant effect on mood or cognitive function 2 hours after a 20 mg oral dose (96). In open-label case reports and case series, ibogaine suppresses cocaine (an opioid and alcohol) withdrawal and craving for several months after a single oral dose (94,96). A retrospective analysis of 66 drug-dependent patients (83% using cocaine, the majority also using alcohol and cannabis) who received oral ibogaine (17-20 mg/kg doses 1-5 times over several months) after maintaining 30-60 days of abstinence on a residential treatment ward found that 70% achieved continuous abstinence without other treatments for a median of 8 months (range 1-53 months), compared with a pretreatment median of 2 months (range 1-22 months) (97). However, all clinical research with ibogaine stopped in the United States about 20 years ago because of cases of cardiac arrhythmia (especially Q-T interval prolongation and ventricular fibrillation) and sudden death, probably due to ibogaine’s inhibition of hERG potassium channels (98). Ginkgo biloba (120 mg/d for 8 weeks) was no better than placebo in a controlled clinical trial (99).

Calcium Channel Blockers Calcium channel blockers have been suggested as treatment for cocaine use disorder because of their effects on neurotransmitter release and inhibition of cocaine’s psychological effects in some, but not all, studies of human research

volunteers (100). However, amlodipine showed no efficacy in a controlled clinical trial (100).

Other Medications A wide variety of other medications have been evaluated for the treatment of cocaine use disorder, often on the basis of promising case reports or animal studies suggesting that they reduced the reinforcing effects of cocaine. Doxazosin, an α1-adrenergic receptor antagonist approved for treatment of hypertension, when rapidly titrated over 4 weeks to a daily dosage of 8 mg, significantly reduced cocaine use in a recent small, controlled clinical trial (101). Numerous medications have been found no better than placebo in (usually small-scale) controlled clinical trials. These include propranolol, a betaadrenergic receptor antagonist (102); hydergine, an agonist at dopamine and serotonin receptors and antagonist at alpha-adrenergic receptors that stimulates blood flow (103); pentoxifylline, a phosphodiesterase inhibitor (21); riluzole, an inhibitor of glutamate release (21); memantine, an NMDA glutamate receptor antagonist (104); N-acetylcysteine, which increases brain glutamate levels (105); celecoxib, a nonsteroidal anti-inflammatory drug (106); citicoline, which is neuroprotective and increases phospholipid turnover and monoaminergic neurotransmission (107); and dehydroepiandrosterone (DHEA), an endogenous steroid precursor of androstenedione, itself a precursor of androgenic and estrogenic hormones (108). DHEA is also a sigma-1 receptor agonist.

Medication Combinations Concurrent use of two different medications is studied in the hope that such combinations will enhance efficacy while minimizing side effects, either by acting on a single neurotransmitter system by two different mechanisms or by acting on two different neurotransmitter systems. Concurrent open-label use of the dopaminergic agents bupropion and bromocriptine in outpatients with cocaine use disorder is safe, albeit with little efficacy (109). Concurrent use of pergolide (a dopamine D1/D2 receptor agonist) and haloperidol (a dopamine D2 receptor antagonist), designed to produce relatively pure D1 agonist action, showed efficacy (110), as did combined use of amantadine and propranolol (102). The combination of extended-release mixed amphetamine salts and topiramate was significantly better than placebo in achieving 3 consecutive weeks of abstinence (111), but there were no individual drug groups to allow

evaluation of the source of the therapeutic effect.

Other Physical Treatments Acupuncture is an ancient Chinese treatment that involves mechanical (with needles), thermal (moxibustion), or electrical (electroacupuncture) stimulation of specific points on the body surface (112). The mechanism of action is unknown; speculation has included stimulation of endogenous opioid systems. Acupuncture of the outer ear (auricular) gained popularity as a treatment for drug withdrawal, especially using five standard locations recommended by the National Acupuncture Detoxification Association (NADA): kidney, liver, lung, shen men (ear), and sympathetic. A systematic review and meta-analysis of seven published clinical trials (six using the NADA locations) involving 1433 participants did not find a significant benefit of active acupuncture over sham treatment (113,114). Transcranial magnetic stimulation (TMS) involves activation of brain cells by magnetic fields generated by electromagnetic coils placed on the scalp. Repetitive TMS (rTMS) is approved as a treatment for depression and is under study as a treatment for addiction (115). Single and multiple sessions of highfrequency (10 or 15 Hz) rTMS applied to the prefrontal cortex (either right or left) reduced cocaine craving (116) and, in a small, open-label pilot study, reduced cocaine use (117).

AMPHETAMINE USE DISORDER Many of the medications evaluated for the treatment of cocaine use disorder have also been studied for the treatment of amphetamines use disorder (amphetamine or methamphetamine), often for the same pharmacological rationale (118). As with cocaine use disorder, most controlled clinical trials do not show efficacy. The most evaluated approaches are agonist treatment with stimulants and blockade of μ-opioid receptors. A systematic review and meta-analysis of 11 published clinical trials involving 791 participants found that stimulants as a class (D-amphetamine, methamphetamine, methylphenidate, modafinil, bupropion) were not significantly better than placebo in reducing proportion of amphetamine-positive urine samples (seven studies involving 473 participants, mean difference −0.26, 95% CI −0.85-0.33) or promoting at least 3 weeks of sustained abstinence

(relative risk 1.12, 95% CI 0.84-1.49) (119). No individual stimulant was significantly effective when evaluated separately. The μ-opioid receptor antagonist naltrexone, both orally or as a subcutaneous implant, significantly reduced amphetamine use in two controlled clinical trials (120,121), although oral naltrexone combined with Nacetylcysteine was not effective in reducing methamphetamine use (122). Baclofen, an antispasmodic that increases GABA activity by acting as an agonist at GABAB receptors, had no overall effect on methamphetamine use in a controlled clinical trial but did significantly reduce use in a subgroup of patients with high medication adherence (123). Gabapentin, an anticonvulsant that increases GABAergic activity, was no different from placebo in terms of methamphetamine use, even in the adherent subgroup (123). Mirtazapine, a norepinephrine–serotonin antidepressant, significantly reduced methamphetamine use in a small controlled clinical trial (124). The second-generation antipsychotic risperidone, either oral or long-acting injectable, reduced methamphetamine use in two open-label trials (125,126). Another second-generation antipsychotic, aripiprazole (15 mg daily), showed no efficacy in a small controlled clinical trial (127). Medications not showing efficacy in the treatment of amphetamine or methamphetamine dependence include tricyclic antidepressants (eg, imipramine, desipramine), SSRIs (eg, fluoxetine, sertraline, paroxetine) (128), ondansetron (a 5-HT3 receptor antagonist) (129), topiramate (130), and the calcium channel blocker amlodipine (131).

SPECIAL TREATMENT SITUATIONS Mixed Substance Use Disorders Concurrent Opioid Use Disorder Concurrent opioid use, including opioid use disorder, is a common clinical problem among individuals with cocaine use disorder. Some individuals use cocaine and opioids simultaneously (as in the so-called “speedball”) to enhance the drugs’ subjective effects. Up to 20% or more of patients with opioid use disorder receiving methadone treatment also use cocaine for a variety of reasons,

including continuation of prior polydrug use, replacement for the “high” no longer obtained from opioids, self-medication for the sedative effects of high methadone doses, or attenuation of opioid withdrawal symptoms (132,133). Three different pharmacological approaches have been used for the treatment of dual cocaine and opioid use disorder among individuals receiving treatment with methadone: adjustment of methadone dose, treatment with another opioid medication (eg, buprenorphine), and addition of medication targeting the cocaine use disorder. Higher methadone doses (usually 60 mg or more daily) generally are associated with less opioid use by patients receiving treatment with methadone. This relationship also holds in general for cocaine use among patients receiving methadone treatment (134,135), although exceptions have been reported (136). Increasing the methadone dose as a contingency in response to cocaine use can be effective in reducing such use (and more so than decreasing the methadone dose in response to a cocaine-positive urine sample) (134,137). Buprenorphine is a partial opioid agonist (μ-receptor partial agonist/κreceptor antagonist) used for the agonist treatment of opioid use disorder (138). Differences from methadone (a pure μ-receptor agonist) include a milder (although still present) withdrawal syndrome and higher therapeutic index (ie, safety in overdose). Some (but not all) studies in patients with concurrent opioid and cocaine use disorders suggest that cocaine use (as well as opioid use) is reduced at higher buprenorphine doses (16-32 mg daily sublingually) (139–141). Making buprenorphine dosing partially dependent on cocaine-free urine samples can also reduce cocaine use in patients with opioid use disorder (142). Nonopioid medications for the treatment of cocaine use disorder frequently are evaluated in patients receiving methadone treatment or buprenorphine treatment for opioid use disorder because the opioid agonist component substantially enhances treatment retention and adherence, improving the internal validity of the trial. A variety of the medications discussed earlier, including desipramine, fluoxetine, amantadine, bromocriptine, disulfiram, and bupropion, have been studied in patients receiving opioid agonist treatment who have cocaine use disorder. There is no evidence that such opioid agonist treatment significantly influences medication efficacy, but no studies have directly addressed this issue.

Alcohol Use Disorder Alcohol use disorder is a common problem among individuals with cocaine use

disorder, both in the community and in treatment settings, with rates of comorbidity as high as 90% (143). Alcohol use by patients with cocaine use disorder is associated with poorer treatment outcome (143,144) that can be related to a variety of factors, including production of the toxic psychoactive metabolite cocaethylene, stimulation of cocaine craving by alcohol, or alteration of medication metabolism by the hepatic effects of alcohol. Two medications used in the treatment of alcohol use disorder have been studied in the treatment of patients with concurrent cocaine and alcohol use disorders. Disulfiram substantially decreased both cocaine and alcohol use in two clinical trials (145,146) and a small case series (66), but not in a third clinical trial (147). Naltrexone also substantially decreased both cocaine and alcohol use at 150 mg daily (147,148), but not at 50 mg daily (149–151) or 100 mg daily, the doses more typically used in treatment of alcohol or opioid use disorders. Naltrexone was not effective when given as a monthly extendedrelease injection (152). Combined treatment with both disulfiram (250 mg daily) and naltrexone (100 mg daily) significantly improved abstinence from cocaine and alcohol (147). A controlled clinical trial found no significant effect of topiramate compared to placebo in reducing cocaine or alcohol use in outpatients with comorbid use disorders, although topiramate-treated participants had better treatment retention and were more likely to be abstinent from cocaine during the final 3 weeks of the 13-week trial (153).

Psychiatric Comorbidities Treatment-seeking individuals with cocaine use disorder have high rates of psychiatric comorbidity (ie, psychiatric diagnoses other than another substance use disorder), with rates as high as 65% for lifetime disorders and 50% for current disorders (154,155). Psychiatric comorbidity is associated with poorer treatment outcome (156). The commonest comorbid disorders are major depression, bipolar spectrum, phobias, and posttraumatic stress disorder (157). Personality disorders are common among treatment-seeking individuals with cocaine use disorder, with rates as high as 69%. The most common of these is antisocial personality disorder (158). Despite these high rates of comorbidity, there are relatively few controlled clinical trials evaluating pharmacological treatment of this patient population (159).

Depression

Antidepressants vary in their efficacy for reducing cocaine use among patients with comorbid major depression, although there are few direct comparisons or controlled clinical trials (160,161). Desipramine, imipramine, and bupropion have usually, but not always (162,163), been found effective, whereas fluoxetine and mirtazapine (164) are usually not effective. Sertraline (200 mg daily) significantly reduced cocaine use in a controlled clinical trial (165). Venlafaxine (150-300 mg daily) and nefazodone (200 mg twice daily) show some efficacy in small clinical trials.

Bipolar Disorder Both anticonvulsant “mood stabilizers” and antipsychotics have been used to treat comorbid bipolar disorder and cocaine use disorder. Case series and openlabel trials suggest that anticonvulsants such as valproate, divalproex, lamotrigine, and carbamazepine have some efficacy in reducing cocaine use in dually diagnosed patients (166–170) and are more effective than lithium (171). Combining lithium with an anticonvulsant may be helpful in treatment-resistant patients (166). The second-generation antipsychotics show mixed results in patients with comorbid cocaine use and bipolar disorders. Quetiapine reduced cocaine use in one of the two clinical trials (172,173); risperidone reduced cocaine use in one trial (173). Switching treated patients to aripiprazole did not reduce their cocaine use (174). One controlled clinical trial found that adding citicoline, a precursor in the biosynthesis of cell membranes, to existing medication was better than adding placebo in reducing cocaine use by patients with coexisting psychiatric disorders (175). Bupropion, as an add-on to mood stabilizers, significantly reduced both cocaine use and depression symptoms in a controlled clinical trial, without inducing mania (176).

Attention Deficit Hyperactivity Disorder Up to one-fourth of adults with cocaine use disorder have either adult attention deficit hyperactivity disorder (ADHD) or a history of childhood ADHD (177,178). Stimulant and dopaminergic medications are the mainstay of treatment for ADHD, suggesting that some of these patients may be selfmedicating their ADHD with cocaine. Case series and clinical trials generally

find that such medications successfully treat ADHD symptoms and reduce cocaine use in adults: dextroamphetamine (up to 60 mg/d), extended-release mixed amphetamine salts (60 or 80 mg daily) (179), methamphetamine (15 mg/d), and bupropion (up to 100 mg three times a day) (180–182). However, one of two controlled clinical trials with sustained-release methylphenidate found no significant reduction in cocaine use (183,184) nor did a controlled clinical trial with immediate-release methylphenidate (185). A controlled clinical trial with sustained-release bupropion (183) and an open-label trial with atomoxetine (186) also found no significant decrease in cocaine use.

Schizophrenia Although schizophrenia is not a common comorbid psychiatric disorder among individuals with cocaine use disorder, cocaine use disorder is common among treatment-seeking patients with schizophrenia (187). Clinical experience indicates that first-generation antipsychotics, at doses that are effective in the treatment of schizophrenia, do not significantly alter cocaine craving or use (188,189). One exception may be flupenthixol, a mixed dopamine D1/D2 receptor and 5-HT2A receptor antagonist that is not marketed in the United States. Depot flupenthixol (40 mg of decanoate intramuscularly every 2 weeks) reduced cocaine use and improved psychopathology in a small case series of cocaine-using patients with schizophrenia (190). Several case series and open-label trials suggest that the second-generation antipsychotics, including clozapine, olanzapine, quetiapine, risperidone, and aripiprazole, may be more effective than older (first-generation) antipsychotics in reducing cocaine and other drug use among patients with schizophrenia (188,189). However, three head-to-head controlled clinical trials found no difference between olanzapine and haloperidol (191,192) or risperidone (193) in reducing cocaine use. Use of cocaine or amphetamines can exacerbate or provoke antipsychoticinduced movement disorders (79,80) and increase vulnerability to the neuroleptic malignant syndrome (78).

Medical Comorbidities Few data are available to guide the pharmacotherapy of cocaine dependence in medically ill patients, making this an important issue for future clinical research. Prudent clinical practice requires a careful medical evaluation of any patient

before starting medication, with special attention to medical conditions common in individuals with cocaine use disorder. Such conditions would include viral hepatitis and alcoholic liver disease, which might alter the metabolism of prescribed medications, and HIV infection. Stimulant use is a risk factor for sexually acquired infection including HIV (194); the presence of the latter necessitates caution in prescribing medications with a known potential for inhibiting immune function. Clinical experience suggests that buprenorphine (195,196) and bupropion can be used safely in HIV-positive patients (197), although antiretroviral medications may decrease bupropion plasma concentrations (198).

Gender-Specific Issues Women tend to be excluded from or underrepresented in many clinical trials of pharmacotherapy for cocaine use disorder (199), in part because of concern, embodied in former FDA regulations, over risk to the fetus and neonate should a female subject become pregnant. Thus, there is a substantial lack of information about gender-specific issues of pharmacotherapy in general and the pharmacotherapy of cocaine use disorder in particular (200,201). This situation should improve in the future because current FDA and National Institutes of Health regulations require appropriate representation of women in clinical trials. Meanwhile, clinicians must deal on an ad hoc basis with the treatment implications of possible gender differences in medication pharmacokinetics (such as those resulting from differences in body mass and composition) and in pharmacodynamics (such as those related to the menstrual cycle or exogenous hormones such as oral contraceptives). A recent 12-week controlled clinical trial found that progesterone (25-100 mg daily) significantly reduced cocaine use in postpartum (within 12 weeks of delivery) women, but only during the treatment period (202). In the absence of directly relevant and systematically collected data, caution should be used when prescribing medications to pregnant women with stimulant dependence and to those with pregnancy potential, keeping in mind both the risks of medication and the risks of continued stimulant use. Some medications proposed for the treatment of cocaine use disorder (such as tricyclic antidepressants, bupropion, and buprenorphine) have little potential for morphological teratogenicity or disruption of pregnancy, although there are few or no data on behavioral teratogenicity. Some medications do pose at least slight risk, such as amantadine (associated with pregnancy complications), lithium

(associated with cardiac malformations and neonatal toxicity), anticonvulsants (associated with increased risk of congenital malformations), and antipsychotics (associated with nonspecific congenital anomalies and neonatal withdrawal). Some medications (eg, disulfiram, naltrexone) may generate different treatment responses in men versus women (40,203). The reasons for such gender differences are poorly understood but may include differences in medication pharmacokinetics, hormonal interactions, or subjects’ psychological or socioeconomic status.

Age Adolescents 12-17 years old comprised 8.2% of the 1.9 million communitydwelling individuals with current (past-year) cocaine use in the United States in 2015 and 3.5% of the 900 000 individuals with current cocaine use disorder (3) but are largely excluded from clinical trials of cocaine pharmacotherapies because of legal and ethical (informed consent) considerations. On the basis of the scarcity of published case reports, it appears that medication is not often used in the treatment of cocaine use disorder in adolescents. Rates of cocaine use and cocaine use disorder among individuals older than 50 years appear to be minimal, although they may increase in the future due to sociocultural factors, for example, continued substance use among the “baby boomer” generation (204). We are not aware of any clinical trials of pharmacological treatment for cocaine use disorder involving elderly participants. Use of cognitive enhancers such as cholinesterase inhibitors has been proposed on theoretical grounds (205).

FUTURE PROSPECTS Future progress in pharmacological treatment for cocaine use disorder is likely to come from development of new medications with novel or more selective mechanisms of action. New medications should evolve from an improved understanding of the neuropharmacology of cocaine use disorder and animal studies of the interactions of cocaine with novel compounds (84,206). Preclinical studies with compounds that bind to the same presynaptic dopamine transporter site as does cocaine (thereby keeping cocaine from acting), but which do not themselves produce robust reinforcing effects (because of slow onset of effect and tight, long-lasting binding), suggest that such compounds

may be useful as functional cocaine “antagonists” (207). Manipulation of brain dopamine activity with selective dopamine receptor ligands, especially for the D3 type, attenuated the rewarding effects of cocaine in several animal studies (208) and awaits the development of compounds suitable for clinical trials. Medications that presynaptically release both dopamine and serotonin also show promise in animal studies (209). Cocaine administration, like stress, activates the hypothalamic–pituitary– adrenal (HPA) axis, and stress may play a role in relapse to cocaine use after abstinence (85). These observations stimulated interest in corticotrophinreleasing factor receptor antagonists, some of which reduce cocaine selfadministration in animals (210). The endogenous cannabinoid (endocannabinoid) brain neurotransmitter system modulates the dopaminergic reward system (85,211). Blockade of cannabinoid CB1 receptors inhibits relapse to cocaine self-administration after abstinence in animals (212). Therefore, CB1 receptor antagonists (or inverse agonists) have promising therapeutic potential if they become available for clinical research, although this will require compounds without the psychiatric side effects seen with previously available agents (213). The failure of existing medications to show consistent efficacy in the treatment of cocaine use disorder has prompted growing interest in pharmacokinetic approaches, that is, preventing ingested cocaine from entering the brain and/or enhancing its elimination from the body (9). The former approach could be implemented by active or passive immunization to produce binding antibodies that keep cocaine from crossing the blood–brain barrier. The latter approach could be implemented by administration of an enzyme (eg, butyrylcholinesterase [BChE, EC 3.1.1.8]) that catalyzes cocaine hydrolysis or by immunization with a catalytic antibody. These pharmacokinetic approaches already show promise in early clinical trials. An anticocaine vaccine (ie, active immunization against cocaine) significantly reduced cocaine use in a phase II controlled clinical trial among the one-third of participants who mounted a substantial antibody response, but only during the first 8 weeks of treatment (214). Parenteral treatment with a genetically enhanced bacterial cocaine esterase (IV) (215) or with genetically enhanced BChE (conjugated to albumin; sc) (216) significantly reduced the acute subjective and cardiovascular effects of an IV cocaine challenge in two phase I studies.

Further work is needed to increase the consistency of the antibody response, lengthen the duration of effect from active immunization and enzyme administration, and evaluate combination treatments, for example, initial enzyme administration to promptly reduce cocaine effects until vaccine-induced antibodies reach effective concentrations (9). Pharmacogenomics offers another approach to improving treatment for cocaine use disorder, by identifying subsets of patients, based on their genetic characteristics, who are more likely to respond better to a specific treatment than does the typical patient. Pharmacogenomics has already shown promise in small phase II studies in identifying treatment-responsive patients receiving disulfiram (43,44) or an anticocaine vaccine (217).

CONCLUSIONS The evidence base for effectiveness of pharmacological treatment of stimulant use disorder is relatively weak. Many clinical trials are underpowered because of small sample size and have limited internal validity because of high drop-out rates (40% or more in many studies). As a consequence, no medication is approved by the FDA or any national regulatory authority for this indication. There is medium quality evidence, based on at least one adequately powered controlled clinical trial or meta-analysis, for tricyclic antidepressants such as desipramine (at least in patients with mild cocaine use disorder), bupropion, and D-amphetamine or mixed amphetamine salts (especially sustained release formulations) in the treatment of cocaine use disorder. There is low-quality evidence to support use of oral naltrexone, varenicline, and disulfiram (especially in men with specific responsive genotypes). For the treatment of amphetamine use disorder, there is medium quality evidence for the use of naltrexone (but not for amphetamines). There is even less good quality evidence to guide the treatment of patients with mixed substance use disorders or psychiatric comorbidity. Disulfiram and naltrexone show some promise for patients with comorbid alcohol use disorder. Several antidepressants (eg, desipramine, sertraline, venlafaxine) have shown promise in reducing both depression symptoms and cocaine use in patients with mild cocaine use disorder. More sophisticated patient–treatment matching could enhance the efficacy of current medications by taking into account both patient characteristics that can influence treatment response (eg, severity of dependence, withdrawal status,

psychiatric comorbidity, concomitant medications, or genotype) and characteristics of the psychosocial treatment accompanying the medication (218). For example, a few studies suggest that some medications (eg, bupropion, L-dopa, SSRIs) that are not effective when used with drug counseling or cognitive–behavioral therapy may be effective when combined with contingency management treatment (6,219,220). Improved understanding of the neurobiology of stimulant use disorders should lead to new and more effective medications in the future, possibly by manipulation of the glutamate or endocannabinoid systems or HPA axis or by a pharmacokinetic mechanism. Regardless of which medications show promise in the future, their adoption into clinical practice should be guided by acceptable scientific proof of efficacy and safety, based on data from replicated, welldesigned, adequately powered controlled clinical trials. Clinicians should also keep in mind the distinctions between efficacy (treatment works in a research setting in a selected research population getting close attention) and effectiveness (treatment works in a heterogeneous population in a realistic clinical environment) and between a statistically significant and clinically meaningful treatment effect (221).

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CHAPTER 60

Pharmacological Interventions Tobacco Use Disorder

for

Jon O. Ebbert, J. Taylor Hays, David D. McFadden, Ryan T. Hurt and Richard D. Hurt

CHAPTER OUTLINE Neurobiology of Tobacco Use Disorder Measuring Nicotine Exposure Nicotine Replacement Therapy Nonnicotine Medications Combination Pharmacotherapy Genetics and Achieving Smoking Abstinence Electronic Nicotine Delivery Systems Treatment of Smokeless Tobacco Use Postcessation Weight Gain Clinical Decisions About Pharmacotherapy Conclusions Tobacco has been used since the earliest recorded history of the Western Hemisphere. Cigarettes began to be mass-produced and marketed in the early 20th century. The resulting annual consumption increased from 21 mg/d) is appropriate for patients who previously failed standard-dose patch therapy (≤21 mg/d) or for individuals who experience nicotine withdrawal symptoms with standard-dose patch therapy (36). Heavier smoking patients will be significantly underdosed with standard-dose patch therapy (16). High-dose nicotine patch therapy has been shown to be safe and well tolerated in patients who smoke more than 20 cigarettes per day (16,37). The 2008 United States Public Health Service Guideline Panel concluded that high-dose nicotine patch therapy did not increase smoking abstinence rates more than standard-dose nicotine patch therapy (38). However, the panel observed that the clinician may consider higher doses than FDA-recommended for patients with a high level of physical dependence. A Cochrane review suggested a small improvement in smoking abstinence outcomes with higher nicotine patch doses (33). By employing the concept of therapeutic drug monitoring, clinicians can use serum cotinine concentrations to tailor the nicotine replacement dose so that it approaches 100% replacement. First, a baseline cotinine concentration is obtained while the patient is smoking his/her baseline number of cigarettes. Then, an initial nicotine patch dose based on the baseline cotinine concentration (or cigarettes per day) is prescribed. After the patient reaches steady state (≥3 days of nicotine patch therapy and not smoking), the serum cotinine concentration is rechecked, and the replacement dose can be adjusted to achieve a steady-state cotinine level that approaches the baseline level. Percentage

replacement for a given dose of nicotine patch therapy can be determined as follows: Table 60-1 shows the recommended initial dosing of nicotine patch therapy based on serum cotinine concentrations. Higher percentage replacement has been shown to reduce nicotine withdrawal symptoms (16), but the efficacy for longterm abstinence of such an approach has not been firmly established (16,39–41).

TABLE 60-1 Nicotine Patch Dosing Based on Baseline Blood Cotinine Concentrations

aNicotine patches are available in the following doses: 7, 14, and 21 mg.

Individualizing the nicotine patch dose is warranted because of interindividual variability of baseline venous nicotine and cotinine concentrations among patients who smoke a similar number of cigarettes per day. Interindividual variability also exists in steady-state serum cotinine concentrations achieved while receiving nicotine patch therapy during smoking abstinence (16,34). Serum cotinine is the test of choice for calculating the percentage replacement, even though urine nicotine or cotinine can be used (42,43). Blood can be drawn at any time of the day for this assessment (42). If cotinine testing is not available, the nicotine patch dose can be estimated based on the number of cigarettes smoked per day (Table 60-2), which has been shown to roughly correlate with the cotinine concentrations shown in Table 60-1. For cigarette smoking patients, using cigarettes smoked per day may be a more practical approach, because cotinine testing is not widely available. For other populations of tobacco using patients (eg, those using pipes, cigars, hookahs, or smokeless tobacco), serum cotinine gives more accurate assessment of nicotine intake than the amount of product used. For all populations, adequacy of dosing can be assessed by determining withdrawal symptom relief.

TABLE 60-2 Recommended Initial Dosing of Nicotine Patch Therapy Based on the Number of Cigarettes Smoked Daily

aNicotine patches are available in the following doses: 7, 14, and 21 mg.

After initiation of nicotine patch therapy on the target quit date, the patient should receive a face-to-face or telephone counseling session within the first 2 weeks and periodically thereafter. Free tobacco telephone quitlines exist in every state and patients can access this resource by calling 1800 QUIT NOW. Abstinence during the first 2 weeks of patch therapy is highly predictive of longterm abstinence (35,44). Alterations in therapy at follow-up should be based upon relief of withdrawal symptoms and the maintenance of abstinence. If tobacco use continues during the first 2 weeks, treatment should be changed through alteration of nicotine patch dose, provision of additional pharmacotherapy, or enhancement of behavioral counseling. Nicotine patch doses should be increased for patients experiencing withdrawal symptoms (ie, irritability, anxiety, loss of concentration, or craving) or for patients who fail to achieve 100% replacement based on the follow-up serum cotinine concentration. A “standard” course of nicotine patch therapy is 8 weeks, but a course of 24 weeks of therapy increases long-term abstinence and reduces relapse rates compared to 8 weeks of therapy (45,46). Side effects of nicotine patch therapy are relatively mild and include localized skin reactions at the patch site (47). Such reactions generally begin to occur about 4 weeks after initiation of patch therapy. Topical corticosteroid therapy may be helpful in controlling these local symptoms. Rotation of the patches to different sites of the skin helps to reduce the frequency of this side effect. In rare instances, a generalized skin eruption can occur requiring that nicotine patch therapy be discontinued. Although sleep disturbance is another

side effect that has been attributed to nicotine patch therapy, it often is difficult to ascertain whether this is attributable to nicotine withdrawal or to the administration of nicotine during the evening hours. In a sleep study of patients who use cigarettes, the best quality of sleep was observed in those who stopped smoking while receiving a 24-hour nicotine patch dose compared with those who stopped smoking with placebo (48). Vivid dreams can occur with nicotine patch therapy. Patches can be left on at night if individuals wake up with significant tobacco cravings and a strong desire to smoke. However, if patches keep patients awake, they can be taken off at night and a new one can be applied the next morning. Shortly after nicotine patches reached the market, some concern was expressed in the lay press that patients might be at increased risk of myocardial infarction if they continued to smoke while using the patch. This exposure in the press led to hearings at the FDA, which concluded that there is no cause for concern. Subsequent studies have shown no adverse effects in patient with a history of coronary artery disease receiving the 14- or 21-mg patch doses (49,50). No adverse effects have been observed on serum cholesterol levels or markers of homeostasis in nonsmoking subjects who receive nicotine patch therapy (51). Nicotine patch doses up to 63 mg/d have not been associated with short-term adverse cardiovascular effects in smoking patients (52). Standard 21mg/24-hour nicotine patch doses reduce exercise-induced myocardial ischemia in patients who are trying to stop smoking (53). In an experimental dog model, nicotine patch doses of up to 44 mg/d for 4 weeks did not adversely affect the early patency of coronary artery bypass grafts (54). Despite the fact that NRT product labeling continues to carry a caution for their use in patients with coronary heart disease, the 2008 Guideline Panel asserts that separate analyses have now documented the lack of association between nicotine patch therapy and acute cardiovascular events (55–58).

NONNICOTINE MEDICATIONS Bupropion Sustained Release Bupropion is a monocyclic antidepressant that inhibits the reuptake of both norepinephrine and dopamine (59). Dopamine release in the mesolimbic system and the nucleus accumbens is hypothesized to reinforce the use of nicotine and other drugs of addiction (60–62). Bupropion does not appear to work through its

antidepressant activity. Rather, bupropion is hypothesized to be effective for patients through its dopaminergic activity on the pleasure and reward pathways in the mesolimbic system and nucleus accumbens. Bupropion also has an antagonist effect on nicotinic acetylcholine receptors (63,64). Bupropion sustained release (SR) is the formulation approved by the FDA for the treatment of tobacco use disorder (65). Bupropion SR 300 mg/d attenuates weight gain during treatment among patients continuously abstinent from smoking. The weight gain attenuation does not persist at 1 year for those who received short-term treatment (7 weeks), but persists in those who take bupropion for 52 weeks (66). Bupropion SR is effective in patients with coronary disease and chronic obstructive pulmonary disease (COPD) or those who have previously failed to achieve smoking abstinence after an initial therapy with bupropion SR (67–69). Bupropion SR appears to be equally effective in patient with or without a history of depression, as well as in recovering individuals with alcohol use disorder and those without (70). Bupropion SR may be more effective than NRT in patients with a history of depression (71). Treatment with bupropion SR should be initiated 1 week before the stop date at an initial dose of 150 mg/d for 3 days and then increased to 150 mg twice daily. Meta-analyses comparing the 300 mg/d dose to a 150-mg/d dose have not demonstrated clear efficacy of the higher dose for long-term abstinence from nicotine/tobacco products (72). These data would suggest that reducing the dose for patients with side effects would be preferred over discontinuing the medication altogether. The usual length of treatment is 6-12 weeks, but bupropion SR can safely be used longer. As with other antidepressants, this medication is associated with a small risk of seizures (0.1%). Therefore, bupropion SR is contraindicated in those who have a history of seizures, serious head trauma with skull fracture or a prolonged loss of consciousness, an eating disorder (ie, anorexia nervosa or bulimia), or concomitant use of medications that lower the seizure threshold (73). The most common adverse effects of bupropion SR are insomnia and dry mouth. If individuals experience insomnia, taking bupropion SR once per day may be as effective and will decrease the insomnia (72). Cardiovascular and sexual adverse effects are uncommon. Treatment-emergent hypertension can occur during treatment with bupropion SR when it is used in combination with nicotine patch therapy, but it is rare. Because of the high prevalence of a history of depression in patients, clinicians often encounter those who want to stop smoking but who already are

being treated with an antidepressant. No drug–drug interactions exist to preclude the use of bupropion SR with either selective serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants. Adding bupropion SR to an SSRI is preferable to discontinuing that medication and using bupropion SR as monotherapy. Although one small study showed no serious adverse effects of using bupropion in patients who were chronically taking an SSRI (74), patients receiving two antidepressants should be monitored for side effects. The use of monoamine oxidase inhibitors is a contraindication for use of bupropion SR.

Varenicline Varenicline selectively binds to the α4β2 nAChRs, where it both blocks nicotine from binding to the receptor (antagonist effect) and stimulates receptor-mediated activity (agonist effect) leading to the release of dopamine (75). Varenicline has been shown to reduce craving and nicotine withdrawal symptoms. Varenicline is not metabolized and is excreted virtually unchanged in the urine with a serum half-life of 17 hours. Seminal clinical trials have demonstrated varenicline to be more effective than placebo or bupropion SR for achieving abstinence, with end-of-treatment continuous smoking abstinence rates (ie, no smoking since the target quit date) of 44% for varenicline, 30% for bupropion SR, and 18% for placebo (odds ratio of 3.85 for varenicline compared to placebo) (76,77). The end-of-treatment 7day point prevalence smoking abstinence rates (ie, no smoking, not even a “puff,” in the last 7 days) were ~50% for varenicline, 35% for bupropion SR, and 20% for placebo. An additional 12 weeks of varenicline (24 weeks total) was effective in maintaining abstinence in patients who had stopped smoking after 12 weeks of open-label varenicline treatment; in this study, 70% of patients receiving varenicline were continuously abstinent from weeks 13-24 compared with 50% assigned to placebo (p < 0.001) (78). A Cochrane meta-analysis concluded that varenicline is superior to bupropion and single forms of NRT but comparable to multiple forms of NRT taken simultaneously (ie, nicotine patch and nicotine nasal spray) (79). A subsequent randomized clinical trial showed that among adults motivated to quit smoking, 12 weeks of open-label treatment with nicotine patch, varenicline, or combination NRT has comparable efficacy at 26 weeks (80). Varenicline has been studied in patients with COPD and patients with stable coronary heart disease with impressive end-of-treatment smoking abstinence rates (odds ratios of 8 and 6, respectively, compared to placebo) (81,82). In a

randomized, placebo-controlled trial of patients with schizophrenia or schizoaffective disorder, varenicline was efficacious (end-of-treatment smoking abstinence 19% vs. 5% for placebo) with no evidence of exacerbation of psychiatric symptoms (83). Among patients with schizophrenia and bipolar disease who attained initial abstinence with varenicline, maintenance of abstinence with varenicline significantly improved outcomes after 1 year of treatment and was not associated with adverse psychiatric effects (84). Treatment with varenicline should be initiated 1-5 weeks before the patient’s stop date at a dose of 0.5 mg daily for 3 days, with an increase to 0.5 mg twice per day for the subsequent 4 days, and a second increase to 1 mg twice per day for the duration of therapy. The initial course of treatment is 12 weeks, but clinical trials suggest that continuing varenicline for a total of 24 weeks increases abstinence rates (78). The long-term safety of varenicline has been evaluated in a 52-week placebo-controlled trial. In this study, 37% of patients who used cigarettes who were treated with varenicline were abstinent, compared with 8% in the placebo group (85). Available data suggest that varenicline is as effective in those with light physical dependence (ie, 5-10 cigarettes per day) as it is in those with heavier physical dependence (86). The most frequent adverse effect of varenicline is nausea, which is reported by ~30% of the participants. The nausea is most often mild to moderate, and study participants infrequently discontinue therapy due to nausea (60 mg/d) can reduce both opioid and cocaine use (63). A 2009 meta-analysis of 37 studies involving 3029 patients receiving methadone demonstrated that high doses of methadone were more efficacious than were lower ones in the achievement of sustained heroin abstinence (RR = 2.24 [1.54, 3.24], p < 0.0001) but had no effect on cocaine abstinence (64). At equivalent doses, methadone was more efficacious than was buprenorphine in promoting cocaine abstinence (RR = 1.63 [1.20, 2.22], p = 0.002) and heroin abstinence (RR = 1.39 [1.00, 1.93], p = 0.05) (64). The meta-analysis did not demonstrate a direct relationship between high doses of methadone and decreased cocaine use. The apparent discrepancy between this result and that of studies demonstrating decreased cocaine use in patients receiving higher doses of methadone is likely due to a two-step process whereby high-dose methadone first reduces heroin use, as shown in the meta-analysis, and this subsequently leads to decreased cocaine use. This review also describes improvements in sustained cocaine abstinence when CM targeting cocaine abstinence is added (RR = 3.11 [1.80, 5.35], p < 0.0001); a similar potentiation occurs with supplementation with indirect dopaminergic agonists (RR = 1.44 [1.05, 1.98], p = 0.03) (64). Whereas CM targeting cocaine abstinence is effective across ethnic groups (65) and its time course defined (66), the literature for adjunctive medication to treat cocaine use disorder in patients receiving methadone is less clear and often negative.

A consensus Treatment Improvement Protocol issued by the U.S. Substance Abuse and Mental Health Services Administration (SAMHSA) (TIP 10: Assessment and Treatment of Cocaine-Abusing Methadone-Maintained Patients) (67) identified nine promising adjunctive agents to potentially treat cocaine use disorder in patients receiving methadone: dopamine (DA) agonists (amantadine and bromocriptine); antidepressants (bupropion, desipramine, and fluoxetine); mazindol, a catecholamine neuronal reuptake blocker; selegiline, a selective irreversible MAO-B inhibitor; and opioid agonists/antagonists (buprenorphine, naltrexone). Including the medications listed above, at least 15 agents have been studied as adjunctive interventions to opioid agonist treatment (OAT). Pharmacological modulation of the DA system reduced cocaine use in some studies (64), including bupropion (68,69), dexamphetamine (70), disulfiram (71,72), mazindol (73), and DA antagonists such as risperidone (70). Two of five studies also demonstrated sustained cocaine abstinence from indirect noradrenergic agonism with desipramine (74). A small placebo-controlled clinical trial of varenicline (2 mg/d) in 31 patients receiving methadone with cocaine and tobacco use disorder found that cigarette smoking was significantly reduced, but there was no impact on cocaine use (75). In a second controlled clinical trial, 145 patients receiving methadone were randomized to receive either fluoxetine (60 mg/d, PO) or placebo alone or combined with a voucher-based incentive program contingent on abstinence from cocaine: the voucher program was effective on its own, but fluoxetine, either alone or added to the voucher program, did not reduce cocaine use (76). The results of this last study are consistent with a recent Cochrane Database Review that did not find sufficient evidence to support the use of DA agonists (amantadine, L-dopa/carbidopa, and bromocriptine) as treatments for cocaine use disorder in patients not receiving OAT; the review results also did not support the combination of the DA agonist agents with established and more potent psychosocial interventions (77). Buprenorphine is marketed as a parenteral and transdermal analgesic and for the treatment of opioid use disorder (as a sublingual tablet or film, as a subdermal implant, or as a subcutaneous extended release injection). In one controlled clinical trial, high doses of buprenorphine (8-16 mg/d as sublingual liquid, equivalent to 16-32 mg/d as sublingual tablet) were associated with reduced cocaine and opioid use in dually dependent patients (78), whereas lower doses were not in this and in other trials (79,80). As noted above, methadone was superior to buprenorphine in reducing cocaine use when compared at equipotent doses (64).

Naltrexone had modest success in small pilot studies in reducing cocaine use in patients without opioid use disorder (81,82) but has not been evaluated in patients with both opioid and cocaine use disorders. A clinical trial (83) using injectable, sustained-release naltrexone preparation in individuals with heroin use disorder found the percentage of urine samples negative for opioids, cocaine, and amphetamine varied significantly depending on the dose (84). At this time, there are no FDA-approved medications for the treatment of cocaine use disorder in the presence or absence of OAT. Studies of cocaine use disorder in OAT patients suggest the potential for dexamphetamine (70), disulfiram (71,72), and anticocaine vaccine (85) as adjunctive agents to OAT; buprenorphine (64,78) and naltrexone (81–84) are similarly under evaluation for the treatment of cocaine use disorder in patients with opioid use disorder.

HALLUCINOGENS Hallucinogens are a varied group of plant-derived alkaloids and synthetic compounds that have in common the ability to produce sensory, perceptual, and cognitive changes without impairing attention or level of consciousness (ie, with a clear sensorium) (86) (see Section 2, Chapter 14). They include compounds that influence serotonergic neurotransmission, such as LSD, psilocybin, and DMT, those that influence catecholaminergic neurotransmission (such as mescaline and amphetamine analogues like 3,4-methylenedioxy-Nmethamphetamine [MDMA]), and those that act at the kappa-opioid receptor (Salvia [salvinorin A]). At present, no pharmacological treatment is available for the treatment of hallucinogen use disorder (86,87). Several retrospective case reports suggest that long-term treatment with monoamine oxidase inhibitors (such as phenelzine) or SSRI antidepressants (specifically fluoxetine, sertraline, and paroxetine) can reduce the acute psychological effects of LSD, whereas treatment with tricyclic antidepressants (imipramine, desipramine) or lithium may enhance LSD effects (88). Single doses of the SSRI antidepressant citalopram or the 5-HT2A/C receptor antagonist ketanserin attenuated many of the acute psychological effects of MDMA in double-blind, placebo controlled human experimental studies (89,90), whereas a dose of the dopamine D2 receptor antagonist haloperidol attenuated only the mania-like mood effect (91). These findings suggest that medications affecting serotonergic neurotransmission are a promising area for development

of pharmacological treatments for hallucinogen use disorder. The mainstay of treatment remains psychosocial intervention, which can require residential treatment in patients with severe personality disorganization. Prolonged psychotic reactions occur chiefly in individuals who have pre-existing psychiatric disorders; these can be difficult to distinguish from hallucinogeninduced precipitation or exacerbation of a pre-existing psychotic disorder such as schizophrenia (92). Regardless of etiology, such psychotic reactions can require treatment with antipsychotic medication (86,87,93). Low doses of a highpotency neuroleptic have been recommended (such as 2- to 5-mg haloperidol) (86,87,93). LSD use is associated with perceptual abnormalities, such as illusions, distortions, and hallucinations, persisting or recurring intermittently for long periods (up to years) after the last LSD use. When these abnormalities occur after a period of normal perceptual functioning, they are termed flashbacks (86,93,94), defined as hallucinogen persisting perception disorder (HPPD) in DSM-5 (93,95,96). Seventeen case reports involving 56 LSD-experienced patients suggest that sertraline, naltrexone, clonidine, benzodiazepines, and possibly lamotrigine can be helpful in the treatment of both persisting perceptual abnormalities and flashbacks, while antipsychotics (esp. phenothiazines, risperidone) have been reported to worsen the condition (94). Additional case reports found that the combination of SSRIs with risperidone or olanzapine resulted in the exacerbation of HPPD symptoms (eg, flashbacks) early in treatment, followed by a gradual improvement of HPPD symptoms (94). One case report (97) describes two adolescents with a long history of LSD use who “had the new onset or worsening of LSD flashback syndrome” when treated with an SSRI for major depression. As there is mixed, very low quality evidence of benefit from sertraline, but harms from SSRIs in general, this class of medications does not represent the optimal initial choice for treatment of HPDD. Psychosocial and pharmacological controlled clinical trials are required to move treatment options forward for hallucinogen use disorder and HPPD. Case reports over the past 5 decades and recent human laboratory trials suggest potential new treatments and research methodologies.

CONCLUSIONS This chapter reviewed approaches to pharmacological treatment of substance use disorders involving cannabis, anabolic steroids, PCP, ketamine, inhalants, and

hallucinogens, as well as to some common mixed substance use disorders, including tobacco or opioids with each other, alcohol and cocaine, and cocaine with PCP. There are no FDA-approved medications for these disorders; in many cases, there is little or no published literature to guide the choice of pharmacological treatment and no clinical trials to support the efficacy of any treatment. The current mainstay of treatment for cannabis, anabolic steroid, PCP, ketamine, hallucinogen, or inhalant use disorders is psychosocial interventions. When the use of pharmacological treatments is considered (eg, due to severe behavioral disturbances or treatment resistance), the clinician must rely almost exclusively on his or her own experience and clinical judgment, with very little help from the medical or scientific literature. Careful consideration must be given that any potential gains from use of such pharmacotherapies not be outweighed by the many and varied potential short- and long-term side effects of their use. Future research may identify effective new pharmacotherapies that enhance the treatment of these substance use disorders and of mixed substance use disorders, especially their combination with tobacco and alcohol use disorders. For example, controlled clinical trials of varenicline and naltrexone suggest that these medications may also be effective for some mixed substance use disorders involving alcohol and tobacco, respectively.

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CHAPTER 62

Neuromodulation for Addiction-Related Disorders David A. Gorelick

Brain neuromodulation uses noninvasive electromagnetic or electrical methods to transiently alter neuronal firing in the brain (1,2). The most studied and widely used method of neuromodulation, transcranial magnetic stimulation (TMS), has been clinically evaluated as treatment for substance use disorders (SUDs) (3). There are relatively few outpatient randomized, sham-controlled clinical trials with substance use as the outcome measure, so that TMS is not approved for the treatment of SUD by the US Food and Drug Administration or any other national regulatory authority, although it is approved for the treatment of depression in several countries, including the United States. TMS uses wire coils placed on the scalp to project a fluctuating magnetic field into the brain. Because brain tissue is a conductive medium, this fluctuating magnetic field generates electrical currents in the brain (in accordance with Faraday’s law of electromagnetic induction). These electrical currents influence neuronal firing. The configuration of the coil determines the brain region(s) targeted by the magnetic field and the depth of penetration. The most commonly used figure-8 coils penetrate about 2-3 cm into the cortical surface; so-called H or deep coils may penetrate 5-6 cm (4). TMS is usually applied as a train of pulses, so-called repetitive TMS (rTMS). Most commonly used are highfrequency pulses (>1 Hz), which generally stimulate neuronal firing and increase cortical excitability and regional cerebral blood flow. Low-frequency pulses (1 Hz or less) generally inhibit neuronal firing. The majority of sham-controlled human laboratory (phase I) studies (usually one or two sessions) find that high-frequency rTMS targeted at the prefrontal (PFC) or dorsolateral prefrontal cortex (DLPFC) significantly reduces selfreported craving for tobacco, alcohol, cocaine, methamphetamine, or heroin for several hours (3,5–7). rTMS targeted at the DLPFC was effective in reducing cigarette smoking in several small, short-term phase II controlled clinical trials

(3), using either low-frequency or high-frequency pulses, figure-8 or deep coils, alone or combined with a nicotine patch (8) and in patients with schizophrenia (9). Of two small phase II controlled clinical trials for cocaine use disorder, one found high-frequency rTMS targeted to the left DLPFC effective in reducing cocaine use (10), while the second, using a deep coil to target the bilateral PFC, did not (11). We are not aware of any outpatient controlled clinical trials evaluating rTMS as treatment for other SUDs. When administered in accordance with international consensus safety guidelines (12) relating to patient/subject selection and pulse intensity and frequency, rTMS has an excellent record of short-term safety and tolerability, for both treatment of depression (13) and studies of SUD (3). Common adverse effects include transient scalp and face discomfort and paresthesia and headache. The only serious adverse effect is seizure, which is very rare. The few reported cases are in individuals taking concomitant medications known to lower the seizure threshold or experiencing substance withdrawal (3,13,14). The mechanism of action of rTMS in reducing substance craving and use remains unclear. It may involve both modulation of neurotransmitter activity (such as dopamine and glutamate) and of neuronal firing in brain circuits, such as the frontal cortex–striatal circuit, that mediate substance craving and seeking behavior (1–3). The latter mechanism may explain the efficacy of rTMS targeting the DLPFC. A less well-studied method of brain neuromodulation is transcranial direct current stimulation (tDCS). tDCS involves passing very low amplitude (typically 0.5-2 mA) direct electrical current into the brain by placing two large electrodes at different spots on the scalp (1,2). The mechanism of action is not well understood but may involve subthreshold depolarization (increasing excitability) of neurons near the anode electrode and hyperpolarization (decreasing excitability) near the cathode electrode. Several human laboratory studies found that tDCS significantly reduced craving for tobacco, alcohol, cocaine, heroin, and cannabis (1,2,5).

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Med Devices. 2016;13(10):987-1000. 5. Rachid F. Neurostimulation techniques in the treatment of nicotine dependence: a review. Am J Addict. 2016;25(6):436-451. 6. Shen Y, et al. 10-Hz repetitive transcranial magnetic stimulation of the left dorsolateral prefrontal cortex reduces heroin cue craving in long-term addicts. Biol Psychiatry. 2016;80(3):e13-e14. 7. Su H, et al. High frequency repetitive transcranial magnetic stimulation of the left dorsolateral prefrontal cortex for methamphetamine use disorders: a randomised clinical trial. Drug Alcohol Depend. 2017;175: 84-91. 8. Trojak B, et al. Transcranial magnetic stimulation combined with nicotine replacement therapy for smoking cessation: a randomized controlled trial. Brain Stimul. 2015;8(6):1168-1174. 9. Prikryl R, et al. Repetitive transcranial magnetic stimulation reduces cigarette consumption in schizophrenia patients. Prog Neuropsychopharmacol Biol Psychiatry. 2014;49:30-35. 10. Ribeiro PL, Arnaut D, Mincovicks ML, Marra HD, Belline BB, Baltieri DA, Marcolin MA. Controlled clinical trial of rTMS for treatment of cocaine addiction. 11th World Congress of Biological Psychiatry. 2013: Kyoto, Japan. 11. Bolloni C, et al. Bilateral transcranial magnetic stimulation of the prefrontal cortex reduces cocaine intake: a pilot study. Front Psychiatry. 2016;7:133. 12. Rossi S, et al. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin Neurophysiol. 2009;120(12):2008-2039. 13. Perera T, et al. The clinical TMS society consensus review and treatment recommendations for TMS therapy for major depressive disorder. Brain Stimul. 2016;9(3):336-346. 14. Dobek CE, et al. Risk of seizures in transcranial magnetic stimulation: a clinical review to inform consent process focused on bupropion. Neuropsychiatr Dis Treat. 2015;11:2975-2987.

SECTION 8

Psychologically Based Interventions

CHAPTER 63

Enhancing Motivation to Change James O. Prochaska

CHAPTER OUTLINE Introduction The Stages of Change Using the Stages of Change Model to Catalyze Motivation Conclusions

INTRODUCTION What motivates people to take action? The answer to this key question depends on what type of action is to be taken. What moves people to start therapy? What motivates them to continue therapy? What moves people to progress in therapy or to continue to progress after therapy? Answers to these questions can provide better alternatives to one of the field’s most pressing concerns: What types of therapeutic interventions would have the greatest effect on the entire population at risk for or experiencing addiction disorders? What motivates people to change? The answer to this question depends in part on where they start. What motivates people to begin thinking about change can be different from what motivates them to begin preparing to take action. Once people are prepared, different forces can move them to take action. Once action is taken, what motivates people to maintain that action? Conversely, what causes people to regress or relapse to their addictive behaviors? Fortunately, the answers to this complex set of questions may be simpler, or at least more systematic, than are the questions themselves. To appreciate the answers, it is helpful to begin with the author's model of change (1–3).

THE STAGES OF CHANGE Change is a process that unfolds over time through a series of stages: precontemplation, contemplation, preparation, action, maintenance, and termination. Precontemplation is a stage in which the individual does not intend to take action in the foreseeable future (usually measured as the next 6 months).

Individuals may be at this stage because they are uninformed or underinformed about the consequences of a given behavior. Or he or she may have tried to change a number of times and become demoralized about his or her ability to do so. Individuals in both categories tend to avoid reading, talking, or thinking about their high-risk behaviors. In other theories, such individuals are characterized as “resistant” or “unmotivated” or “not ready” for therapy or health promotion programs. In fact, traditional treatment programs were not ready for such individuals and were not motivated to match their needs. Individuals who are in the precontemplation stage typically underestimate the benefits of change and overestimate its costs, but are unaware that they are making such mistakes. If they are not conscious of making such mistakes, it is difficult for them to change. As a result, many remain in the precontemplation stage for years, with considerable resulting harm to their bodies, themselves, and others. There appears to be no inherent motivation for people to progress from one stage to the next. The stages are not like stages of human development, in which children have inherent motivation to progress from crawling to walking, even though crawling works very well and even though learning to walk can be painful and embarrassing. Instead, two major forces can move people to progress. The first is developmental events. In the author’s research, the mean age of smokers who reach long-term maintenance is 39 years. Those who have passed 39 recognize it as an age to reevaluate how one has been living and whether one wants to die from that lifestyle or whether one wants to enhance the quality and quantity of the second half of life. The other naturally occurring force is environmental events. A favorite example is a couple who were both heavy smokers. Their dog of many years died of lung cancer. This death eventually moved the wife to quit smoking. The husband bought a new dog. So, even the same events can be processed differently by different people. A common belief is that people with addiction disorders must “hit bottom” before they are motivated to change. So family, friends, and physicians wait helplessly for a crisis to occur. But how often do people turn 39 or have a dog die? When individuals show the first signs of a serious physical illness, such as cancer or cardiovascular disease, those around them usually become mobilized to help them seek early intervention. Evidence shows that early interventions often are lifesaving, and so it would not be acceptable to wait for such a patient to “hit bottom.” In opposition to such a passive stance, a third force that has been created to help patients with addiction progress beyond the precontemplation stage is called planned interventions.

Contemplation is a stage in which individuals intend to take action within the ensuing 6 months. Such persons are more aware of the benefits of changing, but also are acutely aware of the costs. When addicted persons begin to seriously contemplate giving up favorite substances, their awareness of the costs of changing can increase. There is no free change. This balance between the costs and benefits of change can produce profound ambivalence, which may reflect a type of love–hate relationship with an addictive substance, and thus can keep an individual stuck at the contemplation stage for long periods of time. This phenomenon often is characterized as “chronic contemplation” or “behavioral procrastination.” Such individuals are not ready for traditional action-oriented programs. Preparation is a stage in which individuals intend to take action in the immediate future (usually measured as the ensuing month). Such persons typically have taken some significant action within the preceding year. They generally have a plan of action, such as participating in a recovery group, consulting a counselor, talking to a physician, buying a self-help book, or relying on a self-change approach. It is these individuals who should be recruited for action-oriented treatment programs. Action is a stage in which individuals have made specific, overt modifications in their lifestyle within the preceding 6 months. Because action is observable, behavior change often has been equated with action. But in the transtheoretical model (TTM), action is only one of six stages (3). In this model, not all modifications of behavior count as action. An individual must attain a criterion that scientists and professionals agree is sufficient to reduce the risk of disease. In smoking, for example, for the vast majority of consequences, only total abstinence counts. With alcohol use disorders, many believe that only total abstinence can be effective, whereas others accept controlled drinking as an effective action. Maintenance is a stage in which individuals are working to prevent relapse but do not need to apply change processes as frequently as one would in the action stage. Such persons are less tempted to relapse and are increasingly confident that they can sustain the changes made. Temptation and self-efficacy data suggest that maintenance lasts from 6 months to about 5 years. One of the common reasons for early relapse is that individuals are not well prepared for the prolonged effort needed to progress to maintenance. Many persons think the worst will be over in a few weeks or a few months. If, as a

result, they ease up on their efforts too early, they are at great risk of relapse. To prepare such individuals for what is to come, they should be encouraged to think of overcoming an addiction disorder as running a marathon rather than a sprint. They may have wanted to enter the Boston Marathon, but they know they would not succeed without preparation and so would not enter the race. With some preparation, they might compete for several miles but still would fail to finish the race. Only those who are well prepared could maintain their efforts mile after mile. Using the Boston Marathon metaphor, people know they have to be well prepared if they are to survive Heartbreak Hill, which runners encounter at about mile 20. What is the behavioral equivalent of Heartbreak Hill? The best evidence available suggests that most relapses occur at times of emotional distress. It is in the presence of depression, anxiety, anger, boredom, loneliness, stress, and distress that humans are at their emotional and psychological weak point. How does the average person cope with troubling times? He or she drinks more, eats more, smokes more, and takes more substances to cope with distress (4). It is not surprising, therefore, that persons struggling to overcome addiction disorders will be at greatest risk of relapse when they face distress without their substance of choice. Although emotional distress cannot be prevented, relapse can be prevented if patients have been prepared to cope with distress without falling back on addictive substances. If so many Americans rely on oral consumptive behavior as a way to manage their emotions, what is the healthiest oral behavior they could use? Talking with others about one’s distress is a means of seeking support that can help prevent relapse. Another healthy alternative is exercise. Physical activity helps manage moods, stress, and distress. Also, 150 minutes per week of exercise can provide a recovering person with more than 50 health and mental health benefits (5). Exercise of a medically appropriate level thus should be prescribed to all sedentary patients with addiction disorders. A third healthy alternative is some form of deep relaxation, such as meditation, yoga, prayer, massage, or deep muscle relaxation. Letting the stress and distress drift away from one's muscles and one's mind helps the patient move forward at the most tempting of times. Helping patient populations to not smoke, eat healthy, exercise, and manage stress effectively has recently been recommended by three federal agencies that have major responsibilities for substance use disorders and mental illness (6). The Substance Abuse and Mental Health Agency (SAMSHA), the National Institutes of Health (NIH) (7), and the Center for Medicare and Medicaid

Innovation (CMMI) (8) have independently concluded that these health risk behaviors are major causes of chronic diseases and disabilities and premature death in almost all populations. But populations with severe mental illness (SMI) and substance use disorder die an average of 10 years earlier. The new recovery movement also recommends such holistic health care, in part, because any commitment to enhance health can be motivators that can begin the recovery process (9). Termination is a stage at which individuals have zero temptation and 100% self-efficacy. No matter whether they are depressed, anxious, bored, lonely, angry, or stressed, such persons are certain that they will not return to their old unhealthy habits as a method of coping. It is as if they never acquired the habit in the first place. In a study of former smokers and people with alcohol use disorders, fewer than 20% of each group had reached the stage of no temptation and total self-efficacy (10). The new recovery movement also recognizes that many people want to be recovered so that they can dedicate their time and resources to enhancing other aspects of their health and well-being (9). Although the ideal is to be cured or totally recovered, it is important to recognize that, for many patients, a more realistic expectation is a lifetime of maintenance.

USING THE STAGES OF CHANGE MODEL TO CATALYZE MOTIVATION The stages of change model can be applied to identify ways to motivate more patients at each phase of planned interventions for the addiction disorder. The five phases are (i) recruitment, (ii) retention, (iii) progress, (iv) process, and (v) outcomes.

Recruitment Too few studies have paid attention to the fact that professional treatment programs recruit or reach too few persons with addiction disorders. Across all diagnoses in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (11), fewer than 25% of persons with addiction disorders enter professional treatment in their lifetimes (12,13). With tobacco/nicotine use disorder, the deadliest of addiction disorders, fewer than 10% ever participate in a professional treatment program (14). Given that addiction disorders are among the costliest of contemporary

conditions, it is crucial to motivate many more persons to participate in appropriate treatment. These conditions are costly to the addicted individuals, their families and friends, their employers, their communities, and their healthcare systems. Health professionals no longer can treat addiction disorders just on a case basis; instead, they must develop programs that can reach addicted persons on a population basis. Governments and healthcare systems are seeking to treat addiction disorders on a population basis. But when they turn to the largest and best population trials of addiction therapies, they find less than completely positive outcomes (15–18). Whether the trials were conducted in work sites, schools, or entire communities, the results are remarkably similar: No significant effects compared with the control conditions. If we examine more closely one of these trials, the Minnesota Heart Health Study, we can find hints of what went wrong (19). With smoking as one of the targeted behaviors, nearly 90% of the smokers in treated communities reported seeing media stories about smoking, but the same was true with smokers in the control communities. Only about 12% of smokers in the treatment and control conditions said their physicians talked to them about smoking in the preceding year. If one looks at what percentage participated in the most powerful behavior change programs (clinics, classes, and counselors), it is apparent that only 4% of smokers participated in each year of planned interventions. Even when state-ofthe-science tobacco use disorder treatment clinics are offered at no charge, only 1% of smokers are recruited (20). There simply will be little effect on the health of the nation if our best treatment programs reach so few persons with the deadliest of addictions. How can more people with addiction disorders be motivated to seek the appropriate help? By changing both paradigms and practices. There are two paradigms that need to be changed. The first is an action-oriented paradigm that construes behavior change as an event that can occur quickly, immediately, discretely, and dramatically. Treatment programs that are designed to have patients immediately quit using substances are implicitly or explicitly designed for the portion of the population in the preparation stage. The problem is that, with most unhealthy behaviors, fewer than 20% of the affected population is prepared to take action. Among smokers (the vast majority of which have tobacco/nicotine use disorder) in the United States, for example, about 40% are in the precontemplation stage, 40% in the contemplation stage, and 20% in the preparation stage (21). Among college students with alcohol use

disorder, about 85% are in the precontemplation stage, 10% in the contemplation stage, and 5% in the preparation stage (22). When only action-oriented interventions are offered, less than 20% of the atrisk population is being recruited. To meet the needs of the entire addicted population, interventions must meet the needs of the 40% in the precontemplation and the 40% in the contemplation stages. In the clinical guidelines for the treatment of tobacco use disorder, however, there were only evidence-based programs for motivated smokers in the preparation stage (23,24). In spite of there being more than 6000 studies on tobacco, research had excluded the vast majority from treatment studies. By offering stage-matched interventions and applying proactive or outreach recruitment methods in three large-scale clinical trials, the author and others have been able to motivate 80%-90% of smokers to enter a treatment program (25,26). Comparable participation rates were generated with college students with at-risk alcohol use, even though 75% were in the precontemplation stage (22). These results represent a quantum increase in our ability to move many more people to take the action of starting therapy. A treatment program for people with gambling disorder in Windsor, Ontario, used creative communications to let their prospective population know, wherever they are, the program can work with them. This program had generous support of 2% of earnings from local casinos, but they were not reaching many people. So, on the back of city buses, they placed ads with a traffic light logo: red light not ready, yellow light getting ready, and green light ready. Not only did they dramatically increase their recruitment, some clients would take pride in saying, “Hey, there goes my bus!” The second paradigm change that is required is movement from a passive– reactive approach to a proactive approach. Most professionals have been trained to be passive–reactive: to passively wait for patients to seek their services and then to react. The problem with this approach is that most persons with addiction disorders never seek such services. The passive–reactive paradigm is designed to serve populations with acute conditions. The pain, distress, or discomfort of such conditions can motivate patients to seek the services of health professionals. But the major killers today are chronic lifestyle disorders such as addiction disorders. To treat the addiction disorders seriously, professionals must learn how to reach out to entire populations and offer them stage-matched treatments.

There are a growing number of national disease management and disease prevention companies who train health professionals in these new paradigms. Thousands of nurses, counselors, and health coaches have been trained to proactively reach out by telephone to interact at each stage of change with entire patient and employee populations with high-risk behaviors including smoking, hazardous alcohol use, and obesity. With the major movement toward integrated care in patient-centered medical homes, providers on multidisciplinary teams are being trained in how to deliver such stage-based interventions within primary care and other medical settings. Historically, the established wisdom was that therapists should not touch tobacco use disorders with mental health patients (27). The tobacco industry supported this perspective with ads and reports targeting mental health professionals. In the Clinical Guideline for the Treatment of Tobacco (Fiore et al., 2000, 2008), there were no evidence-based treatments for smokers with mental illness, even though they consume over 40% of all cigarettes in the United States (23,24). One unsupported bias that was encouraged was that such patients could not be motivated to quit, in part, because they used nicotine to self-medicate their co-occurring psychiatric disorder. Two studies using computer-tailored TTM interventions (CTIs) provided evidence that such assumptions were invalid. In the first study, smokers engaged in depression clinics were proactively recruited to a randomized clinical trial (RCT) for such CTIs. The results were clear. The treatment group had long-term quit rates of about 25%, which were significantly higher than the controls (19%) and were essentially identical to smokers without mental illness. Furthermore, the treatment group had as good results with depression that were comparable to controls, indicating that stopping smoking did not interfere with depression treatments. The second study was with patients hospitalized for acute episodes of serious mental illness (SMI). Smokers were proactively recruited to an RCT comparing a TTM-based CTI to controls. The treatment group had a long-term abstinence rate (20%) that was not as high as most populations (25%) but was 2.5 times greater than controls (8%) (27) What was particularly striking was that over the next 12 months, the treatment group had significantly fewer rehospitalizations than controls. Rather than stopping smoking resulting in decreasing motivation with mental health treatments, with depression, there was no apparent effect, and with SMIs, the group that stopped smoking actually did better. What happens if professionals change only one paradigm and proactively

recruit entire populations to action-oriented interventions? This experiment has been tried in one of the largest US managed care organizations (20). Physicians spent time with every smoker in an effort to persuade him or her to enroll in a state-of-the-art action-oriented clinic. If that did not work, nurses spent up to 10 minutes encouraging the smoker to enroll, followed by 12 minutes with a health educator and a counselor call to the home. The base rate was 1% participation. This most intensive recruitment protocol motivated 35% of smokers in precontemplation to enroll. However, only 3% actually entered the program, 2% completed it, and none showed improved outcomes. From a combined contemplation and preparation group, 65% enrolled, 15% entered the program, 11% completed it, and some had an improved outcome. In the face of this evidence, there may be several answers to the question: What can move a majority of people to enter a professional treatment program for an addiction disorder? One is the availability of professionals who are motivated and prepared to proactively reach out to entire populations and offer them interventions that match whatever stage of change they are in.

Retention What motivates patients to continue in therapy? Or conversely, what moves clients to terminate counseling quickly and prematurely, as judged by their counselors? A meta-analysis of 125 studies found that nearly 50% of clients drop out of treatment (28). Across studies, there were few consistent predictors of premature termination. Although addiction disorder, minority status, and lower education predicted a higher percentage of dropouts, these variables did not account for much of the variance. At least five studies are available on dropouts from a stage model perspective on addiction disorder, smoking, obesity, and a broad spectrum of psychiatric disorders. These studies found that stage-related variables were more reliable predictors than were demographics, type of problem, severity of problem, and other problem-related variables. Figure 63-1 presents the stage profiles of three groups of patients with a broad spectrum of psychiatric disorders (2,29). In that study, the investigators were able to predict 93% of the three groups: premature terminators, early but appropriate terminators, and those who continued in therapy (29).

Figure 63-1 Pretherapy stage profiles for premature terminators, appropriate terminators, and continuers. (From Brogan ME, Prochaska JO, Prochaska JM. Predicting termination and continuation status in psychotherapy using the transtheoretical model. Psychotherapy. 1999;36:105-113.) Figure 63-1 shows that the before-therapy profile of the entire group who dropped out quickly and prematurely (40%) was a profile of persons in the precontemplation stage. The 20% who finished quickly but appropriately had a profile of patients who were in the action stage at the time they entered therapy. Those who continued in long-term treatment were a mixed group, with most in the contemplation stage. The lesson is clear: Persons in the precontemplation stage cannot be treated as if they are starting in the same place as those in the action stage. If they are pressured to take action when they are not prepared, they simply will leave therapy. For patients in the action stage who enter therapy, what would be an appropriate approach? One alternative would be to provide relapse prevention strategies, like those described by Dr. Alan Marlatt, and described more fully in the chapter on relapse prevention in this textbook in Section 8. But would

relapse prevention strategies make any sense with the 40% of patients who enter in the precontemplation stage? What might be a good match for them? Experience suggests a dropout prevention approach, because such patients are likely to leave early if they are not helped to continue. With patients who begin therapy in the precontemplation stage, it is useful for the therapist to share key concerns: “I’m concerned that therapy may not have a chance to make a significant difference in your life, because you may be tempted to leave early.” The therapist then can explore whether the patient has been pressured to enter therapy. How do such patients react when someone tries to pressure or coerce them into quitting an addiction when they are not ready? Can they tell the therapist if they feel pressured or coerced? It is only feasible to encourage them to take steps when they are most ready to succeed. Patients in treatment for substance use disorders were assessed on their perceptions of the pros and cons of therapy and whether they were in therapy because of coercion or by choice (30). Patients in precontemplation perceived the cons of therapy as higher than the pros and that they were in therapy more out of coercion than by choice. Patients in action, on the other hand, had the opposite pattern: pros > cons and choice > coercion. These patterns were only found when raw scores were standardized to control for ease of responding, with it being harder to endorse cons and coercions. These results indicate that such standardized perspectives are likely revealing implicit cognitions rather than rational choices. These patterns help to explain why patients in precontemplation are so likely to drop out quickly from addiction clinics. The patterns also suggest that as people progress from precontemplation, they are likely to transform coercion into personal choice as motivators driving their engagement in treatment and their changes in their addiction. A large study in the US Air Force supports this interpretation. Wanting a smoking free Air Force, all enlisted people had to be fully nicotine free for 6 weeks of basic training. Random urine samples were drawn, and the consequence of any sign of cotinine was severe—the entire 6 weeks of basic training had to be repeated. Such coercion produced immediate and essentially absolute abstinence for 6 weeks (31). But at 12-month follow-up, the nicotine use rates were remarkable at 123%, meaning that there were 23% more enlisted people using tobacco than when they joined. We concluded that the Air Force was a major risk factor for the enlisted people’s health. To reduce such recidivism, 7000 smokers were given a 45-minute intervention that involved the discussion of the important pros or benefits of

staying quit. This was seen as a relapse prevention program, but in TTM terms, we shall soon see that it would be the first principle (raise the pros) to help people in precontemplation to progress. As it turned out, this intervention had no significant impact on preventing relapse in the total treatment group compared to the 30 000 controls. But, smokers in the precontemplation group who were intending to return to smoking as soon as basic training ended were four times more likely to be quit at 12 months, and enlisted people of color were five times more likely to stay quit. With precontemplators who would be likely to feel particularly coerced, this brief but matched treatment was likely to have helped them progress to choosing to stay quit even after they were fully free to smoke. Here is a brief case illustration of a therapist sharing his concern with a patient in precontemplation. A renowned artist in his late thirties started therapy with multiple problems, including a chronic addiction to cocaine, a troubled marriage, career at risk of collapsing, and affective problems with depression and aggression. With his help, we are able to assess that he was in the precontemplation stage, and his therapist knew that he was at high risk for terminating treatment prematurely. So, the therapist shared his concern: “I appreciate you are helping me to understand that you are currently in the initial stage of change that we call precontemplation. Our first concern needs to be that you might drop out of treatment before we have a chance to make a significant difference in your life. What pressures were there for you to come to therapy?” “My wife threatened to leave if I didn't show up,” he responded. “If you feel me pressuring you to do something you are not ready to do, would you let me know?” the therapist asked. “You will know!” he snapped. “How will I know?” Because I will get angry as hell!” the patient said. “That’s O.K. I can work with that. What I can’t work with is you not coming back.” “That’s cool,” he said. The author and others have conducted four studies with stage-matched interventions in which retention rates of persons entering interventions in the precontemplation stage can be examined. What is clear is that, when treatment is matched to stage, persons in the precontemplation stage will remain in treatment

at the same rates as those who start in the preparation stage (25,26). This result was consistent in clinical trials in which patients were recruited proactively (the therapist reached out with an offer of help) as well as in trials in which patients were recruited reactively (they asked for help). What motivates people to continue in therapy? Receiving treatments that match their stage of readiness to change. Another strategy is to begin therapy with a single session of motivational interviewing. Connors et al. (32) found that a single session reduced dropouts from their 12-session alcohol treatment program from 75% to 50%. A session of role induction designed to prepare people for what to expect from therapy made no difference, even though, clinically, it has been most widely used to try to prevent premature dropout.

Progress What moves people to progress in therapy and to continue to progress after therapy? Figure 63-2 presents an example of what is called the stage effect. The stage effect predicts that the amount of successful action taken during and after treatment is directly related to the stage at which the person entered treatment (2). In the study cited, interventions with smokers ended at 6 months. The group of smokers who started in the precontemplation stage showed the least amount of effective action, as measured by abstinence at each assessment point. Those who started in the contemplation stage made significantly more progress, whereas those who entered treatment already prepared to take action were most successful at every assessment.

Figure 63-2 Percentage of smokers who maintained abstinence over 18 months. Note: Groups were in the

following stages at the time of entry into treatment: precontemplation (PC), contemplation (C), and preparation (C/A) (n = 570). The stage effect has been found across a variety of problems and populations, including rehabilitative success for brain injury and recovery from anxiety and panic disorders after random assignment to placebo or effective medication (33,34). In the latter clinical trial, the psychiatrist leading the trial concluded that patients need to be assessed for their stage of readiness to benefit from medication and to be helped through the stages so that they are well prepared before being treated with medication. One strategy for applying the stage effect clinically involves setting realistic goals for brief encounters with patients at each stage of change. A realistic goal is to help patients progress one stage in brief therapy. If a patient moves relatively quickly, he or she may be able to progress two stages. The results to date indicate that, if a patient progresses one stage in 1 month, the likelihood of his or her taking effective action by 6 months is doubled. If the patient progresses two stages, the likelihood that he or she will take effective action increases three to four times (20). Setting realistic goals thus can enable many more people to enter therapy, continue in therapy, progress in therapy, and continue to progress after therapy. One result for health professionals trained in this approach to addiction disorders can be a dramatic increase in the morale of the health professionals involved. They can see progress with most of their patients, where they once saw failure when immediate action was the only criterion for success. They are much more confident that they have treatments that can match the stages of all of their patients rather than the small number who are prepared to take immediate action. A lesson here is that the models of therapy selected should be good for the mental health of the therapist as well as the patient. After all, the professional is engaged in therapy for a lifetime, while most patients are involved for only a brief time. As healthcare organizations move to briefer and briefer therapies for addiction and other disorders, there is a danger that most health professionals will feel pressured to produce immediate action. If this pressure is transferred to patients who are not prepared for such action, most patients will not be reached or not retained in treatment. A majority of patients can be helped to progress in

treatment through relatively brief encounters, but only if realistic goals are set for both patient and therapist. Otherwise, there is a risk of demoralizing and demotivating both patient and therapist. Given the vast public health needs described above, another misuse of the model is for healthcare organizations or health professionals to limit treatment only to patients who are prepared to take immediate action.

Process To help motivate patients to progress from one stage to the next, it is necessary to know the principles and processes of change that can produce such progress.

Principle 1 The benefits for changing must increase if patients are to progress beyond precontemplation. In a review of 12 studies, all showed that the perceived benefits were higher in the contemplation than in the precontemplation stage (35,36). This pattern held true across 12 problem behaviors: use of cocaine, smoking, delinquency, obesity, inconsistent condom use, unsafe sex, sedentary lifestyles, high-fat diets, sun exposure, radon testing, mammography screening, and physicians practicing behavioral medicine. A technique that can be used in population-based programs involves asking a patient in the precontemplation stage to describe all the benefits of a change such as quitting smoking or starting to exercise. Most persons can list four or five. The therapist can let the patient know that there are 8-10 times that number and challenge the patient to double or triple the list for the next meeting. If the patient’s list of benefits of exercise begins to indicate many more motives, such as a healthier heart, healthier lungs, more energy, healthier immune system, better moods, less stress, better sex life, and enhanced self-esteem, he or she will be more motivated to begin to seriously contemplate such a change.

Principle 2 The “cons” of changing must decrease if patients are to progress from contemplation to action. In 12 of 12 studies, the author found that the perceived costs of changing were lower in the action than in the contemplation stage (36).

Principle 3

The relative weight assigned to benefits and costs must cross over before a patient will be prepared to take action. In 12 of 12 studies, the costs of changing were assessed as higher than the rewards in the precontemplation stage, but in 11 of 12, the rewards were assessed as higher than the costs in the action stage. The sole exception involved quitting cocaine. In that study, a large percentage of treatment was delivered to inpatients. We interpret this exception to mean that the actions of these patients may have been more under the social control of residential care than under their self-control. At a minimum, their pattern would not bode well for immediate discharge. It should be noted that, if raw scores are used to assess these patterns, it would appear that the rewards for changing are seen as greater than the costs, even by persons in the precontemplation stage. It is only when standardized scores are used that clear patterns emerge, with the costs of changing always perceived as greater than the rewards. This suggests that, compared with their peers at other stages of change, persons in the precontemplation stage underestimate the rewards and overestimate the costs of change.

Principle 4 The strong principle of progress holds that, to progress from precontemplation to effective action, the rewards for changing must increase by one standard deviation (SD) (36).

Principle 5 The weak principle of progress holds that, to progress from contemplation to effective action, the perceived costs of changing must decrease by one-half SD. Because the perceived benefits for changing must increase twice as much as the perceived costs decrease, twice as much emphasis must be placed on the benefits than the costs of changing. What is striking here is that the author and colleagues believe that they have discovered mathematical principles for the degree to which positive motivations must increase and negative motivations must decrease. In a recent meta-analyses of nearly 140 studies on 48 behaviors, the pros of changing increased by exactly 1.00 SD, whereas the cons decreased by 0.54 SD (37). Such principles can produce much more sensitive assessments to guide interventions, giving therapists and patients feedback for when therapeutic efforts are producing progress and when they are failing. Together, they can modify methods if movement is needed for the patient to become adequately prepared for action.

Principle 6 It is important to match particular processes of change with specific stages of change. Table 63-1 presents the empirical integration found between processes and stages of change. Guided by this integration, the following processes would be applied to patients in various stages of change:

Table 63-1 Principles and Processes of Change that Mediate Progression between Stages of Change

1. Consciousness raising (get the facts) involves increased awareness of the causes, consequences, and responses to a particular problem. Interventions that can increase awareness include observations, confrontations, interpretations, feedback, and education. Some techniques, such as confrontation, pose considerable risk in terms of retention and are not recommended as highly as motivational enhancement methods such as personal feedback about the current and long-term consequences of continuing the addictive behavior. Increasing the costs of not changing is the corollary of raising the rewards for changing. So consciousness raising should be designed to increase the perceived rewards for changing. 2. Dramatic relief (pay attention to feelings) involves emotional arousal about one’s current behavior and the relief that can come from changing. Fear, inspiration, guilt, and hope are some of the emotions that can move persons to contemplate changing. Psychodrama, role-playing, grieving, and personal testimonies are examples of techniques that can move people emotionally. It should be noted that earlier literature on behavior change concluded that interventions such as education and fear arousal did not motivate behavior change. Unfortunately, many interventions were

evaluated in terms of their ability to move people to immediate action. However, processes such as consciousness raising and dramatic relief are intended to move people to the contemplation rather than the action stage. Therefore, their effectiveness should be assessed according to whether they lead to the expected progress. 3. Environmental reevaluation (notice your effect on others) combines both affective and cognitive assessments of how an addiction affects one’s social environment and how changing would affect that environment. Empathy training, values clarification, and family or network interventions can facilitate such reevaluation. For example, a brief media intervention aimed at a smoker in precontemplation might involve an image of a man clearly in grief saying, “I always feared that my smoking would lead to an early death. I always worried that my smoking would cause lung cancer. But I never imagined it would happen to my wife.” Beneath his grieving face appears this statistic: “50 000 deaths per year are caused by passive smoking.” In 30 seconds, this message achieves consciousness raising, dramatic relief, and environmental reevaluation. 4. Self-reevaluation (create a new self-image) combines both cognitive and affective assessments of an image of one’s self free from addiction. Imagery, healthier role models, and values clarification are techniques that can move individuals in this type of intervention. Clinically, patients first look back and reevaluate how they have lived as addicted individuals. As they progress into the preparation stage, they begin to develop a focus on the future as they imagine how life could be if they were free of addiction. 5. Self-liberation (make a commitment) involves both the belief that one can change and the commitment and recommitment to act on that belief. Techniques that can enhance such willpower include public rather than private commitments. Motivational research also suggests that individuals who have only one choice are not as motivated as if they have two choices (38). Three choices are even better, but four choices do not seem to enhance motivation. Wherever possible, then, patients should be given three of the best choices for applying each process. With stopping smoking, for example, there are at least three good choices: using nicotine replacement therapy to taper nicotine under medical supervision, using nicotine fading (self-taper), and using FDA-approved medications to reduce relapse risk (varenicline, bupropion). Asking clients to choose which alternative they believe would be most effective for them and which they would be most committed to can enhance their motivation and their self-liberation. 6. Counter conditioning (use substitutes) requires the learning of healthier

behaviors that can substitute for addictive behaviors. Counter conditioning techniques tend to be quite specific to a particular behavior. They include desensitization, assertion, and cognitive counters to irrational selfstatements that can elicit distress. 7. Reinforcement management (use rewards) involves the systematic use of reinforcements and punishments for taking steps in a particular direction. Because successful self-changers rely much more on reinforcement than punishment, it is useful to emphasize reinforcements for progressing rather than punishments for regressing. Contingency contracts, overt and covert reinforcements, and group recognition are methods of increasing reinforcement and incentives that increase the probability that healthier responses will be repeated. To prepare patients for the longer term, they should be taught to rely more on self-reinforcements than on social reinforcements. Clinical experience shows that many patients expect much more reinforcement and recognition from others than they actually receive. Relatives and friends may take action for granted. Average acquaintances typically generate only a few positive consequences early in the action stage. Self-reinforcements obviously are much more under self-control and can be given more quickly and consistently when temptations to lapse or relapse are resisted. Contingency management for the treatment of substance use disorders is discussed more fully in Section 8 of this textbook. Stimulus control (mange your environment) involves modifying the environment to increase cues that prompt healthy responses and decrease cues that lead to relapse. Avoidance, environmental reengineering (such as removing addictive substances and paraphernalia), and attending self-help groups can provide stimuli that elicit healthy responses and reduce the risk of relapse. 8. Helping relationships (get support) combine caring, openness, trust, and acceptance, as well as support for changing. Rapport building, a therapeutic alliance, counselor calls, buddy systems, sponsors, and self-help groups can be excellent resources for social support. If patients become dependent on such support to maintain change, the support will need to be carefully faded, lest termination of therapy becomes a condition for relapse. 9. Social liberation (notice the public effort) is the process by which changes in society increase the options and opportunities to have healthier and happier lives freer from addiction. Social networks are examples of a dramatic increase in being able to participate in positive interactions free from pressures to rely on substance use.

Competing theories of therapy have implicitly or explicitly advocated alternative processes of enhancing motivation for change. Is it ideas or emotions that move people? Is it values, decisions, or dedication? Do contingencies incentivize humans, or is behavior determined by environmental conditions or habits? Or is it the therapeutic relationship that is the common healer across all therapeutic modalities? The answer to each of these questions is “yes.” Therapeutic processes originating from competing theories can be compatible when they are combined in a stage-matched paradigm. With patients in earlier stages of change, motivation can be enhanced through more experiential processes that produce healthier cognitions, emotions, evaluations, decisions, and commitments. In later stages, it is possible to build on such solid preparation and motivation by emphasizing more behavioral processes that can help condition healthier habits, reinforce these habits, and provide physical and social environments that support healthier lifestyles freer from addiction.

Outcomes What is the result when all of these principles and processes of change are combined to help patients and entire populations move toward action on their addiction? A series of clinical trials applying stage-matched interventions offers lessons about the future of behavioral health care generally and treatment of addiction disorders specifically. In a large-scale clinical trial, the author and colleagues compared four treatments: (a) a home-based action-oriented treatment program (standardized), (b) stage-matched manuals (individualized), (c) a computerized tailored intervention (CTI) plus manuals (interactive), and (d) counselors plus a CTI and manuals (personalized). Patients (739 smokers) were randomly assigned by stage to one of the four treatments (39). In the CTI condition, participants completed 40 questions by mail or telephone. Their responses were entered into a central computer, from which feedback reports were generated. These reports informed participants about their stage of change, the benefits and costs of changing, and change processes appropriate to their stages of change. At baseline, participants were given positive feedback on what they were doing correctly and guidance on which principles and processes they needed to apply to progress. In two progress reports delivered over the following 6 months, participants also received positive feedback on any improvement in any of the variables relevant to progress. Thus,

demoralized and defensive smokers could begin to progress without having to quit and without having to work too hard. Smokers in the contemplation stage could begin to take small steps, such as delaying their first cigarette in the morning for an additional 30 minutes. They could choose small steps that would increase their self-efficacy and help them become better prepared for quitting. In the personalized condition, smokers received four proactive counselor calls over the 6-month intervention period. Three of the calls were based on the CTI reports. Counselors reported much more difficulty in interacting with participants without any progress data. Without scientific assessments, it was more difficult for both patients and counselors to know whether any significant progress had occurred since their last interaction. Figure 63-3 presents point-prevalence abstinence rates for each of the four treatment groups over 18 months, with treatment ending at 6 months. Results with the two self-help manual conditions were parallel for 12 months, but the stage-matched manuals achieved better results at 18 months. This is an example of a delayed action effect, which often is observed with stage-matched programs and which others have observed with self-help programs (3). It takes time for participants in early stages to progress all the way to action. Therefore, some treatment effects as measured by action will be observed only after considerable time has elapsed. But it is encouraging to find treatments producing therapeutic effects months and even years after active treatment has ended. The CTI alone and CTI plus counselor conditions produced comparable results for 12 months.

Figure 63-3 Point-prevalence abstinence (%) for four treatment groups at pretest and at 6, 12, and 18 months. ALA+, standardized manuals; TTT, individualized stagematched manuals; ITT, interactive computer reports; PITT, personalized counselor calls.

Then, the effects of the counselor condition flattened out, whereas the CTI condition effects continued to increase. Potential reasons for the delayed differences between these conditions include the possibility that participants in the personalized condition may have become somewhat dependent on the social support and social control of the counselor calling. The last call occurred after the 6-month assessment, and benefits would be observed at 12 months. Termination of the counselor calls could result in no further progress because of the loss of social support and control. The classic pattern in tobacco use disorder treatment clinics is rapid relapse that begins as soon as treatment is terminated. Some of this rapid relapse could well be due to the sudden loss of social support or social control provided by the counselors and other participants when active treatment ends. The next test was to demonstrate the efficacy of the CTI when applied to an entire population recruited proactively. With more than 80% of 5170 smokers participating and less than 20% in the preparation stage, this study demonstrated significant benefits of the CTI at each 6-month follow-up (24). Moreover, the advantages over proactive assessment alone increased at each follow-up for the full 2 years assessed. The implications here are that CTI interventions in a population can continue to demonstrate benefits long after the intervention has ended. The efficacy of the CTI intervention was demonstrated again in a health maintenance organization (HMO) population of 4000 smokers, with 85% participation (25). In the first population-based study, the CTI was 34% more effective than was assessment alone; in the second, it was 31% more effective. These differences were clinically significant as well. Although working on a population basis, the investigators were able to show a level of success normally found only in intensive clinic-based programs with low participation rates of more carefully selected samples of smokers. The implication is that, after CTIs are developed and show effectiveness with one population, they can be transferred to, and show replicable results in, other populations. A meta-analysis of 54 studies on computer-tailored interventions across a broad range of behaviors has found that tailoring treatment on each of the TTM variables (stage, pros and cons, processes, or self-efficacy) produces greater effects than do treatments that do not tailor on these variables. Tailoring on some treatment variables, such as perceived susceptibility to negative consequences, produced worse effects. Some other theoretical variables, such as social norms

and behavior intentions, made no difference (40).

Enhancing Interactive Interventions In recent benchmarking research, the author and colleagues have been attempting to create enhancements to the CTI to produce even better outcomes. In the first enhancement, which involved a study of an HMO population, a personal digital assistant designed to bring the behavior under stimulus control was added (25). However, this action-oriented intervention did not enhance the study outcomes on a population basis. In fact, the original CTI alone was twice as effective as the system plus the personal digital assistant enhancement. This result suggests that more is not necessarily better and providing interventions that are mismatched to stage can make outcomes markedly worse.

Counselor Enhancements In the HMO population, counselors plus CTIs were outperforming CTIs alone at 12 months. But at 18 months, results for the counselor enhancement had declined, whereas those for the CTIs alone had increased. Both interventions were producing identical outcomes of 23.2% abstinence, which are excellent for an entire population. Why did the effect of the counselor condition drop after the intervention? A leading hypothesis is that patients can become dependent on counselors for social support and social monitoring. Withdrawing those social influences may place such patients at increased risk of relapse. The CTI, in contrast, tends to maximize self-reliance. It seems clear that the most powerful change programs will combine the personalized benefits of counselors and consultants with the individualized, interactive, and data-based benefits of computer-tailored interventions. However, studies have not demonstrated that the more costly counselors, who have been the most powerful change agents, actually add value over expert system interventions alone. These findings have clear implications for the cost effectiveness of expert systems for entire populations in need of health promotion programs.

Interactive Versus Noninteractive Interventions Another important goal of the HMO study was to assess whether an interactive intervention (specifically, a CTI) is more effective than are noninteractive communications (such as self-help manuals) when the results are adjusted to

control for the number of intervention contacts (41). At 6, 12, and 18 months for groups of smokers receiving a series of one, two, three, or six interactive versus noninteractive contacts, the interactive interventions (CTI) outperformed the noninteractive manuals. The difference at 18 months was at least 5%—a difference between treatment conditions assumed to be clinically significant. These results clearly support the hypothesis that interactive interventions will outperform the same number of noninteractive interventions. These results support the assumption that the most powerful health promotion programs for entire populations will be interactive. Reports in the clinical literature support the hypothesis that interactive interventions such as behavioral counseling produce better long-term abstinence rates (20%-30%) than do noninteractive interventions such as self-help manuals (10%-20%). In assessing these results, it should be kept in mind that traditional action-oriented programs were implicitly or explicitly recruiting for populations of individuals in the preparation stage, whereas the studies cited here involved proactively recruited smokers, of whom fewer than 20% were in the preparation stage. Even so, long-term abstinence rates were in the 20%-30% range for the interactive interventions and in the 10%-20% range for noninteractive interventions. Providing interactive interventions through the use of computer-tailored interventions is likely to produce better outcomes than relying on noninteractive communications such as newsletters, media, or self-help manuals.

Multiple Behaviors A series of studies applied our best practice of TTM computer-tailored interventions plus a stage-based self-help manual for multiple behaviors. Consistent across all studies was that the TTM treatments produced significant impacts on multiple behaviors (42–44). The studies also produced abstinence rates that were in the same narrow 24% range found when the single behavior of smoking was treated. This is the first body of research that has demonstrated that multiple behavior treatments can be as effective as treating single behaviors, but the impacts are greater because more behaviors are treated effectively. The other treated behaviors, such as diet and prevention of skin cancer, were even more effective, with the percentages in the action–maintenance stage at long-term follow-up ranging from 35% to 40%. With male perpetrators of partner violence, TTM computer-tailored interventions were added to the best practice of mandatory 6-month weekly group therapy. At the 6-month follow-up with the first 200 participants, the

addition of the TTM tailoring produced significant reduction in a variety of physical and emotional abuse behaviors compared with the weekly group counseling alone. With the addition of TTM tailoring, only 3% of the female partners of the perpetrators had been beaten in the past 6 months compared to 23% of the women whose partners received only the group therapy (45). With the TTM treatment, about twice as many perpetrators (most of whom also had addiction problems) had progressed to the action or maintenance stage at the 6month assessment. Particularly encouraging was that more than twice as many of the perpetrators in the TTM treatment had voluntarily sought additional therapy. This is another example of how therapy can help transform the motivation for being in treatment from coercion (going to prison for failure to attend) to choice (voluntarily choosing to be in additional treatment).

Multiple Domains of Well-Being: From Suffering or Struggling to Thriving Motivated by a ‘risky test’ philosophy of science (46), we keep raising the bar to have increasing impacts with vulnerable populations, such as moving from changing a single behavior to a riskier goal of changing multiple risk behaviors. A recent challenge has been to simultaneously enhance multiple domains of well-being, for example, physical, emotional, social, and work well-being. Prochaska et al. (2012) conducted a project with 4000 participants from 39 states who had an average of almost four chronic conditions and almost four risk behaviors, with 40% obese, 35% overweight, and 0% exercising adequately or managing stress effectively. A majority had poor diets, were or had been smokers, and had problems with depression (47). Compared to national norms, this population with 59% women, a mean age of 48 and 48% unemployment, had much lower scores on each domain of wellbeing. Most striking was that a majority were suffering or struggling and only a minority were thriving. The only time this pattern was seen in the US was with the economic crash of 2008 (48). With random assignment, one group received telephonic TTM CTI coaching with exercise as the primary target and stress management as secondary. A second group received a CTI with stress management as the primary behavior and exercise as a secondary behavior. Compared to a third control group, both treatment groups produced more multiple behavior change than do controls and more improvement on multiple domains of well-being. In all comparisons, the telephonic coaching that spent most of the time on exercise produced more

positive changes than the CTI that treated stress management primarily and exercise secondarily. What was most rewarding to the investigators was that the majority of both treatment groups but not the control group had progressed from suffering or struggling to thriving. These results led us to produce a follow-up book to Changing for Good (49), which for 25 years has been a guide for many addiction counselors. The new book, titled, Changing to Thrive (50) is designed to help both professionals, their patients, and other populations to reduce multiple risk behaviors, enhance multiple domains of well-being, and progress from suffering or struggling to thriving.

CONCLUSIONS It seems clear that the future of health promotion programs lies in stagematched, proactive, interactive interventions. Much greater effects can be generated through the use of proactive programs because participation rates are increased, even if efficacy rates are lower. But proactive programs also can produce outcomes comparable to those of traditional reactive programs. Although it is counterintuitive to suggest that outcomes for groups that are proactively recruited can match those of individuals who reach out for help, that is what informal comparisons strongly suggest. For example, in a comparison of results at 18-month follow-up for all subjects who received three expert system interventions in a study of reactive intervention and a study of proactive intervention, the abstinence curves were remarkably similar (23,38). The results with the counseling plus CTI conditions were even more impressive. Proactively recruited smokers, working with both counselors and the CTI, achieved higher rates of abstinence at each follow-up than did the smokers who had called for help. These results are partially attributable to the fact that the proactive counseling protocol has been revised and, it is to be hoped, improved on the basis of previous data and experience. But the point is that if it is possible to reach out and offer people improved behavior change programs that are appropriate for their stage of readiness to change, it ought to be possible to produce efficacy or abstinence rates at least equal to those seen with individuals who reach out for help. Unfortunately, there is no experimental design that would make it possible to assign study subjects randomly to proactive versus reactive recruitment programs. Thus, one is left with informal but provocative comparisons.

Results with multiple behavior interventions using some type of TTM tailoring and proactive recruitment have found as good effects as when smoking alone is treated. The results with the other treated behaviors were even better. If these results continue to be replicated, therapeutic programs will be able to produce unprecedented effects on entire populations. To do so will require scientific and professional shifts: (a) from an action paradigm to a stage paradigm; (b) from reactive to proactive recruitment; (c) from expecting participants to match the needs of programs to having programs match the needs of patients; (d) from single to multiple behavior interventions; (e) from clinicbased to population-based programs that apply individualized and interactive intervention strategies; and (f) reducing multiple problem behaviors to enhance multiple domains of well-being to help vulnerable populations to progress from suffering or struggling to thriving.

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16. COMMIT Research Group. COMMunity Intervention Trial for smoking cessation (COMMIT): I. Cohort results from a four-year community intervention. Am J Public Health. 1995;85:183-192. 17. Glasgow RE, Terborg JR, Hollis JF, et al. Take Heart: results from the initial phase of a work-site wellness program. Am J Public Health. 1995;85:209-216. 18. Ennett ST, Tabler NS, Ringwolt CL, et al. How effective is drug abuse resistance education? A metaanalysis of Project DARE outcome evaluations. Am J Public Health. 1994;84:1394-1401. 19. Lando HA, Pechacek TF, Pirie PL, et al. Changes in adult cigarette smoking in the Minnesota Heart Health Program. Am J Public Health. 1995;85:201-208. 20. Lichtenstein E, Hollis J. Patient referral to smoking cessation programs: who follows through? J Fam Pract. 1992;34:739-744. 21. Velicer WF, Fava JL, Prochaska JO, et al. Distribution of smokers by stage in three representative samples. Prev Med. 1995;24:401-411. 22. Laforge RG, Gomes SO, Cottrill SD, et al. Baseline results of proactive telephone recruitment of college drinkers in the College-Based Alcohol Risk Reduction (C-BARR) trial [Abstract]. Alcohol Clin Exp Res. 2001;25(5):147A. 23. Fiore MC, Bailey WC, Cohen SJ, Dorfman SF, Goldstein MG, Gritz ER. Treating Tobacco Use and Dependence, Clinical Practice Guideline. Rockville, MD: US DHHS, Public Health Service, 2000. 24. Fiore MC, Jaén CR, Baker TB, et al. Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services. Public Health Service, 2008. 25. Prochaska JO, Velicer WF, Fava JL, et al. Counselor and stimulus control enhancements of a stagematched expert system for smokers in a managed care setting. Prev Med. 2000;32:39-46. 26. Prochaska JO, Velicer WF, Fava JL, et al. Evaluating a population-based recruitment approach and a stage-based expert system intervention for smoking cessation. Addict Behav. 2002;26:583-602. 27. Prochaska JJ, Hall SE, Delucchi K, Hall SM. Efficacy of initiating tobacco dependence treatment in inpatient psychiatry: a randomized controlled trial. Am J Public Health. 2014;104(8):1557-1565. 28. Wierzbicki M, Pekarik G. A meta-analysis of psychotherapy dropout. Prof Psychol Res Pract. 1993;29:190-195. 29. Brogan ME, Prochaska JO, Prochaska JM. Predicting termination and continuation status in psychotherapy using the transtheoretical model. Psychotherapy. 1999;36:105-113. 30. Tsoh J. Stages of change, drop-outs and outcome in substance abuse treatment. Dissertation, University of Rhode Island. 1995. 31. Klesges R, et al. Tobacco use harm reduction, elimination, and escalation in a large military cohort. Am J Public Health. 2010;100(12):2487-2492. 32. Connors G, Walitzer K, Dermen K. Preparing clients for alcoholism treatment: effects on treatment participation and outcomes. J Consult Clin Psychol. 2002;70:1161-1169. 33. Beitman BD, Beck NC, Deuser W, et al. Patient stages of change predicts outcome in a panic disorder medication trial. Anxiety. 1994;1:64-69. 34. Lam CS, McMahon BT, Priddy DA, et al. Deficit awareness and treatment performance among traumatic head injury adults. Brain Inj. 1988;2:235-242. 35. Prochaska JO, Velicer WF, Rossi JS, et al. Stages of change and decisional balance for twelve problem behaviors. Health Psychol. 1994;13:39-46. 36. Prochaska JO. Strong and weak principles for progressing from precontemplation to action based on twelve problem behaviors. Health Psychol. 1994;13:47-51. 37. Hall KL, Rossi JS. Meta-analytic examination of the strong and weak principles across 48 health behaviors. Prev Med. 2008;46(3):266-274. 38. Miller WR. Motivation for treatment: a review with special emphasis on alcoholism. Psychol Bull. 1985;98:84-107. 39. Prochaska JO, DiClemente CC, Velicer WF, et al. Standardized, individualized, interactive and personalized self-help programs for smoking cessation. Health Psychol. 1993;12:399-405. 40. Noar SM, Benac C, Harris M. Does tailoring matter? Meta-analytic review of tailored print health behavior change interventions. Psychol Bull. 2007;133(4):673-693.

41. Velicer WF, Prochaska JO, Fava JL, et al. Interactive versus noninteractive and dose response relationships for stage matched smoking cessation programs in a managed care setting. Health Psychol. 1999;18:1-8. 42. Jones H, Edwards L, Vallis MT, et al. Changes in diabetes self-care behaviors make a difference to glycemic control: the diabetes stages of change (DiSC) study. Diabetes Care. 2003;26:732-737. 43. Prochaska JO, Velicer WF, Redding CA, et al. Multiple risk expert systems interventions: impact of simultaneous stage-matched expert system interventions for smoking, high-fat diet and sun exposure in a population of parents. Health Psychol. 2004;23:503-516. 44. Prochaska JO, Velicer WF, Redding CA, et al. Stage-based expert systems to guide a population of primary care patients to quit smoking, eat healthier, prevent skin cancer and receive regular mammograms. Prev Med. 2005;41:406-416. 45. Levesque DA, Driskell MM, Prochaska JM, et al. Acceptability of a stage-matched expert system intervention for domestic violence offenders. Violence Vict. 2008;23(4):432-435. 46. Prochaska JO, Wright JA, Velicer WF. Evaluating theories of health behavior change: a hierarchy of criteria applied to the transtheoretical model. Appl Psychol. 2008;57(4):561-588. 47. Prochaska JO, Evers KE, Castle PH, et al. Enhancing multiple domains of well-being by decreasing multiple health risk behaviors: a randomized clinical trial. Population Health Management. 2012;15:1-11. 48. Gallup-Healthways. Well-Being Index, 2009. https://wellbeingindex.sharecare.com/ 49. Prochaska JO, Norcross JC, DiClemente CC. Changing for Good. New York: Morrow, 1994. 50. Prochaska JO, Prochaska JM. Changing to Thrive: Overcome the Top Risks to Lasting Health and Happiness. Center City, MN: Hazelden Publishing, 2016.

CHAPTER 64

Group Therapies Dennis C. Daley, Antoine Douaihy, Roger D. Weiss, and Delinda E. Mercer

CHAPTER OUTLINE Introduction Goals of Group Therapies Organization of Group Therapies Empirical Validation of Group Therapies Group Therapies For Co-Occurring Disorders Survey of Group Therapists Limitations of Group Therapies Conclusions

INTRODUCTION Group therapies are used widely in the treatment of substance use disorders (SUDs), gambling disorders, and co-occurring psychiatric disorders (CODs). These are often the main form of treatment used. We use the term “group therapy” to refer to milieu, psychoeducational recovery, coping skills, family, and therapy groups (also called problem-solving, process, or counseling groups) (1,2). This chapter provides an overview of goals and types of group therapies used to treat SUDs or CODs. It also provides a discussion of studies examining the effectiveness of group therapies for SUDs and their limitations. Training and supervision issues are discussed as well. Groups may address early recovery issues such as initiating abstinence and engaging the patient in a recovery process (3–9), anger management (10), relapse prevention (4,11–14), and CODs (15–20). Group therapies also are widely used in the treatment of specific populations including women (21,22); individuals with alcohol use disorders (23); persons in the criminal justice system (24,25); those with cannabis use disorders (26) or cocaine or methamphetamine use disorders (3–5,27); and families (1,2,4,28–30). Furthermore, cognitive–behavioral group therapy (CBGT) is a promising treatment approach for gambling disorders. It showed significant within-group decreases on most outcome measures up to 12-month follow-up in a sample of 150 primarily self-recruited patients with gambling problems or pathological gambling per DSM-IV screen for gambling problems (31).

GOALS OF GROUP THERAPIES The long-term goals of treatment are to help the individual with the SUD to achieve and maintain abstinence and improve the quality of life. Short-term goals are to evaluate and reduce substance use, become motivated to change, address problems caused or worsened by the SUD, and improve functioning. Group therapies help patients achieve these goals by creating a milieu in which group members can bond with each other, thus reducing the stigma associated with addiction and the humiliation of having lost control of one’s own behavior (1). The specific ways in which groups can help achieve this include providing education on addiction, recovery, and relapse; resolving ambivalence and enhancing motivation to change; evoking hope and optimism for change; providing an opportunity to give and receive feedback from peers; teaching recovery skills to manage the SUD; addressing problems resulting from the SUD; providing a context in which the group member can identify with others and give and receive support; creating an experience of positive membership in a recovery-oriented group in which feelings, thoughts, and conflicts can be freely expressed; preparing the patient for involvement in long-term recovery; and facilitating the patient’s interest in participating in mutual support programs in addition to treatment groups (3,4). Group members learn how those with SUDs think, feel, and act, including the manipulations, schemes, and diversions they sometimes use to rationalize their substance use and other maladaptive behaviors (6).

ORGANIZATION THERAPIES

OF

GROUP

Group therapies vary in their theoretical underpinnings, structure, format, rules, number and duration of sessions, clinical focus, size, types of patients accepted, requirements for abstinence, approach to the group model, relative focus on content or process, and roles of the group leader. An effective group leader should have the same important therapeutic skills as a good individual therapist such as listening skills, empathy, and therapeutic alliance. A client-centered empathic style is crucial in group therapy. However, scientific evidence showed poor outcomes are associated with confrontational group leader (32). Additionally, other skills are needed on know-how. Self-awareness and monitoring are important components of successful dynamics in group therapy.

Yalom (33) described four basic leadership qualities that were associated with positive treatment outcomes: acceptance; caring; meaning attribution; and executive function. So, it matters who provides group therapy. Training in a particular type of therapy is also needed depending on the setting, for example, CBGT. Many recovery-oriented groups are structured and content focused and depend on the leader to facilitate discussion of educational material with specific objectives and issues to cover in each session. These groups can accommodate larger numbers of patients than can therapy groups. Models include psychoeducational (12,34), motivational cognitive–behavioral (35), cognitive therapy (36,37), stages of change (38), recovery and self-help groups (13), or family groups (4,30). Therapy groups usually are limited to 6-10 persons, with the content of discussions determined by the participants. Leaders facilitate members’ exploration of problems and sharing of support and feedback. Although some groups incorporate principles and information from mutual support programs such as Alcoholics Anonymous (AA) or Narcotics Anonymous (NA), therapy groups differ in their focus on exploration of psychological, interpersonal, social, spiritual, and intrapersonal issues. Structured treatment programs can last from several days to a year, exposing patients to considerable heterogeneity in the number and types of group sessions they receive. For example, a large multisite study of outpatient treatment for cocaine addiction (39) offered 24 weekly group counseling sessions, over a period of 6 months of active treatment in addition to individual or brief case management sessions. The Matrix Model offered 8 early recovery skills, 32 relapse prevention, and 36 social support group sessions (for 76 total group sessions) over 6+ months combined with individual and family sessions (4,28).

Orienting Patients to Groups Patients can be prepared for group programs so they understand the goals and structure of groups they will attend, potential benefits, and what is expected from their participation. Clinicians can describe the types and formats of the groups offered and how these differ from AA, NA, or other recovery meetings in the community. Clients can be encouraged to express their anxieties about groups or raise questions during this preparation session. The clinician can focus on how groups can help clients increase self-awareness, gain knowledge of their SUD and/or COD, and learn coping skills to meet the challenges of recovery. Clients can also be told that they will receive support and feedback from other group

members and to self-disclose their struggles, feelings, and thoughts so that they learn to let others help them. Clients can be told the importance of being on time for group sessions, attending all sessions, and talk about any desire to drop out before they decide to do so. Finally, clients can be assured that if they cannot engage in the groups due to a relapse, the clinician or team will help them find a level of care that can help them stabilize.

Types of Group Therapies Many of the problems or issues addressed in different models of group treatment are similar (Table 64-1). The specific issues or problems addressed depend on the treatment model and number of sessions offered.

TABLE 64-1 Issues Commonly Addressed in Recovery Groups

Groups usually fall into one of the following categories (1,2,4,15,16):

Milieu Groups These are offered in residential and hospital programs and involve a meeting to start and/or end the day. A morning group reviews the day’s schedule and issues pertinent to the community of patients and asks each patient to state a goal for the day or reflect on a recovery or inspirational reading. An evening wrap-up group reviews the day’s activities and provides participants a chance to discuss their experiences and what they learned.

Psychoeducational Recovery Groups These provide information about SUD and recovery and help patients learn to cope with recovery challenges such as cravings, social pressure to use, boredom, anger, other negative emotions, sober relationships, and assessing the impact of SUDs on the family. These groups promote recovery from physical, mental, relationship, and spiritual perspectives.

Coping Skill Groups These help patients develop or improve intrapersonal and interpersonal skills. They may teach problem-solving methods, stress management, or relapse prevention (RP) strategies. RP groups help patients identify and manage early signs of relapse, identify and manage high-risk factors, or learn how to intervene early with a lapse or relapse.

Therapy or Counseling Groups (Also Called ProblemSolving or Process Groups) In these groups, participants identify problems, conflicts, or struggles to work on during the session. Any of the issues in Table 64-1 may be discussed. These issues focus on raising self-awareness more than on education or skill development although participants learn many things and are exposed to coping strategies that others use to cope with problems.

Specialized Groups These may be based on developmental stage (adolescents, young adults, adults, older adults), gender, different clinical populations (women, clients involved in the criminal justice system, clients with co-occurring psychiatric illness), or groups addressing specific issues (parenting issues, anger or mood management, relapse prevention, or trauma). More extensive discussions of group approaches for addiction, such as interactional group therapy (34,40), modified dynamic group therapy (29,41), cognitive or cognitive–behavioral therapy, (12,22,35,36,42), psychoeducational and problem-solving therapy, (39,43), skills training therapy (23), recovery stage-specific group therapy (6,9,38,44), or relapse prevention therapy (4,6,11,12), can be found in texts elsewhere.

Format of Group Sessions Group sessions usually last 60-90 minutes. Groups can be limited to a specific number of sessions in which all participants start the group together or be open ended so that new patients can be continuously added to the group. Treatment programs vary in the frequency of group sessions as well as whether individual and/or family sessions are also provided as part of a total “program.” For example, the Matrix Model (4) offered individual and family sessions in addition to their extensive group program. In our multisite trial of treatment for cocaine addiction (37), 24 group sessions were provided to all study participants over 6 months. Three-fourths of patients also received up to 42 individual sessions over 9 months. In our study called STAGE-12 (Stimulant Groups to Engage in 12-Step Programs), participants received five weekly group sessions in addition to three individual sessions over an 8-week period while participating in a structured ambulatory intensive outpatient program (3). The Washton (44) structured outpatient model involved group therapy two to four times each week in combination with weekly individual counseling sessions. These examples show the diversity of treatment programs utilizing groups with clients who have SUDs.

Interventions of Group Leaders A group can have different designs. It can be led by one individual, co-led by 2 facilitators, or led by a primary facilitator with the presence of a secondary facilitator. Two cofacilitators could complement each other’s skills and expertise, provide different social roles, and guide difficult and challenging sessions. Group leaders may use a combination of any of the following: Educational presentations in which members are provided information about substances and their effects, causes and symptoms of SUDs, treatments, recovery, relapse, family issues, medical issues such as HIV or hepatitis, co-occurring psychiatric illness, and other issues that may be specific to the group members (eg, women’s issues, LGTB issues). Interactive discussions can engage members in meaningful discussions of content so they relate information reviewed to their personal situations. Brief stories to illustrate an issue or point discussed. Stories can be told by the group leader, guest presenter, or group members to illustrate success or failure in dealing with specific issues or challenges of recovery discussed.

Guest presenters with expertise in specific areas such as a psychiatrist, psychologist, or therapist on mental health issues; pharmacist on effects of drugs; physician, nurse, or other health professional on medical issues; religious professional on spiritual issues; social worker on family issues or community resources; or recovering persons to share their stories. Videotapes, DVDs, or audiotapes to provide information or hopeful stories of recovery. These should be brief and used to stimulate discussion of SUDs and recovery issues. Workbooks, journals, or worksheets in which clients share answers to questions about their SUDs or CODs, their recovery, or specific issues discussed by the group (eg, managing anger; reducing boredom; dealing with high-risk people). These client workbooks can be used as facilitator guides. Surveys completed by 300+ patients in our treatment programs showed that the majority found workbooks useful in learning information and coping strategies to deal with their SUDs or CODs. Comments to openended questions had a 4:1 ratio of positive (eg, “helped me accept the need for long-term help; helped make me motivated to recover; taught me ways to cope with urges or cravings”) to negative (eg, “need better preparation on how to use workbooks; material was redundant”). In addition, 41 staff members completed surveys and 8 were interviewed by an addiction fellow for their input. Results showed that staff from all disciplines routinely use workbooks and find them very useful or useful with patients. Over 80% used four or more workbooks with patients in the past year. Staff also shared positive responses to open-ended questions. Only a few staff did not use workbooks and stated they preferred focusing on “therapy” issues rather than education or coping skills. Readings on recovery or other related topics. These can be assigned to the group or specific members. Many programs have patients read the “Big Book” of AA or “Basic Text” of NA to educate them about the 12-Step program and stimulate their interest in recovery. Visual handouts to provide information and stimulate discussion. We use a diagram of the brain to show the areas involved in decision-making, emotions, and memory. We elicit examples of members of struggles in recovery associated with different areas of the brain. Pictures of scans of the brain of stimulant drug users, and scans after periods of abstinence show that the brain takes time to change and adjust to a drug-free state. These visuals usually lead to meaningful discussions among patients. PowerPoint slides show visual examples of the effects of substances or SUDs or recovery. Or, these can be used to illustrate ways to think about

recovery. For example, showing pictures of drugs and the works can be used to discuss how these trigger cravings to use. Behavioral assignments. Group members can be asked to complete assignments related to the group topic reviewed in structured recovery sessions. For example, if the group topic is understanding and managing depression, members can be instructed to keep a daily calendar in which they rate their mood so they can see changes between group sessions. Or, they can rate motivation to change daily to show how this may change during the week. In vivo role-plays. These address interpersonal problems such as dealing with a conflict, resisting pressure to engage in risky sex or substance use, or helping a group member practice asking a member of AA or NA to serve as his sponsor. Role-plays can include dyads or triads or use multiple people. Follow-up discussions can focus on the interpersonal interaction observed, thoughts and feelings the issue illustrated generates, and behavioral options to manage the problem that is the focus of the role-play. Monodramas to externalize a problem, conflict, or recovery issue. For example, a member can be asked to create a dialogue between his “healthy recovering self” and his “unhealthy addicted self.” Or, a member can be asked to imagine his craving for drugs, sitting on a chair and trying to convince him to get high. This member goes back and forth between being the craving and the person in recovery with a focus on building confidence to resist giving in to the craving despite how strong or convincing it is during the role-play. Other members coach this person if he feels vulnerable to letting a conflict lead to poor decisions. Creative media (arts, crafts, media) or other health lifestyle strategies (meditation, yoga, exercise). These not only aid recovery but also help members improve their overall health and the quality of their lives.

Recovery Group Sessions In the Collaborative Cocaine Study in which three of the authors participated, patients attended 90-minute recovery group sessions each week for 12 weeks (40,42,43). Each session focused on a specific topic relevant to early or middle recovery. At every session, patients were encouraged to abstain from all substances, seek and use a sponsor, participate in mutual support groups, and use the “tools” of recovery (eg, talking about vs. acting on strong cravings, reaching out for support, and the like). Patients were encouraged to socialize with each other before the start of the session while the group leader administered a

breathalyzer test. Each session began with a check-in (10-20 minutes), in which patients briefly reported any substance use, strong cravings, or “close calls.” This was followed by a discussion of the topic for the session (40-60 minutes). Each session provided materials from a workbook with information about the topic and questions for members to relate the material to their lives. During discussions, patients were encouraged to ask questions, share experiences related to the material, give each other feedback, and identify strategies to manage the issues discussed. Each session ended with a brief review of patients’ plans for the coming week (10-15 minutes). Patients discussed mutual support meetings and other steps they would in their recovery. Patients recited the Serenity Prayer of AA/NA to end the meeting. Topics of phase 1 included (these topics are similar to those offered in other group models) understanding addiction, the recovery process, social and interpersonal issues in recovery, cravings, mutual support programs, recovery support systems, managing emotions, relapse issues (warning signs or high-risk factors or intervention early in a lapse or relapse), and using recovery tools to maintain change over time.

Phase 2: Problem-Solving (Therapy) Groups Phase 2 groups met for 90 minutes weekly for 12 sessions. The goals were to help patients identify, prioritize, and discuss problems in recovery and identify strategies to manage these. Patients gave and received support and feedback from each other. After the check-in period, participants were asked to identify a problem or recovery issue for discussion. Often, more than one member would identify a similar problem or issue. The issues and problems reviewed in the phase 1 groups were revisited frequently. Common issues discussed include struggles with motivation to change or remain abstinent; obsessions or compulsions or close calls to use; lapses or relapses; boredom, anxiety, anger, depression, or other emotions; concerns with mutual support programs, the twelve steps, or a sponsor; interpersonal problems; social pressures to use substances; financial, job, and lifestyle problems; other addiction; and spirituality. At the end of each session, patients stated their plans for the coming week in terms of meetings or other steps to aid their recovery or resolve a problem.

Group Process Issues Counselors had to attend to the group process to keep the group focused and

productive. This required counselors to engage quiet members in discussions and facilitate their self-disclosure and to limit or redirect members who talked too much and dominated discussions, listened poorly, or used the group for individual therapy. Counselors kept the group from going off on unrelated tangents or talking in generalities, balanced the discussions between problems and coping strategies, facilitated group members’ sharing of support and feedback, and addressed impasses or problems in the group. In phase 1 groups, the counselor had to ensure that the curriculum for each session was covered.

Obstacles to Group Therapy Researchers who have written about group treatments identify problems that create obstacles to group treatment. Washton (6) reports the following problems among members of therapy groups: lateness and absenteeism, intoxication, hostility and chronic complaining, silence and lack of participation, terse and superficial presentations, factual reporting and focusing on externals, proselytizing and hiding behind AA, and playing cotherapist. Because the problems affect the group, the leader must have strategies to address any that arise during a group session. For example, if a member consistently rejects the advice or feedback of other members, the leader can point out this pattern and engage the group in a discussion of why this is occurring. The members whose help and support are rejected can be asked to talk about what this feels like so that the member who rejects it is aware of the impact this behavior has on others.

Family Psychoeducational Workshops (FPWs) These aim to educate the family, provide support, help reduce the family’s burden, increase helpful behaviors, decrease unhelpful behaviors, and provide hope (4,28–30). FPWs are semistructured sessions with multiple families and members with SUDs present. Families are encouraged to share their questions, concerns, and feelings. Strong affect often is present in these workshops, and some sharing of emotion is necessary. However, encouraging families to share their emotions too much can be counterproductive, so education and support are the main areas of focus. Thus, the group leader must be careful not to allow the group to become a venue for sharing deep-seated emotions. Interactive discussion is encouraged because it increases participants’ understanding of addiction and recovery. The specific material covered in FPWs depends on the amount of time available. The following topics and issues may be discussed:

An overview of substance use and SUDs: current trends in substance use, prevalence, types, causes, and symptoms of SUDs. Effects of SUDs: on the individual with the SUD, the family system, and family members, including children. An overview of treatment and helpful resources: programs and interventions (including medications) and resources for the affected individual are discussed. These include professional services and community resources such as mutual support programs. Overview of recovery: the recovery process and biopsychosocial–spiritual issues that may be addressed. How the family can help: behaviors for the family to avoid and behaviors that are helpful in supporting recovery of the member with the SUD. Family recovery: how the family member can recover from the adverse effects of an SUD. What they can do to help themselves rather than solely focus on the impaired family member. Mutual support programs: for individuals with SUDs and family members. How these programs can help family members and how to access them (eg, Al-Anon, Nar-Anon, NAMI for psychiatric illness). Relapse: warning signs, high-risk factors, how the family can be involved in relapse prevention plans, and how to deal with setbacks. In the Cocaine Collaborative Study (37,39), we offered a single 2-hour FPW during the first month of treatment. The purpose of the session was to educate families about the study; seek their help in supporting the patients’ compliance with treatment; and provide education about addiction, recovery, effects on the family, and community resources available to the family. The Matrix program offered a group “family education” curriculum to supplement individual and group sessions for program participants (4). This involves 12 sessions that focused on issues of concern for the family such as triggers and cravings for substances, recovery, alcohol and drugs, relapse, family issues in recovery, rebuilding trust, recovery challenges for families, and communication issues. However, not all treatment programs or group approaches incorporate sessions or focus on family issues. The role of interpersonal processes and social support is a critical component of relapse prevention (45). This underscores the value of involving family members in supporting the patient’s recovery efforts through their participation in sessions.

EMPIRICAL VALIDATION OF GROUP

THERAPIES Despite the widespread use of group therapies in addiction treatment, controlled trials of group interventions are limited, and many studies report results from “programs” that involve multiple components (ie, individual plus group, multiple types of group treatments, or group plus other services). In a review of the group treatment of addiction literature, Sobell and Sobell (35) found only five studies that compared the same cognitive–behavioral intervention in both individual and group formats. All studies found both types of treatment to be effective, but none showed a significant difference in outcomes of patients receiving individual versus group treatment suggesting that group is as effective as individual treatment. Weiss et al. (46) reviewed 24 prospective treatment outcome studies comparing group therapy with one or more treatment conditions. The results of the studies were mixed, varying on the nature of the research design, the population studied, and the format of treatment (content, intensity, and length). The findings showed three important patterns: additional specialized group therapy can enhance the effectiveness of “treatment as usual,” no differences were found between group and individual modalities, and no single type of group therapy demonstrated any consistent superiority in efficacy. The content of the group (whether skill based or interpersonal) did not make a difference. The authors concluded that the most notable finding of that study was the paucity of research on this topic. However, researchers and clinicians agree on the importance of group therapies, and groups remain one of the principal modalities of treatment in most SUD or COD treatment programs. Several effective group treatments have been developed and implemented for women with SUDs, many of whom also had mood, anxiety, or other psychiatric issues (21,47–51). A randomized controlled trial of a Women’s Recovery Group (WRG) demonstrated significant reductions of alcohol and drug use and improvements in anxiety, depression, and general mental health symptoms at 6 and 9 month post treatment (50). Compared to a mixed-gender control group treatment condition, women in the WRG endorsed feeling safe, embracing all aspects of the self, having their needs met, and feeling intimacy, empathy, and honesty in group sessions (21). These sessions focused on issues common in other group therapies for SUDs and also on issues specific to women and their recovery such as caretaking, substance use through the lifecycle, substance use and reproductive health, women and their partners including violence and abuse, and psychiatric issues such as anxiety, depression, or eating

disorders. Najavits’ Seeking Safety (SS) is a present-focused coping skills program that addresses substance use and trauma. SS helps clients attain safety in relationships, thinking, behavior, and emotions by addressing both substance use and trauma issues in an integrated way. Cognitive, behavioral, interpersonal, and case management strategies are used in SS to address these issues. SS was initially developed for women in groups but later was implemented with men, in individual sessions, and in mental health as well as SUDs programs (22).

Adherence to Group Sessions and Treatment Dropout Most randomized clinical trials showed significant reductions in drug use, improved health, and reduced social pathology (52). Patients who comply with sessions and attend enough sessions show better outcomes than do those who drop out prematurely. However, two of the major problems in the treatment of SUDs and CODs are poor adherence with session attendance or medications and early termination (53). Integrated supportive group therapy in a randomized trial has shown a differential effect on treatment retention in subjects with severe mental disorders and SUDs (54).

Reasons for Dropping Out of Group Treatment In the NIDA Collaborative Cocaine Treatment Study (37), the reasons patients cited most commonly for contributing to early drop out were time problems (42.7%); relapse to use or the desire to use (30.7%); not finding group helpful (29.3%); wanting a different treatment, such as individual therapy (30.7%); improvement in the problem (18.7%); other unspecified reasons (18.7%); unwillingness to participate in treatment (16%); and need for hospitalization (13.3%).

Limitations of Research Although evidence suggests that group treatments are effective for SUDs, limitations to the research conducted on group treatments arise from two sources: variations in content and differences in process. Also, dropout rates are higher among clients in groups compared to individual therapy. A level of interaction and complexity must be taken into consideration, over

and above the content of the intervention and the counselor’s skill in conducting it. Very often, group programs are evaluated rather than a single-group intervention. For example, studies of intensive outpatient programs often evaluate a comprehensive program that involves several different types of groups that together make up the intensive outpatient program. Some studies of group treatments were conducted on patients who first participated in an intensive residential program or concurrent treatment program, making it difficult to determine the impact of the group or other factors on patient outcome. Therefore, it is unclear how much each type of group contributes to outcome. In addition, studies sometimes involve a combination of group and individual treatments, making it difficult to determine how much each intervention contributes to the outcome. The discrepancy between the widespread clinical application of group therapy and the limited research stems from the inherent difficulties in conducting meaningful research on group therapy (46). Since group treatment is the most common psychosocial intervention offered, more research is clearly needed to study both the efficacy and effectiveness of group interventions.

GROUP THERAPIES OCCURRING DISORDERS

FOR

CO-

Epidemiological and clinical studies document high rates of co-occurring psychiatric and SUDs (16–18,55,56). Research supports the use of group treatments for patients with CODs, including those with chronic and persistent mental disorders (16,18,21,22,57–59). Several investigators have developed and tested integrated interventions in clinical trials using manual-driven group treatments. The Najavits’ SS model mentioned previously involves 24 weekly group sessions, divided into “units” dealing with problems frequently encountered (17,22,60,61). An introductory unit of two sessions provides education on trauma or posttraumatic stress disorder (PTSD) and SUDs and introduces the women to community resources and self-help programs. A behavioral unit of seven sessions teaches skills to manage the SUD and PTSD, addressing issues such as setting a daily schedule, structuring time, nurturing the self, learning to ask for help and support from others, identifying and managing triggers for both disorders, managing ambivalence about change, and learning to deal with life stressors. A unit of six sessions teaches patients how to change maladaptive

thoughts or cognitive distortions associated with SUD or PTSD. A unit of six sessions focuses on improving communication skills and relationships. This also addresses self-protection in relationships, rebuilding trust, and healthy relationship thinking. The final three sessions review the experience of group and termination issues with a focus on ongoing supports, knowing how to judge progress or deterioration, and the importance of a continuing care plan. When the group treatment contract is signed, an interview is conducted with each patient before he or she enters the group, and ways to benefit from this treatment are reviewed. An individual HIV counseling session is provided to each patient within the first 3 weeks of treatment, at which time an HIV risk assessment is completed and education and counseling on HIV issues are provided. Homework assignments and action techniques such as role-play are used throughout this protocol. SS has been used in numerous programs in the United States and other countries, and its efficacy and effectiveness are supported by numerous clinical trials (21). A randomized clinical trial evaluated the efficacy of a 12-session CBGT for alcohol-dependent males with co-occurring interpersonal violence (62). Results showed a significant difference between participants in the integrated approach (SUD–domestic violence) versus the twelve-step facilitation group on alcohol use outcomes. The group assigned to substance use–domestic violence reported using alcohol significantly fewer days as compared with the twelve-step facilitation group. Regarding physical violence, there was a trend for participants in the SUD–domestic violence condition to achieve a greater reduction in the frequency of violent behaviors across time compared with individuals in the twelve-step facilitation group (63). Weiss et al. developed and tested an integrated cognitive–behavioral group treatment (IGT) for bipolar patients with SUDs (64). This involved a 20-week randomized controlled trial (n = 62) with 3 months of posttreatment follow-up, to compare the efficacy of IGT versus an active addiction treatment, group drug counseling (GDC), an adaptation of the model used in the NIDA Collaborative Cocaine Treatment Study (37,39). Both IGT and GDC are manual-driven treatments that involve 20 weekly group sessions of 1 hour each. IGT focuses on issues pertinent to substance use and bipolar illness, whereas GDC focuses solely on SUD. GDC patients address psychiatric issues in separate sessions with a mental health professional. All patients in the study also received medications for their bipolar illness. Patients in both conditions improved, but IGT was more successful at reducing substance use despite more subclinical mood symptoms. A briefer, revised version of IGT with 12 group sessions also favored IGT, with

nearly three times as many patients attaining abstinence throughout treatment. Moreover, more than twice as many IGT patients experienced a “good clinical outcome,” defined as abstinence and the absence of any mood episode during the last month of treatment (62). In a quality improvement study of 117 patients who participated in an integrated COD-intensive outpatient program developed by two of the authors (DD and AD) (15), there was a steady weekly decrease in mean scores for the Beck Anxiety Inventory, Beck Depression Inventory, and Addiction Severity Index from baseline to week 4. The mean rating of both Beck Anxiety Inventory and Beck Depression Inventory scores declined from “moderate” to “mild” by week 4, and the mean Addiction Severity Index scored was 58% lower at week 4 than at baseline (15). A review of studies assessing group interventions for patients with SUDs and psychotic disorders concluded that the most encouraging interventions include assertive outreach, integration within the treatment setting, motivational interviewing (MI), and follow-up longer than 1 year to attain clinically significant reductions in substance use over time (65). Short-term results from a randomized controlled trial among people with psychotic disorders, which used group MI and CBT within a harm minimization paradigm over six 90-minute sessions, showed that compared to a control group that received a single hour-long session of education regarding drug use, the MI/CBT group intervention condition did significantly better in terms of reductions in global psychopathology, drug use, severity of DSM-IV defined dependence, and, in addition, a lower rate of hospitalization at 3 months after intervention (66). Bradley et al. (67) evaluated an open-ended outpatient group intervention (in the context of a service evaluation project with clinicians administered ratings), incorporating the features reported in the previous study (63), consisting of MI and CBT, among patients with psychosis and SUDs. This group intervention was conducted in a rural setting and with groups led by clinicians from mental health and drug and alcohol services, including coleaders who were not originators of the intervention model. Compared with baseline, the group intervention was associated with significant improvements in substance use, symptomatology, treatment noncompliance, and overall functioning. Group MI in a nonrandomized but sequentially assigned study showed promising results when added to standard treatment for psychiatric inpatients with CODs, leading to improved treatment outcomes. Of those patients who attended aftercare and who used alcohol or drugs, those who participated in

group MI were more adherent to treatment sessions, used less alcohol, and engaged in less binge drinking at follow-up compared with those in the control group (68).

The Need for Physician Input and Support Physicians can play a significant role in providing input into group program development and supporting and facilitating patients’ participation in groups. First, physicians can suggest specific topics for recovery groups and/or conduct a group. For example, in one of the first author’s ambulatory programs, a physician developed and conducted a group on “addiction and the brain” and created a curriculum for clinicians to use when they conducted this session. Some treatment programs use physicians to present groups on topics such as medical aspects of addiction, medications that can support recovery, causes of addiction or mental illness, and other relevant topics that can tap the expertise of the physician. Patients often respond very favorable to the “doctor” who conducts a group session, and they often have many questions to ask the physician. Second, physicians can educate, encourage, and persuade patients to participate in treatment groups as part of their overall treatment program. It is helpful for clinical staff to give patients a consistent message about the value of group treatments. The physician can use his or her status as a healer to help the patient make a decision to participate and not underestimate his or her influence, given the power of even brief interventions on substance behaviors (69). Third, the physician can monitor and discuss the patient’s group participation. This allows the physician to identify and resolve any barriers related to the patient’s continued participation, to understand the reasons for poor adherence or early dropout, and to help the patient re-engage in group. Fourth, the physician can collaborate with group therapists about patients’ clinical status or problems with adherence. A physician may also see a patient for management of withdrawal, for management of a COD, or for medication management. If, during such a visit, the physician learns that the patient is not adhering to the plan to attend or participate actively in treatment groups, the physician can facilitate a discussion with the group leader or even hold a joint meeting with the patient and group therapist to try to resolve the problem. The physician or the psychiatrist can also cofacilitate a group session with the group leader. Again, the message the patient receives from this collaboration is that the group is an important part of the overall treatment plan and is valued by the physician.

SURVEY OF GROUP THERAPISTS We conducted a confidential online “Survey Monkey” of 89 staff members employed in addiction Community Treatment Programs that were part of NIDA’s Clinical Trials Network, a national research group (70,71). Our goal was to gather information about current practices of therapists in conducting groups as well as training needs. The majority of respondents were therapists or counselors with a master’s or bachelor’s degree (86.4%). The majority (63.2%) had more than 5 years of clinical experience in addiction treatment programs. The settings in which they provided group services were diverse and covered the continuum of care including outpatient clinics (43.2%), short-term (30 days) or therapeutic community programs (15.9%), withdrawal management units in rehabilitation programs or medical hospitals (12.5%), partial hospital programs providing over 10 hours of clinical services per week (10.2%), or psychiatric hospitals (6.8%). In a typical week, therapists provided an average of 10 hours in structured recovery or psychoeducational groups (2.5 hours), therapy groups (2.2 hours), coping skills or relapse prevention groups (1.9 hours), milieu groups (1.9 hours), expressive arts groups (0.8 hours), and family groups (0.7 hours).

Counselor Training To provide effective group treatment, it is necessary for therapists to be familiar with and skillful in addiction treatment and group therapy. Ongoing training and supervision help to keep counselors abreast of current developments in the field and enthusiastic about their work. The knowledge base to provide competent treatment for SUDs involves understanding effects of substances as well as the medical, psychological, social, family, and spiritual consequences of SUDs. Other areas of knowledge needed include the recovery process, causes and effects of relapse, and the strategies for recovering person to manage the SUD and reduce relapse risk. The clinician should also be familiar with AA or NA and other 12-step programs and with alternative mutual support programs and online resources. Counselors need to have experience in counseling individuals because situations arise that require the group counselor to intervene with an individual member. Conducting groups

thus involve an additional level of complexity compared with working with individuals, in that the group leader must be able to understand and respond to individual as well as group dynamics or group process issues simultaneously. Counselors also need an understanding of stages of groups and the “group process,” which refers to the attitudes and interaction of the group members and leader. The group leader should be familiar with group interventions and how to deal with problem situations that are common in groups. Intervention skills include active listening, clarification and questioning, information giving, summarization, encouraging and supporting, modeling, eliciting feedback, and addressing problems that commonly arise in group (eg, a member who dominates the group, resistant members who are reluctant to participate, a member who tries to assume the role of the leader, mutually hostile members, insensitive feedback, and members who challenge the leader).

Counselor Supervision Supervision is important, yet it often is overlooked or provided in a less than optimal manner. The group counselor should have access to someone who has experience and expertise in the field, to whom the counselor can bring any problems as they emerge. It also is important to communicate that supervision is not primarily about evaluation of the counselor’s work but rather an opportunity for the counselor to air problems, hone his or her skills, and continue to learn. In one of our ambulatory clinics (DD and AD), we provided monthly group consultation to all group leaders in a group format so they could learn from each other. These sessions often focused more on group process issues and patient behaviors in group than on specific content. Therapists in the NIDA Cocaine Collaborative Study protocol received weekly and then biweekly supervision by telephone from a supervisor who viewed videotapes of sessions conducted and rated with an adherence scale. Because this study was for comparative research, adherence to the counseling approach was of utmost importance. An adherence scale provides specific operational definitions of desired interventions. These definitions make it clear to counselors what interventions should be incorporated into their work and make it easy for supervisors to point out strengths and deficiencies when giving feedback. Adherence scales associated with a treatment manual can be a useful tool for both research and clinical purposes, in that they allow researchers to assess whether therapists are following the specified treatment manual. They are

helpful in showing that treatments can be differentiated from one another and in assessing the extent to which counselors incorporate techniques from other treatments. Moreover, they are useful clinically in training and supervision of a model of treatment.

Counselor Satisfaction It is important that counselors feel satisfied with the group services they are providing and with the clinical environment in which they work. When counselors are dissatisfied, burnout, indifferent treatment, and departures from appropriate counseling behavior often result. Dissatisfied counselors also tend to feel less positive about their work and to express less confidence in their patients’ ability to achieve recovery; such feelings can undermine the patients’ own perception of their ability to recover. Therefore, access to group supervision and consultation and training programs are important for counselors conducting groups.

LIMITATIONS OF GROUP THERAPIES Although groups offer many benefits, they also have limitations. One of the most common is an overemphasis on group treatment with little or no individual treatment. As part of an ongoing quality improvement effort, the first author met with small focus groups of patients (totaling more than 1000 over several years) in a broad range of addiction and COD treatment programs to inquire about what they liked and disliked about treatment. He also met with patients from other treatment programs as part of evaluating their programs and making recommendations. Programs with minimal groups were often viewed by patients as lacking in opportunities for learning about their disorders and ways to cope. Patients also report getting bored when they have too much time on their hands while in an inpatient or residential program that does not offer many treatment groups or that does use homework assignments to aid their recovery (eg, keeping written journals, completing reading or workbook assignments). Although most patients participating in group treatments were able to articulate benefits of the group, a consistent criticism heard over many years has been a concern that they did not receive any or enough individual therapy. Patients often reported that there were certain types of problems or issues that they would not discuss in group sessions and that they preferred the privacy and confidentiality afforded by an individual counseling or therapy session.

Examples that patients reported of the personal problems difficult to disclose in group sessions included experiences as a victim or perpetrator of violence, sexual abuse, child abuse, some types of deviant behaviors, the presence of certain psychiatric symptoms, and conflicts related to sexual identity or behaviors. Confidentiality issues were cited as another reason for reluctance to disclose personal information in some group sessions. This was particularly true of patients who participated in a group session in which another member was from the same neighborhood or shared mutual friends. Patients who had difficulty with assertiveness or disclosing personal problems reported that it was easy for them to blend into the background in a group. Although this felt “safe,” the patients recognized that this feeling led to less than optimal gain from group therapy. Some patients described attending group sessions in which the leader did not control participants who talked too much or who listened poorly to others or leaders who did not engage quiet members in group discussions. Social anxiety or phobias are common among patients with SUDs (72). Daley and Salloum (73) administered the Davidson Brief Social Phobia questionnaire to 128 outpatients with CODs and found that more than one-third reported high levels of social anxiety and avoidance behavior. Patients reported high levels of anxiety about speaking at AA or NA meetings or in group therapy. Because of social anxiety, patients may choose to limit participation in group discussions, miss group sessions, or drop out prematurely. They often do so without discussing their reasons with a therapist, counselor, or sponsor.

CONCLUSIONS The research literature and clinical experience suggest several points that are important to an understanding of group therapies for SUDs and CODs. First, group therapies play a critical role in treatment of these disorders and should be supported by all clinicians, regardless of whether they provide group sessions themselves. Second, different group therapies can be used, depending on a given patient’s progress in relation to the stages of change and the treatment context. Third, a combination of group and individual treatment is optimal. This issue is important because group therapy is the primary and often sole modality offered by many SUD treatment programs. Fourth, integrated group interventions that focus on both addiction and psychiatric issues are the preferred approach for patients with CODs. Fifth, staff training and ongoing supervision can enhance the effectiveness of group therapies. Sixth, patients who participate in group therapies often benefit from medications, so the benefits can be discussed in

group sessions (74). Seventh, mutual support programs and group therapies are different in their purpose and structure. Group therapies can encourage attendance at mutual support programs, provide education, and explore experiences and resistances. Therapy groups are designed to explore psychological, personal, and interpersonal issues in a safe environment in which self-disclosure, self-awareness, and self-change are encouraged and valued. Eight, treatment personnel must be sensitive to the fact that SUDs are debilitating and chronic conditions for many patients. As with other chronic disorders, more severe SUDs require ongoing management. Group therapy is an approach to initiating and continuing this process to the maintenance phase of recovery. Ninth, group leaders can utilize recovery materials to aid patient learning of information and coping skills. Our surveys of over 300 patients in multiple treatment programs show that patients rate using recovery workbooks as very helpful in learning information and coping skills (75). They are able to identify numerous ways in which these materials aid their recovery. Finally, leaders can improve group services by eliciting feedback from patients, both in group sessions and with the use of written evaluations. For example, a group leader could say to members “I am interested in knowing what you like and don’t like about our group. Can we discuss what you find helpful, what you think is unhelpful, and suggestions to improve our group?” Or, a group leader could have members anonymously complete a brief questionnaire in which they rate the group sessions in terms of information learned, coping strategies learned, self-awareness gained, or other areas, depending on the type and purpose of the group.

ACKNOWLEDGMENTS The preparation of this chapter was supported by an NIDA grant for the Appalachian Tri-State Node of the Clinical Trials Network (D. Daley, # DA 020036–01).

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CHAPTER 65

Individual Treatment Deborah L. Haller and Edward V. Nunes

CHAPTER OUTLINE Introduction History of Psychotherapy for Substance Use Disorders Development of Behavioral Therapies for Substance Use Disorders: the Technology Model Common Elements of Effective Behavioral Therapies Overview of Evidence-Based Psychotherapies for Substance Use Disorders Role of Significant Others in Treatment of Substance Use Disorders Combining Individual Psychotherapy with Other Modalities: Group Therapy and Medications Differential Therapeutics: How to Match Patients with Therapies Virtual Therapy and Computer-Delivered Technology-Based Interventions Technology Transfer: How to Effectively Train Clinicians to Deliver Evidence-Based Psychotherapies

INTRODUCTION This chapter provides an introduction to behavioral and psychotherapeutic treatments for substance use disorders (SUDs) typically delivered on an individual basis between therapist and patient. The chapter describes the technology model for the development of novel interventions and for testing their effectiveness through clinical trials, summaries of contemporary therapy methods that have evidence supporting their effectiveness (many of which are described in detail in the chapters that follow), and common elements shared by effective behavioral and psychotherapeutic therapies for SUD. The chapter concludes with a discussion of the challenges of implementing evidence-based treatments widely across the real-world treatment system, and the advent of technology-based treatments in part as an effort to bridge the implementation gap. It is hoped that the chapter will provide a foundation that will enable readers to critically evaluate the various therapies currently available for treating SUDs, in terms of their supporting evidence, selecting the most appropriate psychotherapeutic approach for a given patient, and understanding what is necessary to deliver these treatments effectively.

HISTORY OF PSYCHOTHERAPY FOR SUBSTANCE USE DISORDERS The first theory-based individual psychotherapy, psychoanalysis, was founded in the late 19th century by a Viennese psychiatrist Sigmund Freud. Psychoanalysis is based on the premise that mental life is both conscious and unconscious and that early life experiences have a powerful psychological influence on the individual throughout the life span. The goal of psychoanalysis, or the broader family of psychodynamic psychotherapies, is to increase awareness and understanding of unconscious patterns of thought and feeling and, by making them conscious, to correct the overt symptoms. A central focus is the transference, namely the relationship, thoughts, and feelings that the patient develops toward the therapist, and how this reflects conflicts in the patient’s life. However, clinical experience has not found psychoanalysis particularly helpful for directly treating SUDs. Manual-guided psychodynamic or transference-based therapies have been developed and rigorously tested and shown effectiveness for other psychiatric disorders, such as borderline personality disorder or some of the anxiety disorders (1–3), disorders that have substantial comorbidity with SUDs. However, there has been little rigorous research testing of psychodynamic psychotherapies for SUD per se. One potential limitation with respect to the treatment of SUD is that psychoanalytic or psychodynamic approaches do not focus predominantly on overt symptoms such as substance use. In contrast, therapies with demonstrated effectiveness directly address substance use and related symptoms and behaviors and typically provide coping strategies of one form or another. Another potential limitation is that psychodynamic approaches tend to arouse anxiety and other painful affects, which, as a proximal stressor, may promote relapse to substance use in vulnerable individuals. Finally, a psychodynamic therapist typically is expected to maintain therapeutic “neutrality,” which stands in contrast to the relatively supportive and directive stance that characterizes most contemporary, evidence-based psychotherapies targeting SUD (4). In the mid-20th century, help for individuals with SUD arose from self-help approaches. The first of these, Alcoholics Anonymous (AA), emerged in 1935 (5). It was founded by two “alcoholics” (Dr. Bob and Bill W). AA borrowed the principle of spiritual values in daily living from the Oxford Group, a non– alcohol-based fellowship (6), and the concept of alcoholism as an illness of mind, emotions, and body from the first private “drying out hospital” in New

York City (Towns Hospital), where Bill W. began his own recovery (7). AA offered the Twelve Steps (5), which, in many ways, resemble a treatment plan (ie, need for problem recognition, commitment to abstinence and change, and focus on changing “character defects”). The 12-step “program” focuses on drinking as the identified problem behavior and abstinence as the goal. It provides a structured pathway, including a variety of concrete coping skills, thus anticipating many of the features of contemporary, evidence-based psychotherapies. Although AA is a group-based approach, “sponsorship” (8) bears a resemblance to counseling per se, including adoption of a nonjudgmental stance, encouragement, education, advice on how to sustain sobriety, and support for socialization within the context of a long-term relationship. During the 1950s and 1960s, a number of related self-help approaches for addressing SUD emerged. An Addicts Anonymous meeting was held at the US Public Health Hospital in Lexington, Kentucky, in 1947, 12 years after the first AA meeting. Early New York–based Narcotics Anonymous (NA) groups were plagued by organizational problems, fear of police infiltration, slow growth in membership, and relapse among prominent members, leading them to disband in the mid1960s and early 1970s. However, NA today has evolved into a viable resource for patients struggling with drug problems (9). Residential treatment programs began to emerge in the mid-20th century. The classic “Minnesota Model” of treatment for SUDs, which first appeared in 1949, was based on a simple 5-point recovery plan: (a) behave responsibly, (b) attend lectures on the 12 steps, (c) talk with other patients, (d) make your bed, and (e) stay sober; conspicuously, absent from the original model was any sort of counseling or therapy (10). In 1958, the first therapeutic community (TC) (Synanon) was established. TCs seek to rehabilitate individuals with SUD through long-term stays in residential programs that employ a hierarchical model with treatment stages corresponding to gradually increasing levels of personal and social responsibility. (See Section 8 to learn more about TC-based treatment.) In this self-help approach, the community is the primary agent of change (11). Thus, at first there was little involvement of professionally delivered psychotherapy. Over the recent decades, residential treatment models have evolved to include professional psychotherapeutic and medical treatment in addition to self-help. Provisions for “substance abuse counseling” were written into legislation to fund community mental health centers, antipoverty programs, and criminal justice diversion beginning in the 1960s. Concurrently, health insurance companies began paying for treatment for SUDs. Together, these factors resulted

in a dramatic increase in the number of patients with SUD who accessed treatment (12). However, while treatment (including counseling) was readily available, the interventions were poorly defined and delivered mostly by counselors whose primary credential was their own recovery. Furthermore, as treatment outcomes were not assessed, there was no way to determine the extent to which the approaches that were being used were effective. During this same era, evidence-based psychotherapies began to emerge in response to increased scientific knowledge. The field of behavioral pharmacology first recognized that alcohol and drugs serve as “reinforcers,” ushering in the conceptualization of SUD according to classical learning theory. The discovery of the brain reward system and its role in the addictive phenomena established a biological basis for SUD (13). Psychotherapeutic and behavioral approaches to SUD subsequently have drawn heavily from classical learning theory, cognitive psychology, and social learning theory. In the 1980s, researchers became increasingly interested in adapting and testing psychotherapies originally developed to treat psychiatric problems such as depression and anxiety for use with patients with SUD (4,12). Thus, cognitive–behavioral therapy (CBT), originally developed for depression (14), was a forerunner of a broad family of therapies for SUD including cognitive– behavioral relapse prevention (15,16), coping skills therapies (17), and the community reinforcement approach (CRA) (18). Contingency management (CM) techniques for treating SUD (19) grew out of applications of classical behavioral theory and principles of reinforcement. Motivational interviewing (MI) evolved, in part, from social psychological theories of interpersonal influence and social learning (20,21). Finally, contemporary therapies for SUD owe their roots, in part, to the development of interest in the evidence-based practice (EBP) of medicine. During the 1970s, a series of studies showed that only 10%-25% of health care decisions were being made on the basis of findings from high-quality research studies, with the remainder made on the basis of clinical judgment (22). Results of randomized clinical trials (RCTs) were asserted as the “gold standard” for knowledge; in contrast, clinical judgment was seen as less valid, unless backed by data from scientific studies. The principles of EBP apply to psychological, as well as medical, treatments. Adhering to EBP principles thus requires the use of psychotherapies that have been well specified (the ingredients or techniques of the treatment are clearly defined, measurable, and replicable) and proven to be effective in controlled studies with well-defined populations (23). During the 1970s and 1980s, consensus emerged as to the steps needed to specify a

psychotherapy and test its effectiveness (ie, development of a treatment manual, describing the treatment in detail; prescribing methods for training and supervising therapists; specifying methods for monitoring and assuring accurate delivery of the treatment). These principles began to be applied to the development of psychotherapies for SUDs. Early landmark studies in this evolution include those of Woody et al. (24,25) focusing on psychotherapy on treatment of methadone maintenance patients; Project MATCH (26,27), which contrasted motivational enhancement therapy (MET) (28), cognitive–behavioral coping skills therapy (29), and twelve-step facilitation (TSF) for treatment of alcohol dependence (30); and the National Institute on Drug Abuse (NIDA) Collaborative Cocaine Study (31), which randomized patients with cocaine use disorders to either supportive–expressive (SE) psychotherapy or cognitive therapy (CT) (delivered by professional psychotherapists) or manual-guided drug counseling (delivered by experienced counselors working at substance treatment programs). We now further describe the principles for development of effective psychotherapies as they have been applied to SUDs, broadly referred to as the “technology model.”

DEVELOPMENT OF BEHAVIORAL THERAPIES FOR SUBSTANCE USE DISORDERS: THE TECHNOLOGY MODEL For the past several decades, researchers, clinicians, and trainers have worked together with the federal government to develop and improve treatments for SUD at the patient, program, and system levels. The process consists of (a) developing new (or adapting existing) interventions for substance-using populations, (b) specifying a process for determining the efficacy of interventions, (c) creating a network of treatment programs in which promising interventions may be tested, (d) disseminating positive research findings in userfriendly format, (e) training clinicians to deliver interventions with fidelity, and (f) providing technical assistance to clinicians and programs to facilitate adoption of these interventions in a timely manner. A series of events have facilitated these efforts (32). During the 1980s, methodological standards for pharmacological research became more rigorous; not surprisingly, the expectation for similar scientific rigor was applied to behavioral research.

Adoption of the “technology model” (33,34) was a critical step in improving how psychotherapy research is conducted, as it systematized the methods by which interventions were evaluated, increasing internal validity, generalizability, and replicability. In the 1990s, several landmark psychotherapy studies employing these rigorous methods emerged (35,36). However, these therapies were already close to fully developed prior to embarking on these large studies. A revised model was needed to encourage development of new therapies by supporting smaller studies that would encompass the earlier tasks of intervention development and refinement prior to large-scale efficacy testing (32). To remedy this situation and provide the financial support needed for earlystage treatment development, NIDA issued a Program Announcement entitled “Development of Theoretically-Based Psychosocial Therapies for Drug Dependence” in 1992 (37), thus officially launching the “Behavioral Therapies Development Program” (38). NIDA has renewed this Program continually, most recently with three program announcements extending from smaller early-stage (Stage I) intervention development (PA-16-073; PA-16-074) to larger Stage II and III efficacy and effectiveness studies (PA-16-072). The objectives of these funding opportunities include development, pilot testing, and standardization of both novel and adapted behavioral interventions for SUDs. Other objectives included identifying effective therapies for subpopulations that had been overlooked in prior research (eg, patients with substance and other co-occurring disorders), analyzing the effective “components” of interventions, determining mechanisms of action, and demonstrating that treatments developed in research settings with highly selected patients and expert therapists would “transfer” to real-world drug treatment programs. The behavioral therapy development process (39,40) is divided into three discrete stages, summarized in Table 65-1, analogous to the familiar Phases I, II, and III of medications development research.

TABLE 65-1 Stage Model for the Development of Behavioral Therapies

Adapted from National Institute on Drug Abuse. Behavioral & Integrative Treatment Development Program. 2013:NIDA Pub Number: PA-13-077.

Stage I: Initial therapy development and pilot testing: Stage I includes the preparatory tasks that need to be completed before efficacy testing begins. During Stage I, psychotherapy researchers plan the treatment and draft a treatment manual that will be used to train clinicians to deliver the intervention. In Stage I, the intervention is piloted, usually in small uncontrolled or controlled pilot trials, and revised according to this initial clinical experience. During Stage I, the treatment development team establishes protocols for training and certifying therapists as competent to deliver the intervention; they also develop

fidelity rating scales designed to assess the extent to which the psychotherapists are adhering to the treatment protocol and delivering the therapy exactly as envisioned. The treatment manual, training materials and procedures, and methods for measuring fidelity and for supervising the ongoing delivery of the therapy represent the essential basic elements for an empirically based therapy, ensuring that the treatment can be reliably replicated. Stage I also provides a potential stopping point for those interventions that lack sufficient promise. This is important because efficacy trials are costly and should be avoided if an intervention seems to have little chance of yielding positive effects. Key questions at the end of Stage I include the following: (a) is the treatment tolerable and feasible? (ie, are the patients favorably inclined toward the therapy and willing to participate?), (b) is the therapy replicable? (ie, is it possible to train clinicians to deliver the therapy as envisioned and to reliably measure its delivery?), and (c) does the therapy show promise of effectiveness, based on clinical outcomes from preliminary and pilot studies? Negative answers to one or more of these questions might prompt the therapy development team to rethink the treatment or abandon it altogether. The NIDA Program Announcement was a landmark development for the field, because it provided a mechanism for funding Stage I work. As a result of this initiative, a large cohort of Stage I projects was funded, several of which have developed into therapies that have proven effective, advancing through Stage II and III trials. Stage II: Efficacy: Stage II represents formal efficacy testing of psychotherapies showing promises during Stage I pilot testing. Also during Stage II, “mechanisms of action” (ie, therapeutic processes that contribute to treatment outcomes) are identified by examining moderators and mediators suggested by theory underlying the therapy. As efficacy research, Stage II studies generally address the question of whether the therapy is beneficial when delivered under ideal circumstances. Thus, Stage II trials typically take place at one or several clinical sites that are experienced research centers where the therapy is delivered by relatively expert therapists, under the close supervision of the developers of the therapy. The patient samples typically are carefully selected to represent the sample targeted by the intervention, and the sample size is sufficient to detect the sorts of small- to medium-range effect sizes that can be expected from behavioral interventions (usually at least 100 study participants or more). Stage II designs typically are randomized, controlled trials that involve a carefully specified control group, which is often controlled for attentional bias— that is, the control condition is delivered by therapists with similar expertise, under similarly careful supervision. Stage II represents another decision point

where a therapy development effort might be advanced, rethought and reworked, or abandoned if not showing sufficient promise. An intervention that produces a statistically and clinically significant beneficial effect would be considered appropriate to advance to Stage III testing. Or, a Stage II study might indicate that a therapy should be further modified before moving to Stage III, perhaps through more Stage I or II work. Stage III: Effectiveness in real world treatment settings. The goal of Stage III research is to evaluate the generalizability and ease of implementation of treatments that have been shown to have efficacy in Stage II trials. The key question addressed in Stage III, or what are known as effectiveness trials is: How does the therapy work when delivered in real-world, community-based treatment programs (CTPs) and settings when delivered by community-based clinicians? This addresses the ultimate public health impact of the new intervention. Like Stage II studies, Stage III studies typically are randomized controlled trials; however, eligibility criteria are more open for both patients and therapists. In community-based treatment, a therapy needs to be effective for the types of patients that present for treatment, including those who have more medical, psychiatric, and substance comorbidity than would be ideal for a Stage II clinical efficacy trial. Stage III research also needs to evaluate how the therapy will work in the hands of the range of therapists that work in community settings, including those who may have less or more varied backgrounds, training, or expertise than do the research therapists working in Stage II clinical trials. The designs of Stage III trials need to select control groups that will address the practical utility of the therapy. Hence, control groups in Stage III trials typically represent some form of treatment as usual (TAU). In this way, the design answers questions of practical utility to program managers and payors such as… “How much benefit will the new therapy yield when added to the treatment we currently are delivering at our treatment program?” or …“when substituted for the treatment we currently are delivering at our treatment program?” (41). In addition, Stage III research may include an economic or cost-effectiveness analysis, yielding important information for program directors and payors, who must make business decisions about whether or not to implement a new treatment. Stage III studies typically are multisite trials, in order to draw from a representative sample of the treatment programs (42). Sample sizes typically are large, in order to account for potentially smaller sample sizes that result from the greater variation in patients, clinicians, and settings and to be able to understand how these sources of variation may impact the effectiveness of the intervention (moderator and mediator analyses). However, the benefit of effectiveness trials is

greater generalizability of the findings (external validity) compared to the more restricted generalizability of RCTs that have smaller samples of greater internal homogeneity as seen in Stage II studies. To summarize, Stage III studies provide evidence of effectiveness of new therapies in less controlled environments and with a wide range of patients and therapists. If the therapy produces positive results under these conditions, program managers and clinicians can be more confident that a particular treatment is worthy of being considered for implementation, and informed of the costs involved. Several other federal initiatives have had a major impact on the development and dissemination of treatments for SUDs. In 1999, NIDA established the Clinical Trials Network (CTN), a nationwide network of research centers and associated treatment programs dedicated to testing new treatments through multi-site trials in real world treatment settings (ie, mainly Stage III work). The goal both test effectiveness and promote dissemination of effective new treatments into the treatment system. Since its inception, the CTN has completed over 30 multisite studies. A number of these studies have focused on behavioral interventions, including those testing the effectiveness of Motivational Interviewing (43,44), Contingency Management (45,46), Brief Strategic Family Therapy (47), Seeking Safety (48), 12-Step Facilitation (49), and Drug Counseling in the setting of buprenorphine treatment for prescription opioid use disorder (50). Implementation: Once a therapy has been determined to be effective, the next step is dissemination throughout the larger drug treatment community. One analysis found the lag time between the determination of effectiveness of a treatment and its widespread implementation in clinical programs is ~17 years (51). This is an unacceptable delay and reflects the challenges of so called technology transfer. Treatment manuals and didactic sessions (eg, lectures or workshops) may increase awareness and knowledge of new therapeutic methods, but generally do not change the practice. Rather, for new therapy methods to be implemented, clinicians need training that involves practice with feedback and coaching (52). Barriers at the level of treatment systems, including reimbursement and other incentives, also need to be overcome. The challenges of implementation and technology transfer are discussed in more detail in the concluding sections of this chapter.

COMMON ELEMENTS OF EFFECTIVE

BEHAVIORAL THERAPIES A number of behavioral or psychotherapeutic treatment approaches have been developed that have strong evidence of efficacy and/or effectiveness from clinical trials. These are briefly summarized in Table 65-2. Examination of this range of therapeutic approaches suggests a set of common elements that are useful to understanding the psychotherapeutic approach to treating SUD (4). These common elements include:

TABLE 65-2 Summary of Evidence-Based Behavioral and Psychotherapeutic Approaches to Substance Use Disorders

Focusing directly on substance use Enhancing motivation to change Building coping skills Changing reinforcement contingencies Managing painful affects Improving interpersonal functioning Fostering a treatment alliance. While different treatments may approach each of these elements somewhat differently, the weight of the evidence suggests these represent essential

dimensions of effective treatments for SUDs.

Focusing Directly on Substance Use Effective behavioral and psychotherapeutic approaches for SUD generally maintain an overt focus on controlling and ameliorating substance use. Even when the immediate focus of a session may be outside of substance use, the underlying agenda is always the substance problem. For example, in MI, the therapist may “roll with resistance” and change the subject to something else (eg, job functioning, family relationships), but the agenda is to increase the patient’s awareness and understanding of how substance use may be affecting his/her functioning in those areas and to help him/her circle back to a direct focus on the substance problem. Likewise, in cognitive–behavioral relapse prevention or the CRA, a session might be focused on managing painful affects or conflict in relationships, but the reason is that these represent stresses that are likely to engender substance use.

Enhancing Motivation to Reduce/Stop Substance Use and Adhere to a Treatment Plan Addiction is fundamentally a disorder of motivation. Addictive substances interact with the brain reward system and function as positive reinforcers, creating a natural drive to partake. Clinically, this manifests as cravings and repetitive use. Conversely, patients present to treatment because of the adverse consequences of substance use, which create the wish to cut down or quit. These opposing desires to both use and quit create a state of ambivalence, which is typical of patients seeking treatment for SUDs. This manifests as efforts to reduce substance use, punctuated by cravings, lapses and relapses, and/or fluctuating engagement with treatment. For example, patients may miss treatment sessions, fail to carry follow through with parts of the treatment plan (eg, homework), or avoid discussing substance use during sessions. They also may express the wish to cut down or control their substance use without stopping altogether; that is, they may seek to continue to enjoy the positive effects of substances, while minimizing the adverse consequences. Any psychotherapeutic or behavioral approach to treating a SUD must address these variations. MI provides a tactical and strategic persuasion method for talking

with patients with the goal of enhancing their internal motivation to quit substance use. MI can be viewed as a fundamental skill, which clinicians can implement any time motivation for treatment wavers. (For a more detailed look at MI, see the Chapter on Enhancing Motivation to Change in Section 8.) Other approaches, such as individual drug counseling (IDC) or medical management (MM), provide direct advice from the therapist to quit, which can be powerful when coming from someone who is respected as an expert. Contingency management (CM) strategies, where concrete rewards or punishments are established contingent upon substance use (or treatment participation, etc.), can enhance external motivation in the absence of internal motivation to change. Cognitive–behavioral approaches, such as relapse prevention or the CRA, seek to render more salient the adverse consequences of substance use on the one hand and alternative sources of satisfaction and reward on the other, which, in turn, should have an impact on patients’ decisions to use versus abstain. Thus, while MI is considered the preeminent intervention for enhancing internal motivation and “readiness” to change drug use behavior, other therapies for SUD also have the capacity to evoke motivation, albeit by different methods and means.

Coping Skills to Avoid Substance Use and Change Lifestyle Whether patients are struggling to achieve initial abstinence, avoid relapse, or effect other lifestyle changes that will improve their prospects for a long-term recovery, they generally need to be taught skills and strategies to achieve these ends. AA and other 12-step groups can be viewed as conveying such a set of skills (eg, practicing acceptance, maintaining focus on abstinence, avoiding “people, places, and things” associated with use, wariness of strong emotions, taking “a day at a time”). Cognitive–behavioral approaches focus specifically on skills building, providing practice, both in role-plays within sessions and through homework assignments between sessions. Similarly, CRA focuses on building social, recreational, and occupational skills, again through practice and homework.

Changing Reinforcement Contingencies Addictive substances function as reinforcers, becoming increasingly salient and predominant as a SUD progresses. As a patient’s behavior increasingly falls

under the control of the substance, more time is spent seeking out and using the substance while normal or healthy sources of reinforcement are displaced, such as family, friends, recreation, work, and even food and sex. Thus, an effort to reconnect a patient with his or her former sources of healthy reinforcement may help to combat the reinforcement value of substances, resulting in reductions in drug use. When a patient with a SUD achieves abstinence, this often leaves a gap, since important areas (ie, family, friends, work, and recreation) often have been forsaken during extended periods of drug use. In order to reduce the likelihood of relapse, such patients need to literally rebuild their lives by reestablishing their networks of family and friends. To this end, MI focuses on what a patient values in life and how substance use conflicts with those values; for instance, if family relationships are important to a patient, but substance use has contributed to the patient becoming alienated from his/her significant others, this discrepancy could be a focus of MI. CRA specifically emphasizes engagement in healthy social and recreational activities and relationships and teaches skills (eg, conflict resolution) to foster growth in those areas. CM provides concrete monetary rewards for avoiding substance use, often in conjunction with CRA. Rewards likewise can be given for engaging in prosocial behaviors, such as socializing and other forms of drug-free recreation.

Managing Painful Effects and Stress Stress is a risk factor for the development and progression of substance use and use disorders; furthermore, dysphoric affects can contribute to relapse. Thus, patients with SUD need to learn to recognize, label, and tolerate painful affects as part of the recovery process. A number of evidence-based approaches address painful affects. Supportive Expressive (SE) therapy focuses on helping patients to feel comfortable recognizing and expressing their feelings and understanding the relationship between their emotions, substance use, and problematic relationships. MI stresses the fostering of empathy; patients are encouraged to experience and share their feelings, which are reflected back by the clinician so that the patient feels understood. Cognitive–behavioral approaches, such as relapse prevention, CRA, or dialectical behavior therapy (DBT) (53), teach explicit skills for tolerating and managing strong affects similar to those conveyed by versions of CBT developed to treat depression or anxiety disorders. AA and systematized 12-step approaches like IDC also recognize and label the role of strong affect in substance use and relapse, encourage sharing and discussion of feelings at meetings, and provide coping skills (eg, the concepts of acceptance and serenity) to help deal with problematic emotions.

Improving Interpersonal Functioning and Social Support Individuals with SUD have often damaged or lost contact with positive social networks (eg, divorce, alienation from family and friends, loss of connection to social groups and activities), with any remaining relationships revolving around others who also are unstable in recovery or actively using (eg, “drug buddies”). Absence of positive social support can interfere with efforts to recover from SUDs. To enhance interpersonal functioning and improve support, CRA places an emphasis on social skills building by helping patients rebuild and reengage in their social networks. Further, when CRA is combined with CM, patients are encouraged to spend the monetary rewards they earn by engaging in a social activity with family or friends (54). The functional analysis component of cognitive–behavioral approaches often identifies social settings that promote substance use, affording the clinician an opportunity to teach skills to avoid those particular situations and substitute healthy ones instead. MI seeks to help patients become more aware of the relationships they have damaged/lost but would like to reestablish, and to foster self-efficacy to reengage. Approaches like network therapy that involve the family in a supportive way provide an in vivo opportunity for relationship repair work to begin. It is well known that, for some individuals, attendance at 12-step meetings (and sponsored events) can become an important part of their social life; individual treatments that encourage the 12step approach (eg, TSF, IDC) likewise are promoting development of a support network as one of the main objectives.

Fostering the Treatment Alliance Treatment alliance refers to the collaborative relationship that develops between the patient and therapist. It is measured from both the patient’s and therapist’s perspectives using questionnaires such as the Helping Alliance Questionnaire–II (HAq-II) (55). Alliance is composed of three components—that is, shared goals, tasks, and emotional bonds (56)—and accounts for as much as 15% of the variance in treatment outcomes (57). A common mediator of effectiveness of treatments across a wide range of therapies and disorders (58), treatment alliance affects treatment retention, completion, and outcomes among patients with SUD (59). While all psychotherapies acknowledge the importance of a good therapeutic relationship, some focus more intently on this element, namely, those that are more emotionally based (ie, SE therapy and MI). Nevertheless, across

therapies for SUDs, it is necessary for the therapist to monitor the extent to which the patient is engaged in the therapy and to address therapeutic lapses in a nonjudgmental fashion. While breaches in alliance generally are seen as a patient problem, one study found that therapist alliance scores (on the HAq-II) are associated with poorer patient outcomes, even when patient alliance scores are high (60).

OVERVIEW OF EVIDENCE-BASED PSYCHOTHERAPIES FOR SUBSTANCE USE DISORDERS This section provides an overview of individual treatments for SUD that have evidence of efficacy or effectiveness from substantial controlled clinical trials (Table 65-2). Most of these approaches are covered in detail in other chapters in Section 8, the “Behavioral Interventions” section of this volume. Treatment manuals and training materials are available from SAMHSA (http://mentalhealth.samhsa.gov/cmhs/CommunitySupport/toolkits/community). Here we provide a brief synopsis of each intervention and its supporting evidence so that the reader may compare and contrast the approaches and consider how the menu of available therapies might be worked into individual treatment plans or organized treatment programs.

Motivational Interviewing and Motivational Enhancement Therapy MI is a way of approaching and talking to patients that is designed to increase their commitment to reducing or stopping substance use based on tapping the patient’s intrinsic motivation for change and taking the steps necessary to do so (20,21). MI can be viewed as an essential therapeutic skill, to be employed during the initial contact and evaluation of a patient and redeployed periodically whenever a patient’s motivation wavers during treatment. MI can be used either as a stand-alone intervention or as a prelude to another treatment such as CBT. MI is founded on guiding principles, called the “spirit” of MI, namely, collaboration, evocation, and respect for the autonomy of the patient. The most recent formulation of MI also includes acceptance of the patient for who he or she is and empathy as an essential stance of the therapist (21). Collaboration

means that the clinician avoids taking on the role of an authority figure (eg, teacher, expert) but rather creates a sense of partnership with the patient. Evocation means that the clinician makes an effort, partly through the concerted use of open questions, reflections, and reflective listening, to get the patient talking about his or her life and what he or she values. By expressing genuine curiosity and openness to the patient’s experience and values, the clinician builds and communicates empathy. Respect for autonomy means that the clinician makes it clear that the patient is making the decisions about whether and how to change; additionally, the clinician supports the patient’s self-efficacy to change. However, MI is not simply an empathic, exploratory interview. It is tactical and strategic, seeking to guide the patient toward change. MI is not a sales technique in the sense of trying to sell the patient on what the therapist or others may want. However, in common with a good salesman, a therapist practicing MI tries to understand and draw out what the patient most values in order to help the patient find the outcome that will be most valuable and useful to him/her. MI prescribes a set of interviewing skills, which include open questions, reflections, affirmations, summarizations, and avoidance of statements that run counter to MI principles (eg, confrontation, argumentation, or unsolicited advice). Simple reflections are statements made by the therapist that reflect back to patient what the therapist has been hearing—as a way for the therapist to check with the patient that he or she has understood what has been said; reflections convey genuine interest and curiosity, thus building empathy. Complex reflections go beyond simply reflecting, by also expressing some level of inference—that is, by probing for things the patient may not have said directly and thus gently moving the patient toward change. Another tactical strategy, “developing discrepancy,” consists of trying to help the patient become more aware of divergence between the things he or she values and how substance use interferes with attaining these things. Reliable measures of MI therapist behaviors have been developed—for example, motivational interviewing training instrument or MITI (61,62), which can be used to rate the skill of clinicians and provide feedback to them as part of supervision. Thus, MI has the fundamental features of therapy technology, namely, treatment manuals (the Miller and Rollnick texts and other training materials), as well as a reliable method for measuring performance and for training and supervising clinicians. MI therapists also are trained to recognize, elicit, and respond to “change talk.” Change talk consists of statements by the patient that reflect one or more of desire, ability, reasons, need, and commitment (DARN-C) to change their substance using behavior. An instrument to measure DARN-C statements by

patients has been developed and can be used to help train clinicians to recognize change talk. In particular, commitment talk, a clear expression of intent to do something to change—for example, “I have set my quit date for tomorrow,” has been shown to be a strong predictor of good outcome among patients with SUD (63). Hence, an important tactic is for the therapist to recognize and reinforce change talk whenever it occurs. While MI represents a style of interviewing that may take the interview in a variety of directions depending on what the patient brings to the session, MET is a manual-guided approach that is more structured and includes giving patients feedback on their substance use behaviors and other structured activities aimed at enhancing motivation. Motivational interviewing approaches (both MI and MET) have been shown to be effective in multiple randomized trials for a wide range of substance problems and related health behaviors (21,64). The evidence is stronger for nicotine and alcohol use disorders though less consistent for drug use disorders (32,44). The mixed results found for some populations suggest what may seem self-evident, namely, that a single or limited set of MI or MET sessions may be insufficient to effect much change, particularly among patients with more severe SUDs, comorbidity, or disorganization. This suggests the strategy of combining MI or MET within a larger treatment plan, including other evidence-based approaches. For more on enhancing motivation to change, see Chapter 63, “Enhancing Motivation to Change” in Section 8.

Brief Advice Any encounter between a clinician and a patient represents an opportunity for therapeutic effect. While not an elaborate psychotherapy method, brief advice from a clinician, such as a physician, has been shown to be beneficial in influencing patients to reduce alcohol use (65,66), and thus is important to include in this overview of individual psychotherapeutic interventions. In a busy clinical setting, with limited time for encounters with patients, brief advice has obvious advantages. In some respects, brief advice seems a polar opposite to MI. MI instructs clinicians to avoid the role of expert or authority figure, to forego giving direct advice, and to take a more collaborative and exploratory approach. However, clinicians (particularly physicians) command respect in our society. Thus, simple advice from a physician is likely to be salient, and the evidence suggests it can be beneficial in reducing substance use. Brief advice also can be reconciled with, and understood within, the context of the theory of MI. MI does not necessarily proscribe advice giving; rather, it recommends that advice giving

needs to be done in the context of an empathic relationship. One concrete strategy of MI is to ask for a patient’s permission before giving advice—for example “Would it be OK with you if I let you know what I’m thinking about your drinking?” This maintains the collaborative nature of the interaction and respects the patient’s autonomy, by asking the patient’s permission.

Supportive–Expressive Therapy As previously noted, in the early years of psychotherapy development, psychoanalytic therapy was attempted with patients with SUD with limited success. Going forward, treatment development went in a more behavioral direction, with few dynamically oriented interventions for SUD being systematized—that is, with treatment manuals, methods of training, and measuring therapist performance. One exception was supportive–expressive therapy. SE psychotherapy (67) is a time-limited therapy that was adapted for use with patients with both cocaine and heroin (opioid) use disorder. It represents an effort to apply psychoanalytic and psychodynamic principles in a systematic way to the problem of SUD. Drug use and efforts to quit are viewed in relation to the patient’s relationships and intrapsychic world. The patterns that are identified are viewed either as triggers for relapse or as linked to avoidance of appropriate actions needed to achieve sobriety, rather than as direct causes of SUD. Emphasis is placed on development and maintenance of the therapeutic alliance. SE has two main components. The first employs supportive techniques to assist patients in feeling comfortable discussing their feelings and life experiences while addressing the role that drugs have played with regard to problematic feelings and behaviors. In this phase, the therapist focuses on developing a helping relationship with the patient and on identifying and bolstering the patient’s strengths and areas of competence. The second component involves the use of expressive techniques to help the patient understand and work through relationship issues. To achieve this goal, the therapist employs reflective listening, evaluative understanding, and responding to identify problematic patterns in relationships with others. SE helps patients explore the meanings they attach to their SUD and address their relationship problems more directly, thus allowing them to develop better solutions to life problems than drug use. The SE treatment model for SUD is based on Luborsky’s standard SE model (67); however, a more detailed treatment manual is available, which includes adaptations specifically for cocaine users (68). These adaptations were made

when SE was employed in the Collaborative Cocaine Study, described below. Clinical trials testing the effectiveness of SE among patients with SUD have generated mixed results, with some evidence of efficacy. In the NIDA Collaborative Cocaine Treatment Study (31), patients received group therapy (ie, group drug counseling); three of four study groups also got individual psychotherapy—that is, SE therapy, IDC, or Cognitive Therapy (CT). SE (plus group therapy) was associated with reduced cocaine use, but was not superior to the control group, which received group therapy only. Furthermore, IDC produced significantly greater abstinence from cocaine than either SE therapy or CT (31). Among patients with opioid use disorder maintained on methadone pharmacotherapy, those with high psychopathology who received 6 months of SE therapy or CBT in addition to traditional drug counseling achieved better outcomes than did those receiving drug counseling only, although drug counseling was beneficial for those with lower levels of psychopathology (24). A second study found that clients in three methadone clinics who received SE required lower doses of methadone than did those receiving standard drug counseling; not only did they maintain their gains after 6 months of treatment, they also continued to improve compared to those receiving drug counseling only (25).

Cognitive–Behavioral Approaches: Relapse Prevention and Coping Skills Therapies Cognitive–behavioral relapse prevention and related approaches are based on the premise that the development and continuation of substance use is a learning process (15–17). Accordingly, the therapy is founded on a “functional analysis,” where the sequences of thoughts, feelings, behaviors, and circumstances that lead to substance use for a given patient are reviewed and understood. The therapist then introduces coping skills to promote the unlearning of these maladaptive patterns and to substitute more adaptive patterns that will oppose and prevent substance use. This is a structured, time-limited (usually 8-12 weeks in duration), goal-oriented treatment, which can be flexibly adapted for a variety of individual obstacles, skill deficits, settings, and formats. Specific foci of CBTs include recognizing triggers that lead to substance use (eg, places, persons, or particular emotions), avoiding high-risk situations, and coping with cravings. Skills that are taught and rehearsed include drug refusal skills (literally, how to respond when someone asks the patient to use substances), decisional delay (putting off a decision to use for a brief period—eg, 20 minutes during which

time the desire often goes away), and talking oneself through cravings. Patients also are taught to recognize, tolerate, and counteract painful feelings (eg, sadness or worry), much along the lines of skills conveyed in CBTs for depression or anxiety disorders. In addition to role-plays during sessions, patients typically are given homework and instructed to practice particular skills in real life between sessions. Cognitive–behavioral relapse prevention and related approaches, such as coping skills therapies, have extensive evidence from clinical trials supporting efficacy among patients with DSM-IV defined nicotine-, alcohol- (69), and cocaine-dependence (70). One interesting feature of cognitive–behavioral approaches is that the outcome data often show a “sleeper effect,” namely, that the beneficial effect on substance use builds over time after the treatment has been completed; that is, at long-term follow-ups, the treated group often continues to evidence further reductions in substance use, while control group does not (70,71). This suggests that, as intended, the patients have learned skills that must be exercised and practiced to sustain a beneficial effect, even after treatment had ended. Chapter 73 “Relapse Prevention: Clinical Models and Intervention Strategies” in Section 8 explores relapse prevention and further discussion of cognitive–behavioral approaches to treatment of SUDs.

Community Reinforcement Approach CRA is a cognitive–behavioral approach that places greater emphasis on examining the reinforcers in a patient’s life and helps the patient to reengage and reconnect with healthy sources of reinforcement (eg, family, friends, work, and recreation) (18). The theory is that this will interfere with and replace drugseeking behaviors, which are under the control of reinforcement by the drugs or alcohol. CRA involves teaching patients to conduct a functional analysis so that they can better understand their drug use and problem solve ways to decrease the probability of substance use going forward. Other key skills include selfmanagement planning and drug refusal skills, much like in other CBT approaches. Another component of CRA involves encouraging patients to engage in healthy sources of reinforcement to include vocational and recreational activities, as well as positive relationships. CRA often has been combined with CM in which voucher-based rewards are used to enhance abstinence (54). These two approaches seem synergistic, as the vouchers provide concrete rewards within the therapy, while the CRA attempts to foster rewards within the patient’s life outside of therapy.

Contingency Management CM seeks to directly harness the principles of reinforcement and behavior modification by making concrete rewards or punishments contingent upon some key target behavior (72). The target behavior usually has been abstinence from substances as confirmed by urine testing, but other targets (eg, attendance at therapeutic activities) also can be reinforced. The basic principle is that contingent rewards or punishments will help reduce the likelihood of substance use and help patients achieve and sustain abstinence. The key principles of this approach, derived from theory of learning and behavior modification, include the following: (a) the target behavior needs to be well defined and measurable; and (b) the reinforcement should be well defined, delivered as immediately as possible upon production of the target behavior, and be as salient (or valuable) to the patient as possible. CM has been applied effectively for drugs such as cocaine, heroin, and cannabis, where use over the last several days can be readily detected in urine (46,73–75). Alcohol can be detected in blood, urine, or breath but washes out of the system quickly. Thus, while CM with rewards contingent on negative breath testing has some evidence of efficacy (76), false negatives are more likely, defeating the requirement for accurate detection of use. Recently, ethyl glucuronide (EtG), a metabolite of alcohol that is longer lasting, has been used successfully as the basis for a CM intervention for alcohol use disorder (77). In addition to toxicology results, treatment plan adherence (eg, carrying out verifiable homework assignments, attendance at groups) is readily verifiable and also has been tested in clinical trials (78,79); this may be a more natural application of CM when adapted to community-based practice (80). Similar examples of incentives for program participation can be seen in the business world, an example being frequent flyer miles offered to airline passengers. When employing CM based on results of urine testing, direct observation of urine collection is ideal in order to avoid patients adulterating or substituting specimens. However, while direct observation typically has been employed in efficacy trials, this can be a barrier in community-based treatment where bathrooms often are too small to accommodate both patient and observer, where same-sex staff may be unavailable to conduct observation, and/or where clinic staff may be too embarrassed to observe patients urinating. To overcome these obstacles, many urine collection systems now incorporate tests for detecting falsification based on temperature or concentration. Another caveat when using results from urine testing to determine whether or not to reinforce a patient who is on a CM protocol is to make sure that the urine testing method will in fact

detect the drugs that are the target of the intervention. Contingent reinforcement can consist of rewards such as vouchers that are exchangeable for actual dollar amounts contingent on negative urines (81,82) or access to a workplace where wages can be earned (83) or punishments to include loss of methadone take-home privileges or threat of arrest and incarceration—an incentive often inherent in drug courts and other alternative sentencing programs. Principles of learning suggest that positive reinforcement tends to produce behaviors that are more durable and generalizable beyond the immediate context. Hence, many of the most successful CM treatments have worked with rewards, often on an escalating schedule, where the magnitude of the reward increases with each consecutive negative urine; this procedure is intended to shape prolonged periods of abstinence on the theory that sustained abstinence is the most valuable clinical outcome. Principles of learning also suggest that the impact of a reinforcer will be proportional to its magnitude; thus, it is not surprising that larger monetary rewards produce more abstinence (84). This has led to one of the key barriers to widespread implementation of CM, namely, the problem of how to finance the rewards. Typical reinforcement schedules in clinical trials have allowed patients to earn around $1000 for 3 months of sustained abstinence. In response to this problem, Petry et al. developed a lower-cost voucher regimen that involves rewarding patients not with set monetary vouchers but rather with opportunities to engage in a sort of lottery where what is earned are draws from a “fish bowl;” only some draws yield prizes, most of small magnitude, with a few of larger magnitude, whereas other draws simply yield praise (“good job”). This “fish bowl” model has shown strong evidence of both efficacy and effectiveness in community-based treatment settings (46,85). Among psychotherapeutic and behavioral treatments for SUDs, CM has shown the most consistent and strongest evidence of efficacy compared to control conditions, at least during treatment (74). Response tends to be bimodal; however, some patients (usually around 50% of the sample) rapidly achieve and sustain abstinence, whereas the remainder produce little or no abstinence and earn few or no vouchers at all. This raises one immediate question for future research, which is how to better understand which patients will respond to incentives and how to better help those who fail to respond. Another limitation of CM is that its impact tends to wear off, at least partially, when the treatment ends and contingencies are no longer in force meaning that some (but not all) successful patients will relapse (71). CM often has been combined with other treatment methods. As previously noted, CRA, with its emphasis on fostering

reinforcers in a patient’s environment, most commonly has been combined with CM. This approach (CRA + CM), originally pioneered by Higgins (54), has proven to be one of the most effective and consistently replicated treatments for drug dependence. The chapter entitled “Contingency Management and the Community Reinforcement Approach” in Section 8 presents a broader explication of the CRA + CM approach.

Individual Drug Counseling Although drug counseling was readily accessible to patients entering treatment for SUD in the 1970s, its active ingredients and efficacy were unclear. In an effort to learn more about “what good counselors do,” Woody et al. (24,31,86) studied them, both in outpatient drug-free and methadone maintenance clinics. This early work contributed to the development of IDC, one of the first sciencebased treatments for SUD. The IDC manual was developed for use in the Collaborative Cocaine Study and is available as part of the “Therapy Manuals for Drug Addiction” series (87). The first section of the manual is devoted to discussing the contribution of the 12-step approach to the IDC model. An overview of IDC, including a comparison to other approaches to treating SUDs, is provided. The IDC approach includes assessing the patient’s status prior to initiating treatment; recommendations include using the Addiction Severity Index (88), along with urine toxicology to ascertain abstinence. The role of the counselor, including developing alliance and proscribed behaviors (ie, those that should not occur during treatment), is described. The phases of treatment include (a) treatment initiation (targeting denial and ambivalence); (b) early abstinence (which focuses on advice for avoiding relapse such as “people, places, and things”), cravings, dealing with high-risk situations (all reminiscent of cognitive–behavioral approaches), and 12-step meeting attendance; (c) maintaining abstinence by addressing the potential for relapse, dealing with relationships while in recovery, living a drug-free lifestyle, encouraging spirituality, and dealing with character defects; (d) advanced recovery; (e) dealing with specific problems, including relapse; (f) counselor characteristics and training; and (g) counselor supervision. The IDC intervention incorporates the essential elements of the 12-step approach, while also addressing the important issue of intervention fidelity, thus allowing IDC to be compared with other evidence-based interventions for SUDs. The efficacy of IDC was demonstrated in the NIDA-funded Collaborative Cocaine Treatment Study (31) in which patients treated by drug counselors who

were trained and supervised according to the IDC manual produced superior rates of cocaine abstinence at follow-up compared to those who were treated with either CT or SE therapy administered by professional therapists; all patients also received group therapy. The results were surprising as IDC had been designated the control condition, with the hypothesis that the CT and SE interventions would be superior. The results show that high-quality drug counseling delivered by trained clinicians, 12-step meeting attendance, and a commitment to abstinence can make for an effective therapy.

Twelve-Step Facilitation Twelve Step Facilitation (TSF) therapy (89) is characterized as a guided approach to facilitating early recovery and is intended to give clinicians a tool to help their patients engage productively in AA or other 12-step groups. Clinical trials testing TSF are the closest of any research studies to testing the effectiveness of 12-step participation itself. TSF is an individual treatment that, by design, is brief (12-15 sessions) and structured. Like IDC, it is based on the principles of the 12-step program. The therapy focuses on two general goals, acceptance of the need for abstinence and surrender, which includes a willingness to engage in the 12-step fellowship as a means to achieving sobriety. These principles include acknowledging that addiction is incurable and that willpower is insufficient to achieve and sustain abstinence. In this model, it is considered necessary to surrender to the “group conscience.” The act of surrender also involves acknowledging that 12-step programs have helped millions of people to achieve and sustain sobriety and that the best chances at recovery come through following the 12-step path. Hope for recovery comes through recognition of loss of control and by having faith in a “higher power” (such as God or even the 12-step group). In this way, recovery is seen as a process of spiritual renewal. TSF counselors assess patients’ substance use, advocate for abstinence, explain basic 12-step concepts, and actively support and facilitate involvement in AA/NA. Counselors also discuss 12-step reading and share resources with their patients. The TSF manual incorporates material originally developed for Project MATCH, a clinical trial focusing on patient–treatment matching and funded by NIAAA. Project MATCH included two independent (but parallel) study arms, with patients recruited from both outpatient and aftercare programs and randomly assigned to TSF, CBT, or MET. When the data from Project MATCH were analyzed, only 1 of 16 of the hypothesized patient–treatment matches was

confirmed, challenging the idea that patient characteristics could be used to assign patients to alcohol treatments. Patients in all three treatments evidenced substantial improvements in their drinking behavior (from baseline) on the two primary outcome measures—percentage of days abstinent and number if drinks consumed on drinking days, with improvements maintained across the 3-year follow-up period (27). However, when examining total abstinence, which had been specified as a secondary outcome, patients who received TSF were significantly more likely to be abstinent at all follow-up points compared to those receiving CBT or MET; the magnitude of this difference was substantial, about 10% points, and was evident across the entire 3-year follow-up period. Thus, the intervention that focused most on abstinence (TSF) was more likely to produce long term abstinence in this landmark study. Recently, TSF was adapted for stimulant use disorders (cocaine or methamphetamine), and found to increase the likelihood of abstinence at the end of active treatment compared to TAU and to increase 12-step meeting participation (49), and 12-step meeting attendance was associated with better substance use outcomes (90). The advantage on abstinence diminished over long-term follow-up after the TSF intervention ended. It may be that the idea that behavioral interventions for SUD can be delivered as short-term, timelimited interventions is flawed, and that long-term interventions are needed for what is a chronic relapsing disorder. A treatment like TSF could be continued indefinitely, perhaps with a lower frequency of sessions.

Medical Management Manual-guided Medical Management (MM) interventions originally were developed to provide clinicians who were treating patients in pharmacotherapy trials with a standard, well-specified set of goals and talking points to cover during clinic visits. In a sense, this represented an effort to systematize what good prescribing physicians do during medication visits, analogous to the effort in IDC to define what good drug counselors do. Typically, clinicians are asked to systematically address symptoms, side effects, and medication adherence and to troubleshoot any problems in an empathic, supportive, nonjudgmental manner. In the setting of clinical trials for SUDs, MM interventions, in addition to focusing on medication adherence, monitoring side effects, and troubleshooting problems with adherence, also focus on abstinence as a goal and troubleshooting problems achieving or sustaining abstinence, sometimes recommending 12-step participation. In clinical trials examining combinations of medications

with psychotherapies, MM interventions have sometimes been used as control conditions. For example, an intervention called compliance enhancement therapy (K. Carroll and S. O’Malley, unpublished treatment manual, 1996) was used as the control condition in clinical trials, which showed that more elaborate behavioral interventions (eg, CM; significant other involvement) improved adherence with naltrexone treatment for DSM-IV defined opioid dependence (91,92). In another landmark study, the NIAAA-funded COMBINE (93), participants were randomly assigned to an enhanced behavioral therapy including aspects of MI and CBT or a Medication Management control called BRENDA (94) and also randomized to placebo, naltrexone, or acamprosate. While the expectation was that the enhanced behavioral therapy would improve the outcome of medication treatment, there was no main effect for therapy type; if anything, the best drinking outcomes were observed among patients who received MM plus naltrexone. Patients who seek to enter a medication trial probably are more favorably inclined to medication and may be less interested in psychotherapy. However, the results of this trial also could be interpreted as showing that the most essential elements of successful treatment for SUD may involve encouraging a commitment to abstinence and treatment adherence. See Chapter 75 in Section 8, “Medical Management Techniques and Collaborative Care: Integrating Behavioral with Pharmacologic Interventions in Addiction Treatment” for more detail on MM.

ROLE OF SIGNIFICANT OTHERS IN TREATMENT OF SUBSTANCE USE DISORDERS Several individual therapies for SUD involve family and significant others in the treatment in some way. For example, 12-step approaches ask members to “make amends” to family and friends who have been wronged, offer opportunities for significant others to attend “open meetings” with the patient, and provide family support through the 12-step family programs (eg, Al-Anon). CRA encourages patients to reengage with significant others as part of the effort to restore healthy sources of reinforcement. CRA also provides for more direct involvement of family members, for example, by having them monitor medication ingestion. Early work on CRA (95) outlined a strategy for disulfiram monitoring in which the patient, significant other, and therapist all agree that the patient will take his/her medication in the presence of another every day, at a scheduled time. The

significant other then thanks the patient for his/her adherence. If the patient refuses to take the medication, the significant other simply informs the therapist, and the matter is taken up at the next visit. Thus, the treatment remains focused on the patient with the SUD, but the significant other plays a concrete role designed to enhance the patient’s chances for success.

Network Therapy In the 1990s, Galanter (96) developed network therapy in an effort to harness the therapeutic potential of concerned significant others. In network therapy, the therapist employs tools of MI and cognitive–behavioral relapse prevention, but the unique aspect is that one or more significant others is directly involved in the treatment, also attending the therapy sessions. In contrast to family systems therapies, where there is an effort to diagnose and repair dysfunctional family systems, network therapy has more concrete goals. The significant others mainly are asked to support the patient’s treatment, for example, by understanding the treatment and its goals, helping with homework assignments (eg, practicing relapse preventions skills), delivering social reinforcers contingent on abstinence or treatment adherence (eg, a gift, meal, night out), and/or monitoring medication taking. During treatment sessions, the therapist seeks to support the integrity of the network by keeping patient and significant others motivated, by improving communication, and by diffusing any tension that may arise. Such tension is common and can function as a stressor that promotes relapse. Network therapy has been tested and found to be effective as an adjunct to buprenorphine treatment for DSM-IV defined opioid dependence (97); aspects of network therapy also have shown promise in promoting adherence to naltrexone treatment for opioid dependence (98). (For more information about network therapy, see Chapter 68 “Network Therapy” in Section 8 of this volume).

Community Reinforcement and Family Training Model In contrast to Network Therapy, where the family is involved in the treatment in a mainly supportive role, Community Reinforcement and Family Training (CRAFT) trains the family to be an instrument of therapeutic change. Specifically, CRAFT teaches significant others how to get their treatmentrefusing loved ones to engage in treatment (99,100). Unlike in planned “interventions,” where stakeholders (generally with assistance from a clinician

experienced with interventions) confront the person with the SUD with the goal of convincing him/her to go immediately to treatment, the CRAFT model steers away from confrontation. Instead, family and friends are taught to identify contexts in which substance use occurs, to make use of positive reinforcers, and to let the person with a SUD suffer the consequences of substance use without enabling him or her. Studies have suggested that 7 of 10 significant others using CRAFT can induce patients who are in denial to engage in treatment (101), while also improving their own emotional functioning, even if the individual with the SUD does not enter treatment.

Family Therapies In family therapies, the patient is the family unit. While an individual’s SUD may be the identified source of problems (the “identified patient”), there is an expectation that all family members will need to make changes to effect, support, and sustain positive changes in functioning within the family unit as a whole. Several family therapies for treating families that are dealing with a family member with a SUD have been tested and shown to have evidence of efficacy in controlled clinical trials (100–106). However, such family therapies have not been widely adopted in clinical practice. Barriers to implementation of family interventions in routine community-based treatment include the fact that these treatments often require a relatively high level of training and sophistication on the part of therapists, lengthy therapy sessions, and cooperation on the part of family members who often are reticent to participate (107). A recent large-scale effectiveness trial of Brief Strategic Family Therapy (BSFT), conducted by the NIDA-funded CTN, found limited effects of family therapy on short term outcomes (eg, adolescent drug use). In this trial BSFT was delivered by community-based therapists who were new to the method, although carefully trained and supervised during the study (47). This study highlights potential difficulties associated with transporting family systems therapy into broad clinical use. However, the study did yield some interesting findings. BSFT was associated with reductions in parental drinking and drug use, and the benefit of BSFT on adolescent drug use was greater when parents were drinking or taking drugs at baseline (108). BSFT was also associated with better outcome for adolescents in both drug use and functioning over long term (3- to 7-year followup) (109). The latter suggests that family therapy is an approach that can have a durable effect long after the intervention has been completed. More work is needed on how to successfully implement family therapy approaches in the context of routine community-based treatment for SUD (110). Gross et al., in

this volume, Section 8, discusses family interventions in SUD, and recovery in Chapter 71, “Family Involvement in Addiction, Treatment and Recovery.”

COMBINING INDIVIDUAL PSYCHOTHERAPY WITH OTHER MODALITIES: GROUP THERAPY AND MEDICATIONS Group Therapy It is common for patients with SUD who are receiving individual treatment also to be engaged in other interventions. The predominant treatment modality in most CTPs is group therapy, even though there is limited evidence from clinical trials as to its effectiveness. One reason for the popularity of group therapy is its lower cost, because multiple patients can be treated simultaneously by a single therapist. In the Collaborative Cocaine Treatment Study (31), all patients received Group Drug Counseling (GDC) as the background treatment; those who also received IDC had better outcomes compared to those receiving GDC only. Thus, in this trial individual treatment provided additional therapeutic benefits beyond those conveyed by group treatment alone. Similarly, a recently completed NIDA-funded study in the Clinical Trials Network (CTN) demonstrated the efficacy, among patients with stimulant use disorders, of a TSF intervention that consisted of a combination of group and individual formats (see above) (49). Thus, combining group therapy and individual therapy may produce enhanced outcomes and therefore should be considered. More evidence is needed to guide clinicians regarding which combinations of individual and group treatments are most effect and for which SUDs. Chapter 64 “Group Therapies” in Section 8 further explores the research and clinical basis for the use of group therapies in the treatment of SUDs.

Individual Therapy and Medications for Substance Use Disorders Several effective medications are available for treating SUDs, particularly for alcohol use disorder (eg, disulfiram, naltrexone, acamprosate, others) and opioid

use disorder (methadone, buprenorphine, injection naltrexone). Yet, these medications remain underutilized. Individual treatment sessions are a natural setting in which the potential benefits of medications could be discussed, encouraged, and supported; however, non-physicians may not be knowledgeable or comfortable enough to have this conversation with their patients. In addition, many drug treatment programs have limited medication options available to them (eg, only methadone for opioid use disorder) and may be resistant to adding others, especially when additional staff training and expense are involved. Another limitation is that many “unique” combinations of individual treatments and medications simply have not been tested, despite each treatment having shown evidence of efficacy as a stand-alone intervention. That said, several of the psychotherapies that have been reviewed in this chapter have been tested in combination with certain medications (eg, SE therapy with methadone (24,25), network therapy with buprenorphine (98), a version of Medical Management or a combined motivational and cognitive-behavioral intervention in combination with naltrexone or acamprosate (94), and Contingency Management plus Community Reinforcement Approach in combination with buprenorphine (111). Carroll et al. (112) reviewed a number of potential synergistic combinations between behavioral or psychotherapy and medication treatments, which may be considered during treatment planning. Their paper not only provides a roadmap of potential hypotheses to test in clinical trials but also can be used as a framework when tailoring treatment for a patient where pharmacotherapy is planned. These potential combinations and their rationales are summarized in Table 65-3. As can be seen in Table 65-3, there are a number of possible logical combinations, some of which already have been tested in clinical trials; other promising combinations also are suggested. While adherence to treatment is a general problem in the treatment of SUD, adherence to medications is a particular problem. Even agonist treatments like methadone or buprenorphine, which are inherently reinforcing, are accompanied by substantial dropout rates. However, MI could be employed to decrease ambivalence about medication taking. CM could identify medication ingestion as the target behavior and provide rewards contingent on ingestion. Following the CRA approach, or Network Therapy, family members could be enlisted in helping to monitor medication ingestion to improve adherence. Relapse after discontinuation of medications is common, and several therapies, including cognitive–behavioral relapse prevention therapy and TSF, focus specifically on this problem. Cognitive enhancement is a relatively unexplored area, but neuropsychological

deficits are common among patients with SUD (113) and have been shown to predict dropout from cognitive–behavioral relapse prevention (114). Thus, medications to improve attention and reduce impulsivity, such as those used to treat attention deficit disorder (ADHD), might be considered in conjunction with CBT-RP. For example, one substantial placebo-controlled trial among patients with ADHD who were receiving a version of CBT, showed that extended release mixed amphetamine salts (Adderall XR) increased abstinence compared to placebo (115). Further discussion of convergent and complimentary strategies for combining medication and behavioral treatments can be found in “Medical Management Techniques and Collaborative Care: Integrating Behavioral with Pharmacologic Interventions in Addiction Treatment in Section 8. Considerable work needs to be done in this area. Further, the only medications addressed in that chapter are those designed specifically to address SUD. Additionally, medications for psychiatric disorders like depression and anxiety must be considered as possible adjuncts to individual psychotherapy since unstable mood states and co-occurring mental disorders also can destabilize patients and contribute to substance use and relapse.

TABLE 65-3 Rationales for Combining Medications with Behavioral Therapies

DIFFERENTIAL THERAPEUTICS: HOW TO MATCH PATIENTS WITH THERAPIES

As in much of mental health therapeutics, choosing the best treatment for a given patient with a SUD remains more art than science in many instances. Most of the research studies testing individual treatments for SUD tests efficacy or effectiveness against a control condition. Moderator analyses, examining patient characteristics that predict good response to a specific treatment, are usually exploratory. One exception was Project MATCH, which specifically sought to generate information on matching of DSM-IV defined alcohol-dependent patients to one of three individual treatments (MET, cognitive–behavioral relapse prevention, or TSF) based on a broad panel of baseline characteristics. As previously noted, only one of the pre-specified matching hypotheses was supported by the data, although several secondary matching factors were identified. For example, MET was found to be particularly effective, compared to the other treatments, for angry patients. Angry patients may be irritated by being told what to do as in more directive therapies and, conversely, may be more responsive to the collaborative, person-centered approach of MET. In contrast, TSF was found to be particularly effective for patients whose social networks included other substance users, which makes sense, given that 12-step participation encourages access to a substance-free social network. In the absence of strong indicators for matching patients to specific treatments, a sensible approach is to make a best guess as to where to start, and then be prepared to switch interventions if the initial effort fails. For example, should an MET approach fail, one might consider switching to a more directive approach, such as TSF. Unfortunately, clinicians (and treatment programs) tend to offer just one or only a few predominant treatment methods in a “one-sizefits-all” approach. Clinicians or programs may ascribe strongly to a particular theoretical orientation, have limited training in other approaches, and/or lack confidence in their ability to deliver alternative therapies beyond those with which they are most familiar. Many clinicians have not been formally schooled in the evidence-based approaches described in this chapter; accordingly, they may be at a loss as to what to do next when their “go to” intervention fails to produce the desired results. In any case, many patients will fail to respond to the initial treatment to which they are assigned and thus will require recalibration. Clinicians should be prepared to deliver alternative interventions themselves or else refer their patients to other therapists who have different repertoires. Future research should examine adaptive approaches that regularly measure progress and provide opportunities for patients to switch treatments when the first treatment tried is not working. For this to occur, treatment programs must regularly assess for change among their clientele and must foster expertise

among their clinicians in a wider range of approaches, so that patients will have more treatment options available to them should these be needed.

VIRTUAL THERAPY AND COMPUTERDELIVERED TECHNOLOGY-BASED INTERVENTIONS Over the past decade, technology has played an increasingly important role in treatment of SUD. This includes evidence-based interventions that are conducted remotely via Skype, FaceTime, telephonic or videoconferencing methodology (often referred to generically as “telemedicine”) as well as those that are delivered by computer, tablet, or smartphone in the absence of a clinician. One advantage of all technology-assisted interventions is their potential to get more patients engaged in care. It is well documented that a large proportion of patients with SUD do not seek out or otherwise engage in treatment. The reasons for this are speculative, but likely include low motivation to change, stigma, high cost and/or limited availability of services. Technology assisted interventions can help to overcome these barriers by making treatment more accessible. In the case of virtual therapy, the treatment comes to patient to include rural and other underserved areas where services are lacking (116). Although clinical trials comparing outcomes for patients receiving virtual versus face-to-face therapy are lacking, a study of patients with alcohol use disorders who participated in an 8-week group-based video-conferencing intervention (117) demonstrated feasibility and acceptability with 14 of 18 patients (78%) attending at least four sessions—an attendance rate similar to what has been reported for face-to-face treatment. Patients liked the approach and found the treatment to be credible with 82% stating they would recommend it to a family member or friend. Evidence for efficacy was demonstrated in a Brazilian study (118) in which 524 cannabis users received a Brief Motivational Intervention (BMI) by telephone or reference materials. At 6-month follow-up, 73% of those in the BMI group were abstinent versus 59% of the control group although there was no significant difference found for motivation for change. While HIPAA compliance and crossstate practice restrictions (including licensure) must be considered when employing telemedicine, most can be resolved if clinicians are thoughtful when establishing their on-line practices. In the case of computer-delivered interventions, patients who are not yet

ready to seek out treatment may still be willing to complete a screening tool anonymously through the Web, including those that provide feedback and/or advice to change. Furthermore, to the extent that behavioral therapies, such as those reviewed in this chapter, can be automated, or portions of the therapies automated, this lowers barriers to implementation. If an intervention, such a cognitive behavioral intervention, can be delivered through a computer, or an “app” on a phone, then clinicians at a treatment program can prescribe the intervention and monitor patient participation. But the clinicians do not have to be trained and supervised in how to deliver the intervention, and do not need to spend the extra time delivering the intervention. This potentially lowers costs and conserves clinicians’ time for managing issues unique to each individual patient, while the computer delivers some of the routine behavioral programming. Prominent examples of such interventions supported by evidence of effectiveness from controlled trials include: (a) a computer-delivered version of Cognitive Behavioral Relapse Prevention for SUDs, CBT4CBT, which is delivered as seven 30- to 40-minute interactive, computer-delivered modules (119); and (b) a Web-based version of Community Reinforcement Approach plus Contingency Management, called Therapeutic Education System, which combines computer-delivered CRA counseling with a system for tracking target behaviors and rewards of a contingency management regimen (120,121). Other types of interventions take advantage of the ability of a smartphone to deliver text messages with therapeutic content (122). Smartphones and wearable devices can gather data from patients in real time (so called ecological momentary assessment), which can be put to therapeutic purposes. Although there is great potential among these emerging technology-based interventions, an important caveat is that many interventions and “apps,” although developed and marketed, do not have adequate empirical evidence to support their efficacy (123). Another barrier to implementation of technologybased interventions has been funding. The interventions have costs, and mechanisms for treatment programs to bill third parties and recover those costs have been problematic. Technology-delivered therapies for SUD are discussed further in Chapter 74 in Section 8 entitled, “Digital Health Interventions for Substance Use Disorders: The State of the Science.”

TECHNOLOGY TRANSFER: HOW TO

EFFECTIVELY TRAIN CLINICIANS TO DELIVER EVIDENCE-BASED PSYCHOTHERAPIES As the preceding review suggests, a number of different individual psychotherapy and behavioral therapy approaches for the SUD have been developed, which have proven effective in clinical trials. Yet, these treatments are not widely used in the community-based treatment system (124). Technology transfer refers to the process of taking a new technology, evidence-based psychotherapy in our case, and getting it into widespread use in the community. People and systems resist new technologies. Clinicians are no different. A fundamental precept of technology transfer is that clinicians need encouragement, feedback, and supervision in order to learn and successfully use new psychotherapeutic skills. Clinical trials among physicians have repeatedly shown that traditional methods of introducing new treatments (journal articles, lectures, and didactic symposia or workshops) may increase knowledge but do not get physicians to actually practice the new methods. Rather, what is effective in promoting use of new treatments are training methods that include feedback and supervision (52,125–127). This is the reason, for example, that pharmaceutical companies invest heavily in sales forces of well-educated representatives, who visit physicians and engage in “academic detailing”—that is, teaching physicians about their new medical product while also getting physicians to talk about their caseloads, try out the new treatment, and obtain feedback. The representative serves as a champion and coach for the new treatment. Unfortunately, in the field of SUDs, most training takes the form of conferences and workshops. This stands in contrast to the clinical trials of psychotherapies, where clinicians are trained on a treatment manual and receive regular measurement of their performance along with supervision sessions to help them hone and maintain their skills. Studies of methods for training community-based clinicians in MI have tended to confirm the lack of effectiveness of didactic workshops alone (127–129); when skill at MI interviewing was measured at follow-up points after workshop training, some improvement in knowledge can be observed, but little improvement in actual skill. However, in these training trials, clinicians who received ongoing feedback and supervision after the workshop did evidence increases in skill over time.

These findings suggest that efforts to disseminate new psychotherapies and other treatments for SUD into the treatment community should shift focus from didactic exercises to clinical supervision. During initial training (eg, psychology or social work graduate school and internship or physicians’ clinical clerkships and residency training), clinicians usually meet regularly with supervisors to go over cases and may even interview patients with supervisors present. Audio- and videotaping are common. However, this type of supervision often ceases once a clinician graduates and gets a job in a treatment program. Programs and their clinicians are under increasing pressure to see more patients and generate corresponding revenue; putting time aside for supervision sacrifices time that could be spent seeing patients. However, given the likely effect of supervision on quality of care, this probably is an investment worth making. Thus, treatment programs should be encouraged to set aside time for clinical supervision intended to introduce, build, and maintain new clinical skills. A related problem is how to make enough expert supervisors available to clinical programs and how to fund staff training and ongoing supervision efforts. Most psychotherapies have a small cadre of “experts” and certainly do not have anything like the large pharmaceutical companies that are able to fund, train, and deploy extensive sales forces. The NIH Institutes and SAMSHA have recognized this problem over the last several decades and have begun funding research on dissemination, as well as dissemination efforts themselves. Examples of these efforts include the Addiction Technology Transfer Centers (ATTCs) (http://www.attcnetwork.org/index.asp) and the Blending Initiatives (http://www.drugabuse.gov/blending-initiative) that have developed and disseminated training materials for interventions found effective in studies by the CTN. Mandates from government and third-party payors for delivery of evidence-based treatment also have created incentives for programs to adopt new treatment approaches. Technology-delivered therapies, reviewed in the previous section also have the potential to surmount barriers to implementation. The therapies reviewed in this chapter have the potential to improve the public health by improving the quality of care for patients with SUDs across the treatment system. However, in order for this impact to be realized, widespread adoption of these treatments will be needed, along with research to develop innovative methods of dissemination for promising treatments.

DEDICATION This chapter is dedicated to the memory of the late Dr. Bruce Rounsaville, our

friend, colleague, and previous author of this chapter. Bruce’s contributions to the field of psychotherapy research are extensive, dating back more than 30 years. He is best known for his work in developing and validating behavioral treatments for substance use disorders and for the “stage model” of psychotherapy development, which is described in this chapter. Dr. Rounsaville was the Director of the Psychotherapy Development Research Center and the Clinical Scientist Training Program at Yale University, where he served for many years as a Professor in the Department of Psychiatry. We all are indebted to him for his groundbreaking work.

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CHAPTER 66

Contingency Management and the Community Reinforcement Approach Sarah H. Heil, Danielle R. Davis, Christopher A. Arger and Stephen T. Higgins

CHAPTER OUTLINE Historical Perspective Treatment Model Treatment Planning Pretreatment Issues Treatment and Technique Empirical Support Conclusions Contingency-management (CM) interventions and community reinforcement approach (CRA) therapy for treating substance use disorders (SUDs) are based in the conceptual framework of learning and conditioning theory. Especially fundamental to these treatment approaches is operant conditioning, which is the study of how systematically applied environmental consequences increase (ie, reinforce) or decrease (ie, punish) the frequency and patterning of voluntary behavior (1). The approaches are also informed by the disciplines of behavioral pharmacology regarding the fundamental role of the reinforcing effects of substances in promoting SUDs and behavioral economics regarding the potential role of systematic biases in how humans make choices in complex environments and how they may increase the likelihood of SUDs and other health problems (2). In this chapter, we describe how SUDs are conceptualized within such a theoretical framework, describe the treatments, and review controlled studies on the efficacy of CM and CRA in the treatment of SUDs. These interventions have been researched most extensively with regard to treating alcohol, cocaine, and opioid use disorder, each of which is addressed in this chapter. Over time, CM and CRA have been extended to other forms of SUDs and to special populations (2,3). Those and other advances are reviewed as well. The review is restricted to controlled studies published in peer-reviewed journals unless otherwise noted.

HISTORICAL PERSPECTIVE Studying and conceptualizing SUDs within an operant conditioning framework began in earnest in the 1960s and early 1970s (4). Convergent evidence from studies conducted with laboratory animals residing in highly controlled

experimental chambers, humans with SUDs residing in medically supervised hospital settings, and humans seeking treatment for SUDs demonstrated the operant nature of drug use. In the studies with laboratory animals, for example, subjects fitted with intravenous catheters readily learned arbitrary behavioral responses such as pressing a lever or pulling a chain when the only consequence for doing so was the delivery of an injection of a drug that can promote unhealthy use (eg, morphine or cocaine). Effects were pharmacologically specific in that injections of drugs that humans rarely use in unhealthy ways (eg, chlorpromazine) or saline failed to generate or maintain responding. In some instances, the reinforcing effects of drugs like morphine and cocaine were so robust that they promoted in these laboratory animals the dangerous extremes in consumption characteristic of humans with SUDs. Monkeys given unconstrained opportunities to self-administer intravenous cocaine, for example, would consume the drug to the exclusion of basic sustenance, and barring experimenter intervention, to the point of death (5). Substitute saline for the cocaine and the animals would readily discontinue giving themselves injections (ie, responding extinguished). A robust body of evidence demonstrated that the drugs that humans commonly use in an unhealthy manner function as unconditioned positive reinforcers much as food, water, and sex do (4). The residential studies of humans with SUDs often examined the sensitivity of drug use to systematically administered environmental consequences. An elegant series of studies, for example, demonstrated the operant nature of alcohol use among those with severe alcohol use disorders (6). In this programmatic series of studies, participants resided on an inpatient unit where they were permitted to purchase and consume alcoholic drinks. Abstinence from voluntary drinking increased when (a) access to an alternative reinforcer (enriched environment) was made available contingent on doing so, (b) monetary reinforcement was provided contingent on abstinence from drinking, (c) the amount of work required to obtain drinks was increased, or (d) brief periods of social isolation were imposed contingent upon drinking. The studies provided strong evidence that even among individuals with severe SUDs, drug use was sensitive to environmental consequences. Initial studies with treatment seekers typically involved small-sample demonstrations that systematically applied consequences could improve treatment outcome. In a controlled case study, for example, breath samples were collected twice weekly on a quasi-random schedule from a male with severe alcohol use disorder (7). Baseline observations demonstrated a high rate of drinking. During the intervention period, the patient received a $3.00 coupon

book contingent on randomly scheduled alcohol-negative breath samples. Coupons could be exchanged for goods at a hospital commissary. After a discernible increase in the rate of negative breath tests during the period of contingent coupon delivery, the contingency was removed, and booklets were delivered independent of breath results. Under that condition, the frequency of negative specimens decreased toward baseline levels. Reimposing the contingency again increased the frequency of alcohol-negative breath results. Around this same time, several studies were reported suggesting that allowing participants to earn back monetary deposits contingent on objective verification of smoking abstinence improved outcomes among those trying to quit cigarette smoking (8,9). These studies illustrated the clinical implications of the emerging body of evidence supporting the operant nature of SUDs. Such studies provided the empirical foundation for a conceptual model, wherein drug use is considered a normal, learned behavior that falls along a continuum ranging from little use and few problems to excessive use and many untoward effects (4,10). The same principles of learning and conditioning are assumed to operate across this continuum. Within this framework, all physically intact humans are considered to possess the necessary neurobiological systems to experience drug-produced reinforcement and hence to develop drug use and SUDs. Genetic or acquired characteristics (eg, family history of alcohol use disorder, other psychiatric disorders) are recognized as factors that affect the probability of developing SUDs but are not deemed to be necessary for the problem to emerge.

TREATMENT MODEL Within an operant conceptual framework, reinforcement derived from drug use and the associated lifestyle is deemed to have monopolized the behavioral repertoire of the person with addiction. Treatments developed within this framework are designed to reorganize the user’s environment to systematically increase the rate of reinforcement obtained while abstinent from drug use and reduce or eliminate the rate of reinforcement obtained through drug use and associated activities. Primary emphasis is placed on decreasing drug use by systematically increasing the availability and frequency of alternative reinforcing activities either through relatively contrived sources of reinforcement as in CM interventions or more naturalistic sources as in CRA therapy (2,11). Additionally, arranging the environment so that aversive events or the loss of reinforcing events (ie, punishment) occur as a consequence of drug use also can

decrease drug use. As with reinforcement, such aversive procedures can involve relatively contrived (eg, forfeiture of a large-value incentive) or more naturalistic (eg, suspension from work) consequences. This distinction between CM and CRA with regard to the former’s relying primarily on contrived contingencies and the latter’s relying primarily on naturalistic contingencies will become clearer when the treatments are described in greater detail later. By contrived, we mean a set of contingencies that are put in place explicitly and exclusively for therapeutic purposes (eg, earning vouchers exchangeable for retail items contingent on cocaine-negative urine toxicology results). By naturalistic, we mean a set of contingencies that are already operating in the natural environment for nontherapeutic purposes but can be used to support the therapeutic process (eg, teaching a spouse to deliver praise when a patient avoids bars and to withhold praise or express disapproval for going to bars). Some treatments, such as the CRA + vouchers treatment for cocaine use disorder (12,13), are designed to deliver contrived consequences during the initial treatment period, with a transition to more naturalistic sources later in treatment. The rationale for that sequence is that the lifestyle of the patient is often so disrupted upon treatment entry that it is largely devoid of effective alternative sources of reinforcement that can compete with the reinforcement derived from drug use. Contrived sources of alternative reinforcement delivered through CM are designed to promote initial abstinence, thereby allowing time for therapists and patient to work toward reestablishing more naturalistic alternatives (eg, job, stable family life, participation in self-help, and other social groups that reinforce abstinence). Of course, it is these naturalistic alternatives that eventually will need to sustain long-term abstinence once the contrived reinforcers are discontinued. Also important to recognize is that for any number of reasons, some patients may have behavioral repertoires that are too limited to recruit sufficient sources of naturalistic reinforcement to effectively compete with drug use and, as such, these patients will need some form of maintenance treatment involving contrived reinforcement contingencies in order to sustain long-term abstinence. Certainly, that is widely recognized with individuals with opioid use disorder who often need maintenance pharmacotherapy to sustain long-term abstinence from illicit drug use. Others may need lifelong participation in self-help programs in order to succeed. Such programs might be deemed as falling somewhere around the midpoint on the continuum of contrived versus naturalistic sources of alternative reinforcement (11). The following discussion illustrates how this general strategy is implemented in CM and CRA interventions.

TREATMENT PLANNING A thorough patient evaluation is an essential first step in effective clinical management of SUDs and that certainly holds true when using CM and CRA interventions. The assessment framework used in the CRA + vouchers treatment for cocaine use disorder (13) is relatively generic and can be readily applied to other types of SUDs by substituting information specific to cocaine use with pertinent information on whatever other type of SUD is the presenting problem. Every effort is made to schedule an intake assessment interview as soon as possible after initial patient contact with the clinic. Scheduling the interview within 24 hours of clinic contact significantly reduces attrition between the initial clinic contact and assessment interview, which is a substantial problem among those with SUDs (14). Some patients cannot come in to the clinic within 24 hours, so secondary plans are made to get them in as soon as is practicable. Detailed information is collected on drug use, treatment readiness, psychiatric functioning, employment/vocational status, recreational interests, current social supports, family and social problems, and legal issues. Table 66-1 is a list of instruments (15–21) that can be used to obtain such information, listed in the order in which they are typically administered. If it appears that a medication is indicated, the first steps are taken after the initial intake assessment toward implementing the relevant medical protocols. With the cocaine use disorder population, a regimen of clinic-monitored disulfiram therapy can be used to address problem drinking, which also reduces cocaine use (22). As the prevalence of prescription-opioid use has grown, clinic-monitored naltrexone therapy may be increasingly indicated.

TABLE 66-1 Instruments Used in an Intake Assessment to Obtain Detailed Information from Patients With Cocaine Use Disorders

PRETREATMENT ISSUES Motivation Within an operant framework, motivation is not thought of as a characteristic of the patient per se but rather as a product of current and past reinforcement contingencies tempered by potential individual differences in delay discounting, educational attainment, and other matters that may influence behavioral choice (2,10). The overarching focus of the interventions is to directly ensure the availability of sufficient reinforcement to promote and sustain therapeutic change. Following, we discuss how that is accomplished.

Rationale for Choice of Treatment The historical and conceptual background information described previously provides the overarching rationale for the use of CM and CRA interventions. CM and CRA have the potential to be useful with virtually any type of SUDs. There is no minimal or maximal intensity or duration of CM or CRA, and thus there is a great deal of flexibility in terms of adapting them to particular forms of SUDs and special populations.

Selection and Preparation of Patients As noted, we know of no particular type of SUD patient for whom CM or CRA is contraindicated. Both interventions require a detailed and careful patient orientation. With CM, it is quite common to have patients sign a written contract stipulating all aspects of the CM arrangement so as to avoid any confusion about the contingencies. Brief tests (eg, a true/false quiz) are also commonly administered to ensure that patients understand the contingencies. The vocabulary and other information contained in the contract and tests should be prepared with the potential intellectual limitations of the patient population in mind and plans to surmount potential individual difficulties. For example, reading problems are common among patients with SUDs, and certain patients may need to have written materials read aloud to them.

Therapist Characteristics Therapists typically do not manage CM programs owing to the detailed record keeping involved and the need to biochemically verify abstinence, though there are exceptions. Thus, this section largely pertains to characteristics of CRA therapists. CRA is a manual based intervention, which minimizes the influence of therapist characteristics on outcome. In the series of studies examining CRA + vouchers treatment of cocaine use disorder, for example, there have not been any significant therapist effects on outcome noted. To implement CRA effectively, therapists need to be directive but also flexible, which we believe facilitates treatment retention and progress toward achieving treatment goals. Particularly in the early stages of treatment, therapists try to work around patient schedules and generally make participation in treatment convenient to the patient. Therapists try to be flexible with regard to tardiness to sessions, early departure from sessions, and the time of day that sessions are scheduled and will meet with patients outside the office if necessary. With especially difficult patients, improvements in these areas can be worked on as part of the treatment plan. CRA therapists must exhibit appropriate empathy and good listening skills. They need to convey a sincere understanding of the patient’s situation and its inherent difficulties. Throughout treatment, therapists avoid making value judgments and, instead, exhibit genuine empathy and consideration for the difficult challenges that patients face. CRA requires that therapists and patients develop an active, make-it-happen

attitude throughout treatment. Therapists must have good organizational skills, which are important to developing, implementing, monitoring, and adapting treatment plans. Problem-solving skills also are important. Within ethical boundaries, therapists must be committed to doing what it takes to facilitate lifestyle changes on the part of patients. For example, therapists often accompany patients to appointments or job interviews. They initiate recreational activities with patients and schedule sessions at different times of day to accomplish specific goals. They have patients make phone calls from their office. They search newspapers and online postings for job possibilities or ideas for healthy recreational activities in which patients might be able to participate. Without question, the amount of direct support that CRA therapists provide to patients can represent a rather significant departure from more traditional forms of SUD counseling. However, in CRA, these therapeutic efforts are deemed to be very important for at least three reasons. First, while patients may have the aptitude, they may simply lack certain skills to accomplish important tasks (eg, effective job searching). Second, early in treatment, patients may lack the requisite reinforcement history (ie, motivation) with certain healthy activities (eg, attending the local YMCA) to carry through on assigned tasks in the absence of the therapist being present to prompt the response and provide social reinforcement for completing the task. Third, patients may lack the necessary material resources (eg, transportation or materials for résumé preparation) to complete a task in a timely manner. CRA therapists are committed to overcoming such deficiencies in skills, motivation, or resources to facilitate patient movement in the direction of a healthier, non–drug-using lifestyle.

TREATMENT AND TECHNIQUE In this section, the basic elements of CM and CRA interventions are described using the CRA + vouchers treatment for cocaine use disorder for illustration purposes.

Contingency Management The efficacy of CM interventions is very much dependent on how they are structured and implemented. A brief description of a voucher-based CM intervention is described below, followed by an outline of 10 features of CM interventions that are important to their efficacy (23). In the voucher-based CM program, patients sign a written contract

stipulating all aspects of the CM interventions. Vouchers exchangeable for retail items are earned contingent on cocaine-negative results in thrice-weekly urine toxicology testing (Monday, Wednesday, and Friday). The program is 12 weeks in duration. The first cocaine-negative specimen earns a voucher worth $2.50 in purchasing power. The value of each subsequent consecutive cocaine-negative specimen increases by $1.25. The equivalent of a $10 bonus is provided for every three consecutive cocaine-negative specimens. The intent of the escalating magnitude of reinforcement and bonuses is to reinforce continuous cocaine abstinence. A cocaine-positive specimen or failure to submit a scheduled specimen resets the value of vouchers back to the initial $2.50 value. This reset feature is designed to punish relapse to cocaine use after a period of sustained abstinence, with the intensity of the punishment tied directly to the length of sustained abstinence that would be broken. In order to provide patients with a reason to continue abstaining from drug use after a reset, submission of five consecutive cocaine-negative specimens after a cocaine-positive specimen returns the value to where it was prior to the reset. Vouchers cannot be lost once earned. If someone is continuously abstinent throughout the 12-week intervention, total earnings would be ~$997.50. However, because most patients are unable to sustain abstinence throughout the intervention, the average earned is usually about half that maximal amount. The voucher CM intervention contains most of the 10 features important to effective CM. First, as was noted, the details of the intervention are carefully explained to patients in the form of a written contract prior to beginning treatment. Second, the response being targeted by the CM intervention—cocaine abstinence—is defined in objective terms (cocaine-negative urine toxicology results). Third, the methods for verifying that the target response occurred are well specified and objective (urine toxicology testing). Fourth, the schedule for monitoring progress is well specified (each Monday, Wednesday, and Friday). Fifth, the schedule is designed to include frequent opportunities for patients to experience the programmed consequences (thrice weekly). Sixth, the duration of the intervention is stipulated in advance (12 weeks). Seventh, the intervention is focused on a single target (cocaine abstinence). CM interventions that focus on a single target tend to produce larger treatment effects on average than those that try to modify multiple targets (eg, abstinence from multiple substances) (24). Eighth, the consequences that will follow success and failure to emit the target response are clear (carefully detailed voucher reinforcement schedule). Ninth, there is minimal delay in delivering designated consequences (urine specimens are analyzed on-site, and the vouchers earned are delivered immediately after

testing). Delivering the consequence on the same day that occurrence of the target response is verified produces larger treatment effects than delivering the consequence at a later time (24). Tenth, the magnitude of reinforcement that can be earned is relatively substantial (maximal total earnings = $997.50). Larger value incentives produce larger treatment effects on average (24).

Community Reinforcement Approach The CRA component of the CRA + vouchers treatment is implemented in twice weekly 1-hour counseling sessions for 12 weeks and then once weekly during the subsequent 12 weeks. It has seven elements. First, patients are instructed in how to recognize antecedents and consequences of their cocaine use; that is, how to functionally analyze their cocaine use. They are also instructed in how to use that information to reduce the probability of using cocaine. A twofold message is conveyed to the patient: (a) his/her cocaine use is orderly behavior that is more likely to occur under certain circumstances than others, and (b) by learning to identify the circumstances that affect one’s cocaine use, plans can be developed and implemented to reduce the likelihood of future cocaine use. In conjunction with functional analysis, patients are taught self-management plans for using the information revealed in the functional analyses to decrease the chances of future cocaine use. Patients are counseled to restructure their daily activities in order to minimize contact with known antecedents of cocaine use, to find alternatives to the positive consequences of cocaine use, and to make explicit the negative consequences of cocaine use. Second, developing a new social network that will support a healthier lifestyle and getting involved with recreational activities that are enjoyable and do not involve cocaine or other drug use is addressed with all patients. Systematically developing and maintaining contacts with “safe” social networks and participation in “safe” recreational activities remains a high priority throughout treatment for the vast majority of patients. Specific treatment goals are set, and weekly progress on specific goals is monitored. Clearly, plans for developing healthy social networks and recreational activities must be individualized depending on the circumstances, skills and interests of the patient. For those patients who are willing to participate, self-help groups (Alcoholics or Narcotics Anonymous) can be an effective way to develop a new network of associates who will support a sober lifestyle. Third, various other forms of individualized skills training are provided, usually to address some specific skill deficit that may directly or indirectly

influence a patient’s risk for cocaine use (eg, time management, problem solving, assertiveness training, social skills training, and mood management). For example, essential to success with the self-management skills and social/recreational goals discussed is some level of time-management skills. As another example, protocols on controlling depression are implemented with those patients whose depression continues after discontinuing cocaine use (25,26). Fourth, unemployed patients are offered Job Club, which is an efficacious method for assisting chronically unemployed individuals obtain employment (27). The majority of patients who seek treatment for cocaine use disorder are unemployed, so this is a service that can be offered to many patients. For others, assistance is provided in pursuing educational goals or new career paths. Fifth, patients with romantic partners who do not engage in unhealthy drug use are offered behavioral couples therapy, which is an intervention designed to teach couples positive communication skills and how to negotiate reciprocal contracts for desired changes in each other’s behavior (28). Relationship counseling tends to be delivered across eight sessions, with the first four sessions taking place across consecutive weeks and the next four delivered on alternating weeks. Sixth, human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) and hepatitis C virus (HCV) education is provided to all clients in the early stages of treatment, along with counseling directed at addressing any specific needs or risk behavior of the individual patient (29). The potential for acquiring HIV/AIDS and HCV from sharing injection equipment and through sexual activity is addressed with all patients. This involves at least two sessions. First, patients complete an HIV/AIDS and HCV knowledge test. They next watch and discuss a video on HIV/AIDS with their therapist. Patients are also provided HIV/AIDS and HCV prevention pamphlets and free condoms if desired. The HIV/AIDS and HCV knowledge test is repeated and any remaining errors discussed and resolved. Last, patients are given information about testing for HIV and hepatitis B and C and are encouraged to get tested. Those interested in being tested are assisted in scheduling an appointment to do so. Seventh, as noted previously, all who meet diagnostic criteria for alcohol use disorder or report that alcohol use is involved in their use of cocaine are offered disulfiram therapy, which is an integral part of the CRA treatment for alcohol use disorder (30). Patients generally ingest a 250-mg daily dose under clinic staff

observation on urinalysis test days and, when possible, under the observation of a significant other (SO) on the other days. Disulfiram therapy is only effective when implemented with procedures to monitor compliance with the recommended dosing regimen. Having an SO monitor compliance on nonclinic days can work well if an appropriate person is available to do so at the frequency needed. When that is not possible, clients can ingest a larger dose (500 mg) on days when they report to the clinic and skip dosing on the intervening days. Use of other substances is also discouraged in CRA therapy. Anyone who meets criteria for physical dependence on opioids is referred for methadone or buprenorphine therapy. Marijuana abstinence is recommended because of problems associated with its use and because the literature is mixed on whether marijuana’s use interferes with achieving abstinence from other drugs. Abstinence from nicotine/tobacco use is also recommended and there is evidence suggesting that nicotine/tobacco treatment can be successfully integrated into simultaneous treatment for other SUDs and may improve treatment outcomes for those other substances (31). As important, patients are never dismissed or refused treatment owing to other drug use. Upon completion of the 24 weeks of treatment, patients are encouraged to participate in 6 months of aftercare, which involves at least once-monthly brief therapy sessions and urine toxicology screening. More frequent clinic contact is recommended if the therapist or patients deem it necessary.

EMPIRICAL SUPPORT Community Reinforcement Approach + Vouchers A major reason why this intervention garnered significant interest was its efficacy with cocaine use disorders. At a time when most clinical trials investigating treatments for cocaine use disorders were consistently producing negative outcomes, a series of controlled trials examining this intervention produced reliably positive outcomes (12,32–37). The initial two trials involved comparisons of this combined treatment to standard outpatient SUD counseling (12,32). The first trial was 12 weeks in duration, and 28 cocaine-dependent outpatients were assigned as consecutive admissions to their respective treatment conditions (12). The second trial was 24

weeks in duration, and 38 patients with DSM-IV defined cocaine dependence were randomly assigned to the same two treatment conditions (32). Outcomes in both trials were significantly better among those treated with the CRA + voucher treatment than standard SUD counseling. In the randomized trial, for example, 58% of patients assigned to CRA + vouchers completed the recommended 24 weeks of treatment compared to 11% of those assigned to SUD counseling. Regarding cocaine use, 68% of those assigned to CRA + vouchers were objectively verified to have achieved 8 or more weeks of continuous cocaine abstinence as compared to only 11% of those treated with SUD counseling. Other trials examined the CRA + vouchers treatment with other SUDs, using different modalities, and in other settings. One trial tested whether the CRA + vouchers treatment could improve what are usually poor outcomes with opioid withdrawal management (38). Those assigned to CRA + vouchers were more likely to complete the withdrawal management protocol and achieved greater periods of biochemically confirmed abstinence from illicit opioid use. A number of later trials have examined a version of this intervention, wherein CRA was delivered primarily via an interactive, computer-based program known as the Therapeutic Education System (39–41). In the seminal study, retention was comparable but biochemically confirmed abstinence from opioids and cocaine was significantly higher among opioid-maintained patients assigned to therapistdelivered CRA + voucher and computer-assisted CRA + vouchers as compared to standard counseling, with no differences between therapist-delivered and computer-assisted CRA conditions (39). More recently, a randomized controlled trial with cocaine use disorder patients conducted in Spain using CRA plus a variation of the voucher intervention reported positive improvements in retention and cocaine abstinence as compared to standard care during 6 months of treatment, with effects on cocaine remaining discernible through 6 months of posttreatment follow-up (42,43). Together, these trials help demonstrate the generality of the CRA + vouchers intervention across drug classes, modalities, and to communities outside the US. Additional trials dismantled the CRA + vouchers intervention to examine the contribution of each component. A randomized trial designed to isolate the contribution of voucher-based CM was conducted with 40 cocaine-dependent outpatients who were assigned to receive CRA with or without vouchers (33). Average duration of continuous cocaine abstinence across 24 weeks of treatment in the two groups was 11.7 ± 2.0 weeks in the voucher group versus 6.0 ± 1.5 in the no-voucher group (Fig. 66-1) and a separate report documented continued differences between conditions posttreatment (34). Subsequent trials testing

specific parameters of the voucher part of the intervention also demonstrated the importance of the contingency (35) and of voucher magnitude (36).

Figure 66-1 Mean durations of continuous cocaine abstinence. Mean durations of continuous cocaine abstinence documented via urinalysis testing in each treatment group during weeks 1-24, 1-12, and 13-24 of treatment. Solid and shaded bars indicate the voucher and no-voucher groups, respectively. Error bars represent + standard error of the mean. (Reprinted from Higgins ST, Budney AJ, Bickel WK, et al. Incentives improve outcome in outpatient behavioral treatment of cocaine dependence. Arch Gen Psychiatry. 1994;51:568-576, with permission.) Another randomized clinical trial was conducted to isolate the contributions of CRA (37). One hundred cocaine-dependent outpatients were randomly assigned to receive the CRA + vouchers treatment or the vouchers component only. Vouchers were in place for 12 weeks, CRA for 24 weeks, and patients were assessed at least every 3 months for 2 years after treatment entry. Patients treated with CRA + vouchers were better retained in treatment, used cocaine at a lower frequency during treatment but not follow-up, and reported a lower frequency of drinking to intoxication during treatment and follow-up as compared with patients treated with vouchers only. Patients treated with CRA + vouchers also reported a higher frequency of days of paid employment during treatment and 6 months of posttreatment follow-up, decreased depressive symptoms during treatment only, and fewer hospitalizations and legal problems during follow-up. The results provided a strong case that CRA contributed in numerous ways to the

positive outcomes observed during treatment and posttreatment follow-up with the CRA + vouchers treatment.

Contingency Management Interventions Initial Contingency Management Studies Up to this point in the chapter, the emphasis has been on the combination treatment of CRA + vouchers. However, prior to the introduction of CM in the form of vouchers, there was a strong empirical literature on CM for the treatment of SUDs using other forms of reinforcement. Among the most impressive of the early CM studies on SUDs was a randomized controlled trial conducted with 20 chronic public drunkenness offenders (44). Subjects randomly assigned to the CM group earned housing, employment, medical care, and meals based on sobriety (measured by direct staff observation or blood alcohol level (BAL) of 70% of doses) with the medications (37).

Medical Management MM is a manualized intervention that is a composite of several different psychosocial interventions focusing upon medication compliance and psychosocial treatment engagement and adherence, all of which were integrated for use in the Project COMBINE study (38). The MM intervention is semistructured and brief in duration (about nine sessions) and, for each session (about 20 minutes after the initial 40-minute session), suitable for delivery in a primary care environment by a medical professional and, with some adaptation, could focus upon medications other than that used in COMBINE and on SUD other than alcohol use disorder (39). The manual is available for hard copy order or online (http://pubs.niaaa.nih.gov/publications/combine/) and is highly recommended as probably the most clinically useful, evidence-based practice manual available to the addiction clinician who combines medications and psychosocial interventions in typical office visits. The initial intervention has several components, each of which has evidence supporting its use—using targeted feedback of medical information and individualized advice, the intervention motivates the patient toward medication adherence and reduction in harmful substance use, educates the patient about the need for medication, and offers referral to support groups, such as AA. Brief interventions have a substantial evidence base, and brief motivational interviewing–type interventions have been demonstrated as more effective than traditional advice giving in the treatment of SUDs, with small to moderate effect sizes (40–42). Giving the patient self-help materials and supporting involvement in mutual self-help groups, each has support in the research literature (43–45). In Project COMBINE, the most expensive multisite trial that NIAAA has performed to date, which evaluated the effect of both psychosocial therapy and medications (acamprosate and naltrexone), this relatively brief but well-rounded biopsychosocial therapy accounted for the bulk of positive treatment outcome whether the patients took active or placebo medications. Thus, MM is a model that the busy clinician can use, whether using medications as part of treatment or not. Further, as mentioned above, though not yet tested, it is likely that the MM strategy and structure of sessions would also allow apply for better adherence to both psychosocial and psychiatric medication interventions, and thus outcomes, for those with addiction and co-occurring psychiatric disorders. The intrinsic themes of MM are educating the patient about the disorder and its specific personal impact; advising the patient about the nature of the treatment, the specific rationale for the medication, and the importance of

medication adherence; and recovery support in the form of discussion and advice for implementing medication adherence and alcohol or drug abstinence strategies (46). The initial MM visit takes place after comprehensive clinical evaluation and lasts 40-60 minutes. In many cases in clinical practice, this may be shortly after the initial evaluation, but it is optimal to have an interval within which the clinician can compile the relevant medical information necessary for the initial feedback to the patient. In the case of alcohol problems, these data will typically include blood pressure, liver enzymes, other significant lab findings (eg, urine or blood), findings on physical exam, recent alcohol intake (days, amount/day), self-reported alcohol problems, and description of specific alcohol use disorder symptoms (47). The MM manual offers a Clinician Report (form A1) that offers a concise format in which to record the salient data. The clinician reviews the results of the evaluation with the patient, first focusing on the medical data and then moving to a review of the symptoms of alcohol use disorder that the patient endorsed. Any medical concerns of the patient are addressed. The intent is to link the patient’s use of alcohol in this case to each biopsychosocial consequence that has been identified. Having done so and answering his or her questions, the patient is then given information about alcohol use disorder in a clear, nonthreatening, and supportive manner and advised to stop drinking. Framing the problem as a routine medical one and offering a friendly “cando” attitude about treatment and recovery support the patient in not feeling impugned by the clinician, since patients with SUD are frequently full of shame or hopelessness about their drinking. Communicating a judgmental attitude is likely to engender more resistance to treatment engagement. The clinician advises the patient about the rationale and use of pharmacotherapy as an important medical strategy in assisting recovery. The patient is then instructed about how to take the medicine, and potential side effects are discussed in advance so as to minimize their contribution to nonadherence (46). The clinician also discusses the rationale of checking the patient’s adherence with medication at each subsequent session. The patient’s past patterns of medication adherence are evaluated and discussed, so that the patient and clinician together can elaborate a specific plan to assist the patient in remaining adherent with the regimen. The MM manual appendix has a Medication Compliance Plan (form A13) that can assist the clinician in formalizing the plan with a patient. Finally, the patient is given education and encouragement for attendance at support groups such as AA and is given brochures and other written materials that have source information on medications, alcohol use disorder, and recovery groups. Time is

given to the patient to raise questions about the diagnosis or treatment plan (47). In each of the subsequent visits, which typically range from 15 to 25 minutes, the clinician checks the patient in terms of medical status, appropriate laboratory data, vital signs, and weight and evaluates the blood alcohol concentration. Then, the question about drinking status is asked, focusing upon how the patient coped: with difficulty or ease, the strength of the desire to drink, or, in the case of continued drinking, what was the context of use. If the patient is abstinent, other problems, such as an increase in other substance use, are evaluated. Since patients often stop medications when they feel better, it is important that the patient is instructed that even if he or she is doing well in treatment and is abstinent, that is not the time to stop the medication. The patient should be given positive feedback for medication adherence, and the positive health and lifestyle impact of abstinence are reiterated. If the desire to drink has reduced but the patient is still drinking, that reduction is reinforced as a first step toward change. A nonjudgmental attitude is key in supporting that change may occur slowly, that there may be ups and downs along the way, and that continuing attempts are associated with success. Any positive step, however small, in reduction in use or craving is given positive feedback, and consistent with supportive therapy, the clinician looks for opportunities to provide appropriate, data-based praise (7). If it is earlier in treatment and the patient is continuing to drink but adherent to the medication, it is important that the patient is told that the medication has not yet had sufficient time to work completely. If the patient confirms adherence with the medications at the prescribed dose and frequency of oral naltrexone or acamprosate, and at least 2-3 weeks has passed with no alteration in drinking pattern, then the prescribing clinician should evaluate the medication dose, and if the dose is optimal, consider nonresponse to that medication with plans for another class of pharmacotherapy. With certain anticonvulsant medications, such as topiramate, because the optimal dose requires many weeks of titration, the length of time to decide whether the medication effect is clinically sufficient must be similarly extended. In addition, the patient is encouraged to attend mutual support groups. In determining the patient’s context of use, the patient can be advised to avoid “people, places, and things” associated with use or to substitute a different healthy pleasure at the time when use usually occurs. Clinician: “So, how have you been doing over the past week?”

Patient: “I’m taking the naltrexone, but it makes me a little jittery and queasy after I take it.” Clinician: “We discussed that it might do that. Is it severe enough to make you want to stop?” Patient: “No, It’s not too bad. I just distract myself, and it gets better as the day goes on. I’m using the plan we talked about!” Clinician: “Well, it’s really good that you are able to continue on it, and usually, those side effects tend to go away over time. Any effects on your desire to drink?” Patient: “I think so, maybe a little. I hadn’t really thought about it. I still get pretty strong urges at times, but I think maybe they’re less frequent.” Clinician: “Changes in your desire to drink may be an early sign of a change for you. How well were you able to keep from drinking?” Patient: “I’m still drinking, but I think it’s less twice this week—Wednesday and yesterday—I started and basically had had enough after two drinks. That’s not regular for me. Actually, I didn’t even finished the second one yesterday. Funny, I don’t know why, I just lost interest!” Clinician: “Well, you’ve only been on the medication for a week, and we know it takes time to fully kick in. What’s happening with going to AA?” Patient: “I went to a meeting on the day after I saw you; then I started drinking again and sort of figured “what the hey?” Clinician: “You know that “what the hey” attitude frequently comes with the experience of relapse almost automatically. One of the benefits of going to meetings is that it offers social support for abstinence. Listening to all those stories and folks succeeding in their recovery can really help motivate and support you in your own recovery.” Patient: “I know, I think I need to plan it out in advance, so I know where I’m supposed to go. That way, it’ll be easier to get to the meetings.” Clinician: “That’s an excellent way to anticipate problems in getting support for yourself by planning properly. Can we review? In spite of it giving you some uncomfortable feelings, you are sticking with the medications and coping with unpleasant effects according to your plan, which demonstrates your commitment. And though you briefly relapsed, your alcohol intake has diminished somewhat… All in all, I’d say that was progress. You are making better plans to get to AA meetings—in fact, let’s talk about what specific

meeting you are going to go to next, where it is, and what you will say when you get there.” The patient who is abstinent but not taking medications as prescribed is given positive feedback for not drinking, and the general benefits of abstinence are reinforced. The reasons for the nonadherence (eg, side effects, forgetting, misinformation) are explored with the patient, and the clinician presents the patient with the information that over time the risks of relapse are reduced by the medication. The compliance plan is amended with strategies addressing the reasons for nonadherence. The patient who is nonadherent to medications and is drinking but motivated to stop is encouraged to engage in treatment more fully. The medical rationale for treatment that was explained in the initial MM visit is repeated. As above, the reasons for nonadherence with medication are explored, and the compliance plan is amended with strategies addressing the reasons for nonadherence.

Strategies to Integrate Medication Treatment and Behavioral Therapies There is not yet a wealth of empirical data to support the concept, and there clearly has not been a great deal of positive results for attempts at elucidating the beneficial effects of treatment matching (45,48). Nonetheless, since no singular treatment is a “slam dunk,” it is still clinically sensible to have an approach to relapse to substance use that places as many barriers as practicable of differing content and strategy in the way of the person with an addiction struggling with craving and relapse opportunities. This means that both external and internal structures can be brought to bear in this process and that a combination of different interventions, whether psychosocial or pharmacological, may have convergent or complementary effects on the inhibition of relapse. In the context of providing an appropriate behavioral therapy platform for use in pharmacotherapy trials, Carroll et al. (49) described the available empirically supported and well-operationalized behavioral therapies as having a range of possible targets such as enhancing medication adherence, reducing attrition, addressing co-occurring problems, promoting abstinence, and targeting specific weaknesses of the pharmacological agent. Poldrugo (50) conceptualized the impact of pharmacotherapy for SUDs, in this case, alcohol use disorder, as biologically enhancing mechanisms of either

external or internal control. For example, disulfiram, as an aversive agent, would be considered as supporting of external control. Medications that purportedly affected the endogenous reward system, such as neuromodulators like acamprosate, or inhibitors of substance-induced reward, like naltrexone, would be considered enhancers of mechanisms of internal control. So, in constructing a combination medication and psychosocial intervention for alcohol use disorder, one could consider aligning psychosocial interventions that either augment the control impact of the medication or offer a complementary control locus. Expanding the concept along similar lines, Mattson and Litten (51) described four strategies for combining medications and behavioral therapies in alcohol use disorder, probably the addiction domain best researched for treatment matching and combining behavioral therapy with medication: (a) targeting the same drinking behavior with both the medication and behavioral intervention; (b) medications and therapy each targeting one of two different drinking behaviors; (c) targeting a drinking behavior and a secondary problem that creates a context for drinking or impairs recovery, such as co-occurring mental illness, family problems, or comorbid medical disorders; and (d) adding to a medication regimen a behavioral therapy specifically targeting medication adherence or treatment retention, which was discussed above. The other strategies will be discussed below, in the context not only of alcohol use disorder but also with other SUDs.

Using Matching Data to Facilitate Integration In a recent post hoc analysis of Project MATCH data, DSM-IV–defined alcoholdependent patients with social networks supportive of drinking had better shortterm outcomes if they were assigned to twelve-step facilitation (TSF) (52). This has face validity as a convergent strategy in that TSF attempts to reduce social support for drinking behavior through linkage with the proabstinence social support found in AA. Patient characteristics may also interact with the effectiveness of certain types of behavioral intervention. In another Project MATCH data reanalysis using growth mixture modeling, individuals with lower self-efficacy who received cognitive–behavioral therapy (CBT) drank far less frequently than did those with low self-efficacy who received motivational enhancement therapy (MET) (53). This also has face validity in that CBT attempts to increase the patient’s self-efficacy related to abstinence (54). Certain character traits may also have negative impact in the context of specific therapies. For example, across Project MATCH therapies (CBT, MET, and TSF), patients with DSM-IV alcohol dependence (n = 141) treated in a more

confrontative and directive therapy who had moderate to high trait reactance (the tendency to resist relinquishing control) had worse 1-year alcohol outcomes than those with low trait reactance, but especially so in the MET group (55).

Convergent Strategies Naltrexone has been demonstrated in meta-analyses to be a medication effective in the treatment of alcohol use disorder with the greatest effect on reduction in relapse to heavy drinking, modulated either by reductions in cue-induced reward or by reducing the rewarding effects of alcohol, or both (56–59). Work by Myrick et al. (60) demonstrated that naltrexone reduces alcohol cue-induced brain activation. Therefore, with naltrexone therapy in alcohol use disorder, one could use a complementary behavioral intervention strategy that supported noninitiation of drinking or a convergent one that increased the likelihood of a slip remaining a slip (a drink or two) rather than becoming a relapse (a binge). Similarly, the craving reduction aspect of naltrexone could be paired as a convergent strategy with the craving attenuating effects of CBT or cue extinction therapy. In randomized trials of a convergent strategy, Balldin et al. (61) and Heinälä et al. (62) found that CBT focused on coping with a slip produced better reductions in relapse to heavy drinking than abstinence-focused supportive therapy when paired with naltrexone. In contrast, O'Malley et al. (63) in a fourcell randomized comparison (n = 97) of naltrexone versus placebo, and also CBT versus supportive therapy, demonstrated better cumulative alcohol abstinence rates in the naltrexone-treated patients who were given supportive therapy as compared to CBT. However, taking into consideration that the main effect of naltrexone is reduction in relapse to heavy drinking, the O'Malley et al. study also demonstrated this in the CBT group compared to the group receiving supportive therapy. Anton et al. (64) tested naltrexone against placebo in a 12week RCT in 131 detoxified outpatients with alcohol dependence who were offered weekly CBT. The group treated with naltrexone had fewer subjects who relapsed, a longer time to relapse to heavy drinking, fewer drinks per drinking day, and higher percentage of days abstinent. Interestingly, the naltrexone-treated group appeared to make better use of CBT—they had more resistance to alcoholtreated thoughts and urges as measured on the Obsessive Compulsive Drinking Scale. More recently, Anton et al. (65) completed a 12-week RCT testing of naltrexone versus placebo, combined with either CBT or MET in 120 outpatient subjects with alcohol dependence. Again, subjects receiving CBT and naltrexone had significantly fewer relapses to heavy drinking (OR = 0.40) than the other

groups, and those that did had a longer time to subsequent relapses. It is hypothesized that CBT offers specific skills to deal with craving, high-risk situations, and family conflict that may be a more complete adjunct to the effects of naltrexone than MET provides. Thus, taken together, it is reasonable to provide CBT and naltrexone in combination as a convergent strategy to decrease relapse to heavy drinking in patients with alcohol use disorder.

Complementary Strategies Stanton and Shadish (66) demonstrated in a meta-analysis of randomized trials that compared to individual and peer group therapy, family and couples therapies have significantly better impact on recovery from SUD. As a complementary strategy, behavioral couples therapy (BCT), a well-researched and effective behavioral intervention, can provide elements of increased social support for the patient’s efforts to change and contingency for sobriety, while disulfiram can assist the maintenance of sobriety through deterrence (67). Meta-analysis of BCT studies demonstrates its superiority over individual interventions for SUDs at treatment follow-up on frequency of use, consequences of use, and relationship satisfaction (68). As one part of BCT, the couple enters into a disulfiram contract, an agreement that stipulates that the spouse observes and records on a calendar the patient taking the daily disulfiram dose, and the patient and spouse then thank each other for their efforts and refrain from arguments or discussions about the patient’s drinking behavior (69). The structured way of relating around the patient’s use of sobriety-supporting medications helps to reduce relationship dysfunction in the couple, which is seen as a major driver of substance use. In a variant of BCT, Fals-Stewart and O'Farrell (70) used naltrexone contracting with 124 men with opioid dependence and the family members they lived within a randomized 24-week trial of behavioral family contracting (BFC) and individual therapy versus individual therapy alone. The BFC patients took more doses of naltrexone, were more compliant with scheduled sessions, and had longer continuous abstinence and more opioid and other illicit drug abstinence during and for the year after treatment. They also had fewer drugrelated, legal, and family problems at 1-year follow-up. In this example of complementary strategies, BFC increased medication adherence and provided social support for continuing opioid abstinence, while naltrexone blocked the rewarding effects of opioids. Since the effects of BCT tend to fade over time, as couples tend to regress back toward dysfunctional relating, a study of booster relapse prevention sessions provided to couples after the main treatment had

ended supported the maintenance of treatment gains (71). Other psychosocial interventions may introduce similar convergent factors or complementary factors other than increasing social support or reducing relapse potential that have equivalent impact as CBT in the context of naltrexone. Latt et al. (72) demonstrated in an RCT (n = 107) that naltrexone with adjunctive medical advice in a primary care setting was effective in reducing the relapse to heavy drinking by about 50% irrespective of whether it was accompanied by counseling and supportive therapy. Similarly, in a comparison of CBT and primary care management in 197 subjects with alcohol dependence treated with naltrexone, O'Malley et al. (73) found that the primary care intervention (including referral to and support of AA attendance, medication issues and adherence support, and clinical advice) had similar impact over 10 weeks on reducing relapse to heavy drinking as did CBT. However, the CBT group was better at maintaining days of abstinence over time. The interaction of bupropion and CM is another complementary strategy, where the bupropion may affect subjective negative mood and cognitive symptoms post–cocaine withdrawal and the CM reinforces retention in treatment and rewards abstinence. Poling et al. (74) conducted a 25-week, double-blind RCT in methadone-maintained patients with DSM-IV cocaine dependence (n = 106) with 4 cells: CM that gave vouchers for negative cocaine urine screens and abstinence-related activities and medication placebo, CM and bupropion 300 mg/d, control vouchers for giving urine specimens and placebo medication, or control vouchers and bupropion. Although bupropion had independent effects upon cocaine use over the 12 weeks, results demonstrated that bupropion plus CM significantly improved cocaine outcomes relative to bupropion alone. Sometimes, reasonable complementary strategies do not work synergistically, perhaps as one of the interventions is more robust. Disulfiram is hypothesized to reduce cocaine use through direct impact on neurotransmitter metabolism, reducing the pleasurable effects of cocaine, whereas CBT supports maintenance of abstinence through cognitive restructuring in the form of functional analysis and new skills acquisition (75,76). CBT was tested by Carroll et al. (77) against interpersonal psychotherapy (IPT) in a four-cell (disulfiram/CBT, disulfiram/IPT, placebo/CBT, placebo/IPT) 12-week comparison with disulfiram versus placebo in 121 patients with cocaine dependence. Cocaine use was reduced significantly in the disulfiram group and in the CBT group compared to the IPT group in the context of placebo, but there was no difference between therapies in the context of disulfiram. The effects of the disulfiram on cocaine use were greatest in subjects who were abstinent from

alcohol or without alcohol dependence at baseline, suggesting that the effects of disulfiram are not moderated by its effect on alcohol use.

Other Strategies Combination strategies can also target the SUD and in addition attempt to treat co-occurring mental or medical disorders. It is clear that both disorders need to be targeted independently, although there may be some convergent effects in treating the co-occurring disorder. For example, depression and depressive symptoms have an adverse effect upon recovery from SUD. Although it has been reasonable to test a parsimonious treatment such as an SSRI to attempt to treat both the depression and the SUD, meta-analysis of this strategy has demonstrated that (with one exception below) antidepressant medications are efficacious for the treatment of depression in patients with SUD but that other interventions are necessary for treating the SUD (78). For example, Stein et al. (79) conducted an RCT of citalopram plus 8 sessions of CBT for depression compared to an assessment control condition in 109 active injection drug users with a DSM-IV mood disorder spectrum diagnosis and a Hamilton Rating Scale for Depression score > 13. At follow-up, more than twice the patients receiving the intervention were in remission of the depression, but there was no impact on heroin or cocaine use. In addition to the lack of evidence that treating other cooccurring mental disorders is clinically effective for SUD, some interventions for mental disorders can have adverse impact on SUD. Recent data have suggested that a subset of patients with alcohol use disorder, type A (later onset), may respond differentially to SSRI treatment compared to placebo with reductions in drinking but that type B (early onset, prior to age 25) patients with alcohol use disorder may actually do worse (38,80). Patients treated with methadone maintenance often have problems in multiple life dimensions other than SUD, and some of these are likely to respond to psychosocial interventions that may also promote abstinence from illicit opioids. Specific gains in psychosocial therapy of methadone-maintained patients tend to be related to the type of therapy (eg, supportive–expressive, CBT) the patient is exposed to over and in addition to counseling alone and impact of psychiatric symptoms (81). The improvement in psychological functioning is correlated with better overall functioning, including SUD; thus, it is sensible to provide behavioral therapies to patients on methadone who have psychiatric symptoms (82).

Principles for Care Integration There are no research data to demonstrate whether convergent or complementary strategies have more robust effects. In the spirit of constructing multiple obstacles to relapse, clinical practice often engages multiple strategies that may be both convergent and complementary. It is likely that there will be individual patient characteristics such as genetics, addiction severity, comorbidity, and drug of choice that will impact what the optimal combination of medications and psychosocial interventions will be. As such, a stage-wise approach to recovery may help to guide the clinician in choosing an appropriate mix of medication and therapy. The clinician can determine what the important tasks are for this stage in treatment. For example, in establishing abstinence, there are several acute issues that typically need to be dealt with: negative mood states and craving, conditioned cues, access to substances, and immersion in contexts supportive of substance use. Thus, one could pick treatments based upon the impact in those various domains, for example, reducing social isolation and offering social support for sobriety with mutual self-help groups and TSF, BCT, or Network Therapy, supporting treatment engagement with MI, supporting cognitive and coping skills functioning in early recovery with CBT/relapse prevention and/or improving baseline cognitive deficits with appropriate medications, reducing alcohol craving with naltrexone and opioid craving with buprenorphine or methadone, supporting self-efficacy and resilience for craving and negative states with CBT, and reducing substance use with CM and supporting alcohol abstinence with disulfiram or acamprosate. Fortunately, in most cases, appropriately applied interventions are not usually mutually exclusive, but on occasion, this occurs (eg, disulfiram and moderation management).

COLLABORATIVE CARE COUNSELORS PSYCHOTHERAPISTS

WITH AND

Psychosocial interventions typically are provided by practitioners from a variety of disciplines, ranging from noncredentialed counselors (frequently persons in recovery) to licensed psychologists, social workers, licensed professional mental health counselors, registered nurses and nurse practitioners, and marriage, family, and child counselors. Such practitioners differ widely in their attitudes,

preparation, and skills; however, the trend within many states has been to create a licensed group of professional counselors with standardized training and credentials that will slowly become the predominant form of addiction counseling as noncredentialed counselors age out of the workforce. Addiction treatment personnel also vary in the degree to which they are accustomed to working with physicians and other medical personnel. Understanding the background and orientation of specific staff can enhance communication and teamwork.

Counselors In most states, treatment programs that are not certified, licensed, or accredited are ineligible to receive state or federal funding; thus, most state-approved addiction treatment programs require addiction counselors to meet certain competency standards established by state boards or other certification bodies such as the International Certification and Reciprocity Consortium or the Association for Addiction Professionals (NAADAC) (83). Although most states have moved toward credentialing counselors, noncredentialed counselors have been integrated into treatment teams on inpatient units since the 1950s, when the Minnesota Model was developed by Hazelden and Wilmar (84). Before that time, alcoholism was seen as a psychological vulnerability to be treated on mental health units; however, this theoretical framework failed to produce effective treatment. Collaboration by the leaders of Hazelden and Wilmar led to an adaptation of the principles of AA to create a new model within hospitalbased treatment. The blended approaches of Wilmar and Hazelden produced the Minnesota Model, which was the prototype of the 28-day inpatient program. Proponents of the model refined their treatment practices and restructured institutional relationships to emphasize collaboration between professional staff and noncredentialed recovering persons. By 1954, counselors without professional degrees shared both responsibility and decision-making authority. Therapeutic communities (TCs), which developed and expanded in the 1960s, historically relied on recovering noncredentialed staff (85–88). Some of these gifted clinicians and managers subsequently were hired into the private, insurance-funded treatment system, to which they brought their perspective on the importance of developing a culture that supports recovery. Their appreciation of the need to strengthen environmental or microcommunity forces to foster change added an important dimension to the developing professional addiction care model, which presumed that professional services were the primary factor

in promoting change. Currently, nonlicensed, recovering personnel are found in short-term, Minnesota Model, addiction or so-called “chemical dependency” inpatient programs, as peer counselors in co-occurring disorder programs and in community-based addiction treatment programs. They also predominate in TCs that integrate 12-step elements into their conceptual model. Some counselors return to school and obtain graduate degrees and licenses, building the cadre of professionals in recovery. Like licensed staff members, noncredentialed counselors vary widely in talent, experience, and skill. Some have little training, except for occasional inservice training sessions. Others have completed comprehensive credentialing programs and are far more sophisticated than some licensed staff. For example, certificate programs (often attached to universities) may require 200-300 hours of course work plus supervised field placement experience. However, many programs still use the 12-step perspective as a sole orientation and do not include important evidence-based or alternative approaches, including FDA-approved medications for addiction. The current emphasis on incorporating evidencebased approaches exerts a growing influence on these certificate programs. Some counselors have superb skills, as their “street savvy” and personal experience in recovery can produce a highly sophisticated clinician. Others, however, may have rigid, non–patient-centered concepts of recovery (“what worked for me will work for you”) and have difficulty tolerating the ambiguities of complex clinical populations, such as those with co-occurring psychiatric disorders, who may need extended time or harm reduction approaches on the path toward abstinence. Harm reduction approaches are increasingly available in the community and may be effective as engagement strategies, as damage control, or as sufficient intervention for mild to moderate problems (89). These complex patients have always been in the addiction treatment system and are well documented in the epidemiological literature (90) but were not recognized as such, due to lack of training, skills, professional diagnostic evaluation, and program ideology, and so had typically poor outcomes including dropout or termination. In short, physicians should draw conclusions about the skill level of the counselors with whom they work from direct observation, not from inferences based on the presence or absence of credentials. At their best, such counselors, as peers, can present powerful role models, a contribution deeply valued by addicted patients, especially those in early recovery.

Licensed Providers Within addiction treatment settings, one finds licensed professionals, some of whom are recovering, others who are not. Though most such professionals have basic clinical skills, as with any clinician, their ability and comfort in adapting those skills to the addicted patient population may vary greatly. The rigidities of some licensed professionals arise from devotion to theoretical models in which they have extensive training, in addition to their own personality traits. Physicians should be cautious about drawing conclusions from the presence of academic credentials and professional licenses. Graduate schools of nursing, psychology, medicine, and social work typically fail to integrate sufficient training in the assessment and treatment of addiction into their core curricula. This is in spite of the fact that patients with whom graduates will work frequently have SUDs. Typically, such training is provided as an elective (if at all) or in a course mandated by the increasing number of states that require an introductory course for initial licensure or license renewal. Other programs offer extensive training through extension courses or specialized training institutes, and some graduate programs offer addiction treatment as a subspecialty. However, nonphysician health professionals can improve their ability to diagnose and manage SUDs by obtaining additional addiction training and certification, leading to a Certified Addictions RN, Licensed Chemical Dependency Counselor, Certified Tobacco Treatment Specialist, or Masters in Addiction Studies. Physicians should never assume that a professional is knowledgeable in this area. Professionals may underestimate their own lack of knowledge, preferring to believe that the models they acquired in training can be adapted to treating addiction with little modification or that specialized knowledge about treatment of SUDs is unnecessary. Clinical experience alone may tell little about qualifications. A therapist may say, “I’ve been seeing alcohol and drug users for 20 years.” Many psychotherapists have evolved comfortable practice styles whose content bears little relation to those supported by the evidence base or to the experience of addiction specialists. The comfort level of these therapists is sustained because they do not track their patients who drop out of treatment and so do not incorporate those rates and the reasons for those rates as quality feedback into their clinical practice. As such, they have no objective means of monitoring patient progress in becoming alcohol-free and drug-free. This process is also found in many freestanding drug treatment centers, where the failure of the patient to adhere to the strict rules leading to dropout or premature discharge is

explained as “he hasn’t reached his bottom,” compared to the reality that the patient has an untreated co-occurring mental disorder that impairs his abilities to participate in groups, speak coherently, control affect and impulse, etc. Patients frequently report concealing or minimizing their alcohol and drug use during psychotherapy, so this is of clinical importance. In selecting good therapists for referral, physicians should look for evidence of recent systematic training, through either conferences or course work. Such evidence increases the likelihood that the therapist will be familiar with sound treatment practices. Tensions can occur between recovering and nonrecovering staff and between those with and without professional training and licenses. Passions can run high, and clinicians can use basic addiction treatment concepts to express disapproval or to discredit one’s colleagues. The concepts of enabling and codependency in particular have been used to disparage colleagues who take certain positions. They often are used to discourage appropriate forms of helping and to terminate treatment prematurely. Time in treatment is correlated significantly with positive outcomes in a large number of treatment outcome studies (91–94). Thus, engagement and retention of patients in treatment are paramount. Terminating patients for manifesting symptoms of their psychiatric or addictive disorder is simply bad treatment. Physicians also may struggle in dealing with this phenomenon, although other chronic diseases such as asthma, diabetes, and hypertension have compliance rates comparable to those of addiction treatment (26,95). Physicians may need to be the voice of reason, preventing premature termination of the patient while avoiding colluding with patient behaviors that have a negative impact on their or others’ course of treatment or on the overall recovery environment. Physicians in leadership roles should establish weekly in-service training sessions that address both basic and specialized topics. A multidisciplinary team can develop a shared language and will become knowledgeable about integrating the treatment of addiction, psychiatric, and other medical disorders. Some excellent training materials are available at no charge (eg, downloadable Treatment Improvement Protocols published by the federal Center for Substance Abuse Treatment [http://www.ncbi.nlm.nih.gov/books/NBK82999/]) (96). These materials can be used to organize on-site training sessions. Securing continuing education credits for each discipline of the staff enhances participation and commitment to a high-quality training sequence. The National Addiction Technology Transfer Center (www.nattc.org) offers a comprehensive list of institutions offering a certificate, associate, bachelor, master, and/or doctoral program in SUDs. Also included in this directory are

institutions offering a concentration, specialty, or minor in the addiction field. It also offers licensing and certification requirements by state and organization.

Collaboration with Psychotherapists in the Community The diversity of psychotherapists in the community can make effective collaboration even more challenging. The programmatic approach to addiction treatment typically is highly structured, with multiple behavioral expectations. More traditional psychodynamically oriented therapists may have difficulty incorporating behavioral commitments, as their treatment style tends to be more patient and process driven, whereas cognitive–behavioral therapists (who are directive and offer a structured approach to treatment) or those with MI experience (who are comfortable being directive) or with a supportive orientation (7) may more easily adapt to working with an addiction medicine physician. Therapists and counselors in addiction treatment are active and directive, whereas the treatment style of private practice psychotherapists may be more or less compatible with addiction treatment styles. In a recovery-oriented psychotherapy model, the therapist focuses his or her activity according to the tasks faced by the recovering person. These tasks can be conceptualized as recognizing the negative consequences of substance use, making a commitment to abstinence, becoming abstinent and getting sober, and shaping lifestyle transitions to support a comfortable and satisfying sobriety (97). Addiction treatment often includes breath and urine testing if resources permit, whereas general psychotherapists without addiction training rarely arrange for such testing, and many consider it invasive and abhorrent. These differences pose an adaptive challenge to the physician who is arranging for treatment of patients with co-occurring substance use and other mental disorders. Most programmatic outpatient addiction treatment is abstinence oriented, although medical center–based or medical center–affiliated programs have tended to integrate newer, evidence-based treatments into their protocols that can use MI techniques to engage and support patients at the recovery stage they are currently at, in the pathway to abstinence.

Pharmacotherapy

Support

from

Nonphysicians Recovering patients who have conditions that require psychotropic or other medications have clinical needs that have historically been out of the scope of practice of addiction treatment programs, and more traditional programs have slowly incorporated on-site or referral for pharmacotherapy for either addiction or other mental disorders (98). However, in more recent years, the use of pharmacotherapy in conjunction with addiction treatment appears to be picking up, especially with support of professional counseling organizations and nationally known private recovery systems. The use of drugs with a high addiction liability, such as benzodiazepines or opioids, may precipitate relapse to the primary substance. Patients who present for treatment may be taking medications prescribed by physicians who are not trained in addiction medicine. In settings wherein physicians see patients only when specific problems emerge, counselors should use a screening tool that incorporates warning signals (such as prescriptions for benzodiazepines or opioids for pain) that warrant a physician review. Recovering patients may have complex feelings and attitudes toward medications that need to be understood and addressed. Many define recovery as living a comfortable and responsible lifestyle without the use of psychoactive drugs. However, some disorders require psychiatric medications for appropriate treatment, such as antipsychotic agents for schizophrenia or mood stabilizers for bipolar disorder, for without which, risk for relapse to substance use is increased. Family members or 12-step program participants may criticize the patient or pressure them for discontinuation of medication, generating conflict that undermines treatment. Because physicians often lack adequate time to deal with such issues, these tasks should be delegated specifically to other members of the treatment team. Such providers may need additional training to handle medication issues. Family psychoeducation about addiction and co-occurring psychiatric disorders can be helpful in aligning family members to the treatment team and the goals of treatment (5).

Collaborating to Achieve Patients’ Treatment Adherence As discussed above, adherence to treatment recommendations is a key factor in successful treatment outcomes. Hence, physicians should monitor how well the treatment team attends to this issue. As compliance with medication regimens is

far from perfect, even in well-educated middle-class patients who do not have a stigmatized illness, addicted patients, who often have additional psychiatric and medical disorders, have difficulty in this area. As with other patients, carefully eliciting patient concerns and objections is worthwhile. Many behavioral strategies yield poor results because no one took the time to identify the actual obstacles to adherence. Sympathetic, reflective listening, combined with welltimed doses of information, can improve medication adherence significantly. Physicians can help counselors and psychotherapists to understand and explore these issues in their counseling sessions with patients. Nonphysicians vary considerably in their attitudes and education about medication. Time spent on educating therapists usually yields multiple benefits. Certain forms of resistance occur frequently (99). Patients on psychotropic medications often feel ashamed and guilty, believing that they have failed if they cannot master their illness by themselves. For recovering persons, there are added layers of difficulty. Taking a medication to feel better is highly charged, as many link this motive inextricably with their substance use. Even in the case of medications such as antidepressants, which produce no feelings of euphoria or “high,” such guilt can persist. Some patients report they feel they are “cheating,” even though their depression precipitated multiple relapses during the time it was untreated. Rejecting a recommendation for medication may reflect the “all-or-none” thinking characteristic of the person with an SUD. The same patient who at one time consumed every available substance becomes horrified at the idea of “putting something foreign in my body” or “relying on drugs.” With respect to disulfiram (Antabuse), Banys (100) notes that many patients disdainfully describe it as a “crutch.” Even though these are the same patients who used alcohol as a “crutch” for years, they are paradoxically fastidious about this one. Medications such as disulfiram or naltrexone (ReVia) can provide an invaluable (and lifesaving) opportunity to alter behavior patterns; however, patients who use these medications may feel unable to take credit for their achievements. Reliance on the medication can undermine the sense of mastery that ultimately promotes lasting sobriety; for others, it becomes an intermediate stage while recovery concepts are internalized and mastered. Thus, it is important to handle this issue carefully and specifically to each patient when such treatment adjuncts are used. Medication is not a substitute for the work of recovery. For example, a patient taking disulfiram can be asked to keep a daily journal describing situations that would have been hazardous if he or she were not on the medication. The patient then can be asked what behaviors need to be

strengthened (often assertive behaviors) to create safety even in the absence of medication. The decision to discontinue can be implemented once the patient has developed coping skills for the high-risk situations previously identified. However, for some patients with high risk of relapse with major consequences, use of medications over a long period is clinically appropriate. Adherence with medication regimens can be monitored through refill requests. Many states now have prescription monitoring programs for controlled substance, where prescribers of a controlled substance must check a database to make sure the patient is not obtaining the same or similar medications elsewhere. Patients who are adhering to their regimens typically initiate contact with their physicians for refills before the existing supplies expire. Prescribing sufficient doses for a long period deprives the physician of this potential warning signal. Communication with other treatment staff is essential when noncompliance is suspected. Discontinuation of psychotropic medication often is a harbinger of relapse, as distressing psychiatric symptoms begin to reemerge. It may also be an indicator that a relapse already has occurred. It is important to train counselors to follow up on adherence issues and to make sure they know when to contact the physician directly. TIP 42 has good recommendations on this (101). Once counselors are “onboard” with the concepts and recovery utility of pharmacotherapies, it is important for them to identify medication side effects that influence adherence, discuss them with the patient, and facilitate a plan to coordinate with the physician. For example, Johnson et al. (102) have documented that patients with bipolar disorder are more likely to be consistent about medications that reduce the severity of their depressive episodes and do not cause weight gain or cognitive effects. Supporting the patient in a problem-solving process with the physician is an important role for the counselor. In prescribing medications to address withdrawal phenomena, physicians need to communicate to nonphysician therapists what to expect and what might constitute warning signs of impending problems. For example, the therapist may not be aware that a patient given a 3-day supply of chlordiazepoxide (Librium) for alcohol withdrawal by an addiction specialist also may have obtained a month’s supply of diazepam (Valium) from his or her family physician for “back spasm” and thus be in a high-risk situation. Patients who are drinking and using may skip their prescribed medication because they fear their interaction with drugs and alcohol. Physicians should provide guidance to therapists about whether to encourage adherence to medication during these episodes, based on the preferable scenarios. As therapists spend considerable time with their

patients, they are in a good position to detect developing problems and initiate communication with the physician or clinician responsible for coordinating care. The physician needs to discuss with the patient and other members of the treatment team the indications for discontinuing medications and the process by which such discontinuation should occur. Many patients with prescriptions for disulfiram report that they have not had discussions with their physicians on this topic. Physicians should clarify that disulfiram is a tool to allow other accomplishments to take place. The patient needs to review his or her progress with the program staff, a private therapist, or the prescribing physician before discontinuing medication. Patients who are taking antidepressants may go into denial about their psychiatric disorder once they feel better and thus discontinue use of the medication prematurely. The physician needs to educate both patients and nonphysician therapists about the dangers of psychiatric and addiction relapse that attend such a decision. Control issues are common. Some patients will accept the need for prescribed drugs but will tinker with frequency and dose, much as they did with their illicit substances. Some may operate on the assumption that if one pill is good, three are better and escalate their dose of medications even though [that] drug is not usually considered abusable. Drug mixing is another common practice. “Surrendering control of medication use to your physician” is a concept that can be proven useful; under such a scenario, any deviation from the prescribed regimen is the subject of inquiry. Patients who are engaged in serious self-examination may spontaneously report such behavior as a residual part of their addictive pattern. The encouraging news is that collaborative care models have a significant impact on engagement in SUD treatment with improved outcomes in primary care settings. In a federally qualified health center, the SUMMIT RCT of collaborative care provided a population-based management approach including measurement-based care and integrated addiction expertise supporting a 6session brief MI/CBT psychotherapy treatment and/or sublingual buprenorphine/naloxone treatment for OUD or long-acting injectable naltrexone treatment for alcohol use disorder or OUD and, compared to treatment as usual, demonstrated more than doubled SUD treatment engagement (39.0% vs. 16.8%, p < 0.001) and greater alcohol or illicit opioid abstinence at 6 months (32.8% vs. 22.3%, p = 0.03) (103).

REFERENCES

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SECTION 9

Mutual Help, Twelve-Step, and Other Recovery Programs

CHAPTER 76

Twelve-Step Programs in Addiction Recovery Edgar P. Nace

CHAPTER OUTLINE Introduction Other 12-Step Programs Other Non-12-Step Recovery Groups Physician Facilitation of 12-Step Participation Outcome Studies (See Chapter 70 for more Details) Why are 12-Step Programs Effective? Conclusion

INTRODUCTION This chapter describes the structure and usefulness of 12-step programs. Emphasis is placed on Alcoholics Anonymous (AA) as it is the progenitor of all subsequent 12-step programs. The history of AA is described in order to express the complex and varied background to 12-step programs. AA is a fellowship of men and women who offer their hope, strength, and experience to anyone desiring to not drink. Meetings are held at various times throughout the day and evening. There are speaker meetings, step discussion meetings, women’s meetings, and other formats. Participation is anonymous, there is no cost, and questions are not asked of newcomers. Participants are not told what to do but learn what worked for experienced members. The 12-step programs have been beneficial to most of their participants as they attempt to overcome substance use disorders and have been lifesaving for some is well recognized. Empirical support exists for the effectiveness of 12-step programs, although controversy and divergent interpretations will be found (see Chapters 72 and 77). The continuing expansion of such programs and the endorsement of 12-step programs by medical and judicial systems lend further support to their credibility. In this chapter, the physician is encouraged to learn about 12-step programs and urged to educate and encourage patients about this readily available therapeutic modality.

ALCOHOLICS ANONYMOUS AA is an organization that has a single purpose: “to carry its message to the

alcoholic who still suffers” (1). In 2010, AA membership exceeded 2 million, and there were 115,770 groups registered (2). AA does not engage in fundraising or lobbying; it endorses no causes and does not promote itself. It is interested in the person with alcohol use disorder, not alcoholism per se. AA will decline outside contributions and does not provide treatment or educational services. Personal anonymity is a guiding principle. AA refers to itself as a “fellowship.” A fellowship is a “mutual association of persons on equal and friendly terms; a mutual sharing, as of experience, activity, or interest” (3). There are no dues, but a collection is commonly taken at meetings to assure that AA remains self-supporting and not dependent on outside funds. There are no age or educational requirements. All are welcome based on a desire to stop drinking. Admitting that one is an “alcoholic” is not necessary, nor will AA attempt to proffer a diagnosis on an attendee. It is left to each participant to decide whether or not he or she is an “alcoholic” as per AA.

The Program To “work” the AA program means to study the 12 steps (Table 76-1) and to follow the directions contained within these steps. In addition, AA members and AA groups will respect and adhere to the 12 traditions (Table 76-2). The person with an alcohol use disorder learns the steps and traditions and how to follow the same by attending AA meetings, reading AA literature, and working with a sponsor. Working the 12 steps and adhering to the 12 traditions lead to the possibilities listed in the 12 promises (Table 76-3) (4).

TABLE 76-1 12 Steps

TABLE 76-2 12 Traditions

TABLE 76-3 12 Promises

AA meetings may be “open” or “closed.” Closed meetings are for those who consider themselves a “person with an alcohol use disorder” per AA (or as “a person with alcohol use disorder” as medical professionals would refer to them) or are questioning whether they might have this disease. Open meetings are for anyone interested in attending a meeting. For example, when medical students are required to attend an AA meeting as part of their training in psychiatry, they will be taken to an open meeting. If a person with alcohol use disorder did not wish to be seen at an AA meeting except by other people with this disease, she/he would attend only closed meetings. A meeting is usually 1 hour in duration and may be followed by informal socializing. A “speakers” meeting will consist of a member telling her story— emphasizing “what it was like” (the drinking experience), “what happened” (the process of recognizing the consequences of drinking and doing something about it), and “what it is like now” (how life has changed since beginning recovery from alcoholism). Step meetings will focus on one of the 12 steps in a discussion format. Discussion meetings are those where a topic is picked (eg, “gratitude”)

and the group shares thoughts and experiences of the same. Each group is autonomous. A small collection is commonly taken, but groups are cautious not to let a till be built up as that can lead to conflict over how to use the money. Instead, the collection is spent on coffee, on purchases of the book Alcoholics Anonymous, or on other AA literature. Today, it is common for the leader of any group to initial a proof of an attendance form for an attendee who may be required to document his or her attendance for the court, for a professional organization, or for any other reason. An issue that many groups may confront is whether to include persons who attend because of a drug use disorder rather than an alcohol use disorder. Some AA members and some groups will believe that those with a substance use disorder (other than alcohol) would be better served in similar 12-step programs such as Narcotics Anonymous (NA) or Cocaine Anonymous (CA). If a new person arrives at an AA meeting and indicates that his or her problem is heroin or cocaine or pills, occasionally that person will be advised to attend other 12step meetings such as those mentioned above. This can be awkward or embarrassing and occurs infrequently. Since clinical wisdom typically advises those with drug problems to avoid alcohol as well, the person who uses drugs can fit into AA based on his or her desire not to drink (even if alcohol was not the problem). Most new members will attend several different groups in order to find one where they feel most comfortable (a “home group”). It is not unusual to hear persons say as they struggle to get comfortable with AA that they hear the same thing over and over again, that one person talks too much, or that they cannot identify with those in the meeting (“I’ve never been in jail,” “I’m better educated,” etc.). With time, such individuals may see that they do have a common bond with those who are different from them in terms of life experiences as they recognize that they all share the struggle to not drink. A good attitude toward meetings was expressed by a recovered alcoholic counselor who when asked “Hey, how was the meeting last night” would respond “It was great; I didn’t drink the whole time I was there.” Most AA groups will have people who serve as the “group conscience.” This is a committee of sorts that will address group problems should they occur. An example would be the member who took money from the collection basket for personal use. This action, noticed by another member, took the issue to those who comprise the group conscience. The member who took the money would be confronted and asked to make amends—that is, confess, apologize, and return the money to the group. This direct process usually proves to be satisfactory. The group conscience might also determine when and how to spend whatever monies

have accrued.

Sponsorship Sponsorship may be seen to derive from Steps 5 and 12 (see Table 76-1). A sponsor is an experienced AA member with sustained sobriety. How long should one be sober before serving as a sponsor? There is no fixed rule as to length of sobriety, but most AA members would expect at least 1 year of continuous sobriety and preferably 2 years. It is not expected that all AA members will eventually be a sponsor for another AA member. It is expected that those who sponsor other members remain committed to attending meetings, read AA literature, and be available to meet with those they sponsor. AA estimates that 78% of members are sponsored (5). Sponsors are more likely to be older than those sponsored and are more likely to be married and/or be parents and be religious/spiritual compared to those who do not serve as sponsors. The details of one’s substance use do not distinguish those who sponsor or those who seek sponsoring (6). New members to AA, as well as members who have relapsed or been without a sponsor for a prolonged period of time, are encouraged to ask for a sponsor. The sponsor offers a helping hand and serves as a mentor. He or she guides the person being sponsored in understanding the 12 steps and typically goes over each step with the person being sponsored. A very specific function of a sponsor is to have the member make “a searching and fearless moral inventory” of himself or herself (Step 4). The person being sponsored then admits “to God, to ourselves, and to another human being (the sponsor, usually) the exact nature of our wrongs” (Step 5). Sponsors often have their member do the steps over again or review specific steps or read selected passages from Alcoholics Anonymous (referred to informally as the “Big Book”). Some sponsors will ask to be called each day to review the day’s activities. Other sponsors are less intense but most will meet their member at a meeting on a regular basis. The relationship is informal, and styles of sponsoring vary. A rule of thumb is to have a same-sex sponsor. The neophyte to AA need not hesitate to ask someone to be a sponsor out of fear of being a burden, as those who sponsor feel that they benefit from the relationship—“you keep it (sobriety) by giving it away.” Further, the new member need not look for the perfect person to be his or her sponsor nor be looking for the best friend he or she might find. Certainly, the member will want to ask a person to be a sponsor because the member respects how the prospective sponsor works the program and because he or she feels

some general compatibility. Having a sponsor is a major part of working the program and has priority over the “personality” of the sponsor.

Predecessors to Alcoholics Anonymous June 10, 1935, is the founding date of Alcoholics Anonymous. That date is the last day that Dr. Bob Smith took a drink—a beer to steady his nerves before surgery. Dr. Bob and Bill Wilson had met in Bob’s hometown of Akron, Ohio, in May 1935, and became the cofounders of AA (7). Their unplanned yet fateful meeting would spur the formation of the most successful self-help movement known. However, for at least the 100 years prior to the founding of AA, various grassroots efforts had emerged to address the disease of alcoholism. Their brilliant yet brief efforts failed and are historically obscure. Nevertheless, as we shall see, these efforts laid a foundation upon which AA would grow. Nearly 100 years before the founding of AA, the Washingtonian Total Abstinence Society was formed in 1840 in Baltimore, Maryland. Six men, members of a drinking club, decided after hearing a lecture on temperance to quit the club and form the Washingtonian society. They initially held private meetings, met nightly because they had been drinking nightly, and invited local people with this disease of alcoholism to attend. Later, they held public meetings as interest in their society was growing, assessed dues, and formed committees to recruit others struggling with alcohol (8). In 1841, a branch for women was formed—the Martha Washington Society (9). The Washingtonians grew rapidly but did not develop a central organization, became divided over the issue of alcohol prohibition, and began to fade away by the end of the decade. AA is similar in that mutual self-help, personal shared commitment, and a religious/spiritual foundation are utilized. AA has wisely avoided political concerns (eg, the prohibition issue) and, unlike the Washingtonians, does not rely on charismatic speakers to carry the message, nor does AA assess dues. Following on the heels of the Washingtonians was the Independent Order of Good Templars, founded in 1851. A pledge of abstinence was required, and expulsion could be expected if the pledge was not kept. Many other fraternal temperance societies and reform clubs formed during the 19th century and emphasized anonymity, a principle later adopted by AA. Early in the 20th century, numerous mutual aid societies to help people with alcohol use disorder flourished at least for awhile. They included, for example, the United Order of Ex-Boozers, the Keeley Leagues, the Emmanuel Clinic, and the Oxford Group (7). The Oxford Group, also now out of existence, was a

direct predecessor of Alcoholics Anonymous. The Oxford Group considered spiritual growth as the solution to many of mankind’s problems. “Four absolutes”—absolute honesty, absolute purity, absolute unselfishness, and absolute love—were necessary as well as the “five Cs,” confidence, confession, conviction, conversion, and continuance, for spiritual change to occur. Founded in the early 1900s, the Oxford Group strove to recapture the fervor of 1st-century Christianity. The group was not founded to specifically help people with alcohol use disorder, but under the leadership of Episcopal priest Rev. Sam Shoemaker, it became active with such people in New York City (7). Shoemaker’s church, Calvary Episcopal, was the headquarters of the Oxford Group in New York City where a seminal figure in the early days of AA found a spiritual home. This figure was Roland H. who was from a wealthy Connecticut family had suffered from a chronically active alcohol use disorder (many periods of intoxication) and who had exhausted his family’s financial resources. Roland H. went to Zurich for analysis with Carl Jung and subsequently returned to New York confident that he had been cured. He promptly was intoxicated again, returned to Jung, and was told that psychiatry and medicine could do nothing for him, but there was hope, however uncertain, of a spiritual experience that might release him from drink. While visiting with Jung, Roland H. joined the Oxford Group, which was very active in Europe. Apparently, he had a conversion experience, returned to New York, and began to share his experience with others with alcohol use disorder (10). Using his experience with the Oxford Group, Roland H. encountered an old friend Edwin Thatcher (a.k.a. Ebby) who in 1934 was about to be committed to a state institution. Ebby responded to Roland H.’s outreach and attended Oxford Group activities. This led to a period of sobriety for Ebby, which was accompanied by friendship from the Oxford Group. It must be apparent now to any familiar with AA that a nascent process of one person with alcohol use disorder reaching out to another was in effect. Ebby had a friend, the hopeless alcoholic Bill Wilson. Kurtz (10) describes Ebby’s outreach to Bill wherein they sat at Bill’s kitchen table in Brooklyn as Ebby describes that he is not “on the wagon” but that he has religion and is a changed person. Bill, drinking, offers Ebby the same but is turned down. Ebby explained to Bill the impact of the Oxford Group, its origins on the Princeton campus, and its spread to Oxford and beyond. Bill was apparently embarrassed, if not feeling betrayed, by his friend’s display of religion and the resulting change. Thomsen (11) reports that Bill had heard of the group but considered them too zealous for Christ, too rich, and too social. According to Thomsen, Ebby sensed Bill’s discomfort with talk of God and began to use the term “another power” or

“higher power” (p. 209). This watering down of religious terms may have influenced current language of AA, which uses the phrase “higher power” in addition to referencing God.

The Birth of Alcoholics Anonymous Bill Wilson continued drinking, and Ebby continued to visit and brought other Oxford Group members with him. Bill finally went to an Oxford Group meeting, was intoxicated, and spoke but does not remember what he said (11). Bill, fearing brain damage, checked himself into Towns Hospital where he had been detoxified several times in the past. William D. Silkworth was a neurologist who took care of Bill and who had a reputation for helping people with alcohol use disorder—an estimated 50,000 over the course of his medical career. During this hospital stay, Bill was depressed and resistant to the notion of a “higher power.” Bill described that during that stay in Towns Hospital, he had cried out in despair, experienced the room lit up with a white light, and felt ecstatic. He asked Dr. Silkworth if this was the effect of brain damage, and Silkworth reassured him that it was not (10). Bill then returned to the Oxford meetings sober and with his wife. Encouraged by Rev. Shoemaker and counseled by Dr. Silkworth, Bill shared his drinking experiences with others with this same disease after the Oxford meetings and began to sense that one such person talking to another in a nonjudgmental manner was a tool or a dynamic that helped him stay alcohol-free. Over the next 6 months, Bill fervently told his story to other people with alcohol use disorder. He stayed sober, but they did not. Bill, discouraged, returned to his work as a stockbroker. A proxy fight took him to Akron, Ohio, in May 1935. The proxy fight was lost, and Bill found himself alone in Akron on a Saturday afternoon. He wanted to drink and headed toward the hotel bar but became very anxious over what he was about to do. Providentially, he went back to the lobby and called a minister, Rev. Walter Tunks, who was listed on the church directory. Tunks provided some names of people Bill might talk to. He reached Henrietta Seiberling, a member of the local Oxford Group and who was the daughter-in-law of the president of Goodyear Tire. She, who did not have alcoholism herself, had been trying to help a local surgeon who was in her Oxford Group and invited Bill to her house the next day to meet Dr. Bob Smith. Dr. Bob Smith had been through numerous treatments and was considered hopeless. He apparently looked poorly, and Bill planned that the meeting would be brief. Bill talked about his past broken promises and his failures related to his

disease. He did not talk down to Dr. Smith but reviewed his treatments and his visits from Ebby. Kurtz (10) described the conversation: “This stranger from New York didn’t preach; he offered no ‘you must’s’ or even ‘let’s us’s.’ He had simply told the dreary but fascinating facts about himself, about his own drinking.” Bill thanked Bob for hearing him out and knew now he (Bill) was not going to take a drink. Bob, while listening to Bill, would say “Yes, that’s like me, that’s just like me” (10). Bill remained sober thereafter, but Bob went to a medical convention in Atlantic City and returned intoxicated to Akron. With Bill’s help and the help of Dr. Bob’s wife, Bob acquired lasting sobriety on June 10, 1935. That date is considered the founding of Alcoholics Anonymous.

The Growth of Alcoholics Anonymous The identity of AA gradually took shape beginning in the late 1930s. Initially, AA meetings were held within the structure of the Oxford Group. But the Oxford Group wanted publicity and AA did not. The Oxford Group was protestant and many coming to AA were Catholic. The Oxford Group was zealous about their beliefs, and AA wanted to accept all comers, believers or not. AA was able to form its own identity by 1939 when the book Alcoholics Anonymous was written by Bill Wilson (11). The book—Alcoholics Anonymous (12)—remains the “bible” of AA, and every member is encouraged to read it. Its reviews when first published were discouraging—“no scientific merit or interest” (11). There were about 100 members when AA officially adopted the name “Alcoholics Anonymous” in 1939. Articles in popular magazines such as the Saturday Evening Post helped with publicity, and growth began to rapidly take place. As sales and membership increased, AA wisely curbed dissension and conflict by committing itself “to corporate poverty, group authority rather than personal authority and leadership, and the lowest level of organization necessary to carry AA’s message of recovery” (7). When Dr. Bob Smith, cofounder of AA, died in 1950, there were about 90,000 members. A 2007 survey by the General Service Office of AA estimated that worldwide, there were nearly 2 million members with about 1.2 million of these members being in the United States. This survey found that 74% of members’ doctors know that they are in AA and that 63% of members had received some counseling or treatment by physicians, clergy, or others prior to joining AA. Members reported attending an average of 2.4 AA meetings a week, and 79% of members had an AA sponsor (2).

OTHER 12-STEP PROGRAMS Narcotics Anonymous NA is the second largest 12-step program focused on substance use disorders. NA grew out of AA in Los Angeles in the late 1940s and follows the format of AA with its 12 steps and 12 traditions. NA substituted the word “addiction” for alcohol removing drug-specific references. NA is open to all people with substance use disorders without regard to the type of drug or combination of drugs. NA literature describes the purpose of NA as follows: “NA is a nonprofit fellowship or society of men and women for whom drugs had become a major problem. We … meet regularly to help each other stay clean. … We are not interested in what or how much you used … but only in what you want to do about your problem and how we can help” (12). In 1983, NA published its basic text—“Narcotics Anonymous.” The organization has continued to grow with over 2900 weekly meetings by the mid1980s and, as of May 2010, reported meetings worldwide involving 58,000 weekly meetings and NA literature available in 39 languages. NA members are likely, on the average, to be younger than AA members. NA in its 2009 survey reports that 2% are under age 20, 14% age 21-30 (contrasting with 8% per the 2007 AA survey), and only 4% over age 60 (contrasting with AA with over 16% over age 60).

Cocaine Anonymous CA began in Los Angeles in 1982. CA is adapted from the AA program and follows the 12-step model. It is open to all individuals who want to stop using cocaine as well as all other addictive substances. CA literature is available in French and Spanish as well as English. Its first book was published in 1996: Hope, Faith, and Courage: Stories from the Fellowship of Cocaine Anonymous. As of 1996, membership was estimated to be 30,000 members in 2000 groups (13).

Marijuana Anonymous Marijuana Anonymous (MA) was founded in June 1989 and is based on the 12-

step program of Alcoholics Anonymous (14). MA is for those who experience marijuana as controlling their lives. The above website states: “We lose interest in all else; our dreams go up in smoke. Ours is a progressive illness often leading us to addiction to other drugs, including alcohol. Our lives, our thinking, and our desires center around marijuana-scoring it, dealing it, and finding ways to stay high.” MA meetings are far fewer in number than the older 12-step programs but can be found in most urban areas and can be accessed online. Attitudes about marijuana use lean toward legalization in some circles, and “medical marijuana” (perhaps better termed “cannabis as medicine”) is available in several states. If the latter trend continues, it will be important to determine if increased rates of cannabis use disorder develop. Potentially, MA could become more prominent in countering pathological use.

Nicotine Anonymous Nicotine Anonymous, formerly Smokers Anonymous, was founded in the early 1980s and is modeled on AA. There are fewer meetings than the more commonly used 12-step programs, for example, 14 meetings are listed in the state of Texas and 38 in the state of New York (15). Nicotine Anonymous, as with other 12-step programs, emphasizes that the user is neither unique nor alone. They emphasize the importance of sharing experiences and reaching out to sponsors, for example, their slogan—“to postpone it, phone it.” That most smokers have quit without formal help, including nicotine replacement treatment, may account for the underutilization of Nicotine Anonymous by the public and the medical profession. Since ~15%-20% of Americans continue to smoke, an awareness of this resource is important.

Gamblers Anonymous Gambling disorder was included in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) (16). It is part of the “substance-related and addictive disorders” section as a “non-substance-related disorder.” Decades before gambling disorder became an official diagnosis, those inflicted by “gambling addiction” found a way to organize their own “self-help” organization: Gamblers Anonymous. As with substance use disorders, a 12-step approach is seen as helpful to those with gambling addiction. Gamblers Anonymous had its first meeting September 13, 1957, in Los Angeles, California. The prelude to this formal beginning was the experience of

two men who had been meeting with each other since January of 1957, encouraging each other to avoid relapses. They used spiritual principles that they understood had helped others struggling with compulsive behaviors. These principles included honesty, humility, kindness, and generosity (17). Gamblers Anonymous follows a 12-step program nearly identical to that of Alcoholics Anonymous. The compulsive gambler is seen to be in the grip of a progressive illness where one bet is the same as one drink to a person with alcoholism—the start of a progressive destructive process. The only requirement for attendance is a desire to stop gambling. This starts with conceding fully that they are compulsive gamblers, out of control over betting, and in need of bringing about a character change within themselves (18).

Al-Anon and Alateen Al-Anon is an international fellowship of friends or relatives of people with alcohol use disorder who have been impacted by another’s drinking. They share their experience, strength, and hope and follow their own 12-step format. AlAnon is not family or group therapy and does not provide counseling in any formal sense. Alateen grew out of Al-Anon and is for teenagers 13-17 although the age range may vary by group. An Alateen meeting is sponsored by Al-Anon members; adults do not attend except for a few Al-Anon sponsors. Al-Anon was founded in 1951 by Lois Wilson who was the wife of AA cofounder Bill Wilson. In “Lois’s Story” (19), Lois Wilson describes her own unhappiness even after her husband became sober. She realized that much of her life had been directed toward helping Bill get sober and that now she had to develop her own spiritual life. Al-Anon meetings will focus not on the drinker but on the family member or friend of a drinker who tolerates abuse, or who indulges in excessive caretaking, and who may have developed low self-esteem because he or she thought he or she should be able to help the person with alcohol use disorder stop or control alcohol use. Al-Anon members will learn that they did not cause the alcoholism and cannot cure it or control it but are affected by it and, therefore, need help for themselves. Al-Anon members in the United States are mostly women (60% to 80%). One-half of members are married, and a third have a college degree (20). A 2006 survey by Al-Anon reported 88% of members were Caucasian, 58% were married, and 85% were female. Eighty-two percent reported that their mental

health was improved since attending Al-Anon (21).

OTHER GROUPS

NON-12-STEP

RECOVERY

SMART Recovery In 1985, Rational Recovery was founded; it was the forerunner to what is now Smart Recovery. Rational Recovery’s first meeting took place in a hospital in Cambridge, MA, in 1990. In 1994, the board of Rational Recovery Self Help, Inc. voted to change the name to SMART Recovery (Self Management And Recovery Training). A full chronology of SMART Recovery has been compiled by Shari Allwood and William White and can be downloaded from www.smartrecovery.org. SMART Recovery offers tools and techniques to implement its four-point program, which involves: (a) building and maintaining motivation; (b) coping with urges; (c) managing thoughts, feelings, and behaviors; (d) living a balanced life. Reliance on self-empowerment is emphasized, rather than commitment to a spiritual orientation, although each participant is encouraged to use what is found helpful. Online meetings, as well as face-to-face meetings, are available, and the organization states that it is committed to evolving as more scientific knowledge becomes available.

Women for Sobriety Women for Sobriety, founded in 1976, is an abstinence-based program. Although physical recovery is claimed to be the same for both sexes, Women for Sobriety asserts that the psychological recovery is different for women. A 13-point program of affirmations is to be utilized daily in order to remove negative thinking and to develop a sense of self. The organization claims to have a worldwide presence and states that hundreds of meetings are held daily. Their website is www.womenforsobriety.org.

Secular Organizations for Sobriety

A nonprofit group founded in 1985, Secular organizations for Sobriety is directed at those who wish to avoid a religious or spiritual approach to recovery, such as might be expected in traditional 12-step programs. Information on where to find meetings, products related to the organization, and meeting locations can be found on the website www.sossobriety.org.

PHYSICIAN FACILITATION OF 12-STEP PARTICIPATION Physicians and other clinicians would do well to inform patients of the existence, format, and benefits of participating in a 12-step or other self-help programs. This obligation is based on empirical evidence that AA participation (and by extension use of other 12-step programs) and engagement/commitment to AA are consistent predictors of positive outcomes for those patients (22). Even attendance at AA (apart from “commitment”) produces modest yet positive results (23). Should AA or other 12-step programs be recommended for only certain individuals? There is no basis to restrict recommendations to participate in 12-step programs based on individual demographics or characteristics. Strickler et al. (24) found that patients referred to self-help groups while in formal treatment programs are significantly more likely to attend after completing the program and that race, employment status, marital status, and education did not affect who followed through with 12-step participation. However, some patients, for example, those with a social anxiety disorder, may find it difficult to engage in a 12-step setting although it should not be assumed that anxiety states preclude participation. The patient with a severe mood disorder or a psychotic disorder may not be able to participate until stabilization or remission is accomplished. Today, there are AA meetings for persons with an additional psychiatric disorder such as bipolar disorder, schizophrenia, etc. These groups are sensitive to “coexisting psychiatric disorder” concerns. AA does not diagnose or offer medical advice. Twelvestep programs are not “against” prescribed medications for members. This is true for maintenance medications including buprenorphine and methadone. The pamphlet “The AA Member-Medications & Other Drugs” (available from Alcoholics Anonymous World Services, Inc., 475 Riverside Drive, New York, NY 10115) explains the AA position and emphasizes to AA members that they be honest with their physicians about their alcoholism and any use of drugs as

well as how medications may be affecting them.

Practical Information and Advice for Your Patients 1. Offer a brief explanation of 12-step programs. For example, they are a fellowship of men and women who offer their hope, strength, and experience to anyone desiring not to drink or do drugs. There is no cost, the meetings are at various times throughout the day or evening, participation is anonymous, questions are not asked of a newcomer, and there are different formats—for example, women’s meetings, speaker meetings, step discussion meetings, and so forth. 2. After your patient has attended 12-step meetings, ask what they have heard, whether it has been helpful, and whether or not there are aspects of the program that they do not understand or agree with. Try to discern whether your treatment approach and advice to the patient are in synchrony with what they are learning in the 12-step program. If you find contradictions or conflict between your treatment approach and what the patient is reporting from AA, try to resolve and explain any possible differences. Occasionally, an AA member may advise that one not take certain medications. AA as an organization offers no opinion on medical matters, so it may be necessary to review with a patient the rationale for your course of treatment that an AA member (not AA itself) finds objectionable. Obviously, this requires tact and patience. It is important that the patient see that he/she can benefit from your medical input as well as what the 12-step program has to offer.

Countering Objections The clinician encouraging a substance using patient to attend a 12-step program can expect to counter objections, reasons, or excuses as to why this recommendation is objectionable. Resistance to attending may be based on the following: 1. Fear of stigma. To attend confers an identity of having a “problem” and thereby the potential stigmatizing effect. That one may feel stigmatized or, in fact, be stigmatized by others is not uncommon. The patient may be reassured that if others learn of his or her “problem” but see that it is being effectively addressed (as may occur through 12-step participation), the issue

of stigma typically is replaced by respect for this positive change. 2. “I can’t identify with them.” A patient may go to a 12-step meeting and feel out of place not on the basis of the substance experience that brought him or her there but on the characteristics of the group itself. The usual recommendation is that a person try several different meetings and eventually find a “home group” where he or she is most comfortable on the basis of the people he or she has met or where the meeting is located. It is recognized that in some instances, a woman may be most comfortable in an all-female group and a professional more comfortable in groups with people of similar daily experiences.

OUTCOME STUDIES (SEE CHAPTER 70 FOR MORE DETAILS) Support for encouraging AA (and by extension other 12-step programs) is found in several large studies. Please also see Chapter 70 in this textbook. Project Match compared patients with alcohol use disorder randomly assigned to cognitive–behavioral therapy (CBT), motivational treatment (MT), and 12-step facilitation (TSF). TSF is a professionally led group therapy, which points patients to 12-step participation. In the outpatient arm of this study, TSF patients had significantly higher rates of abstinence at 1- and 3-year follow-ups (25,26). AA participation for those in the other treatment arms—CBT and MT—also predicted abstinence (25). A large Veterans Administration study found that at 1 year and at 18 months, those whose aftercare was only AA or another 12-step program had abstinence rates twice those who did not attend any 12-step program (27). The rate of abstinence for the 12-step participants was ~45%, whereas for the nonparticipants, it was just under 25%. Further, the number of meetings attended functions in a dose–response relationship. Fifty or more meetings attended in months 9-12 in a 1-year follow-up resulted in higher rates of abstinence (about 60%) compared to 1-19 meetings (30%) (28). Addiction is well known to be a chronic illness that requires monitoring over time to assess outcomes. In that regard, AA attendance on a regular basis for at least 27 weeks in a given year has been found to yield to 70% abstinence by year 16 of followup (29). For those interested in detailed accounts of follow-up studies, see Ferri et al. (30).

WHY ARE EFFECTIVE?

12-STEP

PROGRAMS

No one answer or variable is known to explain why any one individual benefits from 12-step participation. There are, however, several dynamics that may account for or explain, at least in part, why benefit ensues. 1. Group dynamics clearly are in effect in 12-step meetings. Elements of group process include hope, information, learning, catharsis, and universality (31).

Universality refers to feeling connected to others’ experiences and the value for others of one’s own experience. Catharsis follows from being allowed to speak without condemnation. Group cohesiveness, which includes a sense of belonging, predicts continued engagement and increased rates of abstinence for those who experience “cohesion” at meetings (32). 2. Growth of the self: the self can be thought of as the collection of ideas we have about ourselves including our motivations, feelings, and ideas as they are expressed in and formed by relationship to others and by the choices we make (33). The maturing or growth of the “self” is a potentially vital aspect of 12-step participation and possibly occurs by virtue of the following: a. Improved self-governance—Self-governance refers to the capacity to sense oneself as an autonomous being capable of taking charge of one’s life yet in need, interdependently, of relationship with others. It differs from what are called the executive functions of the ego (planning, initiating, correcting, and completing behavior) as it acknowledges interdependence between self and others. A sharing of control with others is implied, which is particularly apt for the person with alcoholism who has lost control over alcohol consumption. Acceptance of supportive, caring interaction with others provides a counterbalance to the drive to drink through a “borrowing” of self-governance from the group (34). As a result, self-care skills are improved as the individual internalizes from the group the values of impulse control, anticipation of consequences, and good judgment. b. Self-awareness—Persons with substance use disorders not infrequently have undeveloped skills in recognizing, regulating, or tolerating affect (35). Fear of painful emotions or difficulty tolerating emotional pain is resolved by the immediate gratification of a drug. Further, some will have poor stress management skills and seek immediate gratification from substances. The 12 steps emphasize reflection (see Table 76-1), and the 12 promises (4) include “we will comprehend the word serenity” and “we will know peace.” Thus, participants learn from the experiences of others that change is possible and are asked to take to heart AA slogans such as “easy does it,” “one day at a time,” and “live and let live.” c. Self-deflation—Early students of alcoholism (36) recognized that defiance and grandiosity would stand in the way of accepting “powerlessness” over alcohol (or other drugs). An overvaluation on self-sufficiency and counter-dependent attitudes may form if one has experienced early empathic failures and thereby compensate by only

relying on oneself (37). Therefore, it may be a struggle to accept the “powerlessness” required in Step 1 and the turning of will and “our lives over to the care of God as we understood him” (see Table 76-1). Twelve-step programs counter narcissistic (self-sufficient) attitudes by emphasizing humility, service, and acceptance of vulnerability (10). Acquisition of these attitudes may lead to fulfillment of the 12-step promise: “Self-seeking will slip away” (4). 3. Experiencing Empathy—The person with a substance use disorder is used to feeling ashamed or debased. How differently he or she is treated at a 12step meeting: others understand what the person has been through and what struggles lie ahead; the person feels protected in this environment; his or her experience is valued not criticized as it might be useful to someone else; demands to change are not made, but one is encouraged to “keep coming back”; and the attraction of drugs or alcohol is openly acknowledged but linked with the understanding that “we couldn’t handle it” (38). 4. Spirituality—12-step programs emphasize spirituality rather than a specific religious creed. Reference to God occurs throughout the 12 steps and the 12 traditions, but an emphasis is put on each individual’s understanding of “higher power.” But how is spirituality manifested in the context of a 12-step program? Spirituality may be experienced as a release from the compulsion to use substances. This “release” may occur slowly or, in some instances, suddenly and is experienced as having been “given” rather than being achieved. From a decrease in the compulsion to use substances emerges a feeling of gratitude, which promotes thankfulness for what one has rather than what one does not have. Humility is part of spirituality and accompanies acceptance of being “powerless” over alcohol (or drugs). Further, a sense of forgiveness likely occurs and can be a powerful incentive for continuing constructive changes. Steps 5-10 imply a seeking of forgiveness as one honestly addresses behaviors connected to the addicted state or which have been embedded in one’s character. Emmonds (39) has empirically demonstrated that goals that have religious significance promote personality integration and help to resolve the pernicious effects of mental conflict. The above-proposed mechanisms as to why 12-step programs change persons’ lives are, of course, incomplete. Many in AA or other 12-step programs would explain the benefits simply from their having “worked the steps.” This may be as sufficient an explanation as we need and certainly is the most practical.

CONCLUSION Understanding 12-step programs, as well as programs that are not 12-step based, will allow physicians as well as other clinicians to confidently recommend these programs to patients in need. Referral requires no variables to be considered beyond the desire to be free from alcohol or drugs. No cost is incurred by the patient beyond the expenditure of time. Age, gender, ethnicity, education, or status will not limit the potential utility of active participation. Resistance to and objections about 12-step programs can be expected. A calm encouraging stance will usually overcome initial fears or concerns. Participation in a 12-step program does not conflict with or replace other clinical interventions such as medicine, psychotherapy, or commitment to a religious preference. As careful consideration of the costs of medical care continues to grow, we welcome volunteer, supportive entities with demonstrated records of accomplishment and acceptance such as 12-step programs.

REFERENCES 1. Alcoholics Anonymous. Alcoholics Anonymous: Twelve Steps and Twelve Traditions. New York, NY: Alcoholics Anonymous World Services, 1978. 2. Alcoholics Anonymous. A.A. Fact file. http://www.aa.org/pdf/products/m-24_aafactfile.pdf. Accessed November 21, 2013. 3. Webster’s New Twentieth Century Dictionary of the English Language, Unabridged. 2nd ed. New York, NY: William Collins Publishers, 1980. 4. Alcoholics Anonymous. Alcoholics Anonymous: The Story of How Many Thousands of Men and Women have Recovered from Alcoholism. 4th ed. New York, NY: Alcoholics Anonymous World Services, 2001. 5. Alcoholics Anonymous. Alcoholics Anonymous 2007 Membership Survey. New York, NY: Alcoholics Anonymous World Services, 2008. 6. Young LB. Alcoholics anonymous sponsorship: characteristics of sponsored and sponsoring members. Alcohol Treat Q. 2012;30:52-66. 7. White WL. Slaying the Dragon: The History of Addiction Treatment and Recovery in America. Bloomington, IL: Chestnut Health Systems/Lighthouse Institute, 1998. 8. Tyrell I. Sobering Up. Westport, CT: Greenwood Press, 1979. 9. Maxwell M. The Washingtonian movement. Q J Stud Alcohol. 1950;2:410-451. 10. Kurtz E. Not-God: A History of Alcoholics Anonymous. Center City, MN: Hazelden, 1979. 11. Thomsen R. Bill W. New York, NY: Harper & Row, 1975. 12. Narcotics Anonymous. An introduction to narcotics anonymous. http://na.org/admin/include/spaw2/uploads/pdf/servicemat/2012Jun_Intro_to_NA_Meetings.pdf. Accessed November 21, 2013. 13. Cocaine Anonymous. Cocaine anonymous fact file. http://ca.org/pdf/Conference/PI/WSCPI_FactFile2007.pdf. Accessed November 21, 2013. 14. Marijuana Anonymous. For the newcomer. https://www.marijuanaanonymous.org/images/pamphlets/p01-en-ltr.pdf. Accessed November 21, 2013.

15. Nicotine Anonymous. Introducing nicotine anonymous. http://www.nicotineanonymous.org/publications_content.php?pub_id=533. Accessed November 21, 2013. 16. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Association, 2013. 17. Gamblers Anonymous. History. Gamblers Anonymous website. http://www.gamblersanonymous.org/ga/content/history. Accessed December 2, 2016. 18. Gamblers Anonymous. About Us. Gamblers Anonymous website. http://www.gamblersanonymous.org/ga/content/about-us. Accessed December 2, 2016. 19. Al-Anon Family Group. “Lois’s story”. In: How Al-Anon Works for Families and Friends of Alcoholics. Virginia Beach, VA: Al-Anon Family Group Headquarters, 1995:136-137. 20. Humphreys K, Kaskutas L. World views of Alcoholics Anonymous, Women for Sobriety, and Adult Children of Alcoholics/Al-Anon Mutual Help Groups. Addict Res. 1995;3(3):231-243. 21. Al-Anon Family Groups. Member Survey Results. Virginia Beach, VA: Al-Anon Family Group Headquarters, Inc., 2006:2-5. 22. Weiss R, Griffin M, Gallop R, et al. Self-help group attendance and participation among cocaine dependent patients. Drug Alcohol Depend. 2000;60(2):169-177. doi: 10.1016/S0376-8716(99)001544. 23. Forcehimes A, Tonigan J. Self efficacy as a factor in abstinence from alcohol/other drug abuse: a meta-analysis. Alcohol Treat Q. 2008;26(4):480-489. 24. Strickler GK, Reif S, Horgan CM, et al. The relationship between substance abuse performance measures and mutual-help group participation after treatment. Alcohol Treat Q. 2012;30:190-210. 25. Project MATCH Research Group. Matching alcoholism treatment to client heterogeneity: project MATCH posttreatment drinking outcomes. J Stud Alcohol. 1997;58:7-29. 26. Project MATCH Research Group. Matching alcoholism treatment to client heterogeneity: project MATCH three-year drinking outcomes. Alcohol Clin Exp Res. 1998;22:1300-1311. 27. Kaskutas LA. Alcoholics Anonymous effectiveness: faith meets science. J Addict Dis. 2009;28:145157. 28. Ouimette PC, Moos R, Finney J. Influence of outpatient treatment and 12-step group involvement on one-year substance abuse treatment outcomes. J Stud Alcohol. 1998;59:513-522. 29. Moos R, Moos B. Paths of entry into Alcoholics Anonymous: a 16-year follow-up of initially untreated individuals. J Clin Psychol. 2006;62:735-750. 30. Ferri M, Amato L, Davoli M. Alcoholics Anonymous and other 12-step programs for alcohol dependence. Cochrane Database Syst Rev. 2006;3: Art. No. CD005032. 31. Yalom ID. The Theory and Practice of Group Psychotherapy. 2nd ed. New York, NY: Basic Books, 1975. 32. Rice SL, Tonigan JS. Impressions of Alcoholics Anonymous (AA) group cohesion: a case for a nonspecific factor predicting later AA attendance. Alcohol Treat Q. 2012;30:40-51. 33. Vitz PC, Felch SM, eds. The Self: Beyond the Postmodern Crisis. Wilmington, DE: ISI Books, 2006. 34. Mack JE. Alcoholism, AA, the governance of self. In: Bean MH, Zinberg NE, eds. Dynamic Approaches to the Understanding and Treatment of Alcoholism. New York, NY: The Free Press, 1981:128-162. 35. Khantzian EJ, Mack JE. Alcoholics anonymous and contemporary psychodynamic theory. In: Galanter M, ed. Recent Developments in Alcoholism. New York, NY: Plenum Press, 1989:67-89. 36. Tiebout HM. Surrender versus compliance in therapy. Q J Stud Alcohol. 1953;14:58-68. 37. Kohut H. The Restoration of the Self. New York, NY: International Universities Press, 1977. 38. Bean MH. Alcoholics Anonymous: AA. Psychiatr Ann. 1975;5(2):3-64. 39. Emmonds RA. The Psychology of Ultimate Concerns. New York, NY: The Guilford Press, 1999.

CHAPTER 77

Recent Research into Twelve-Step Programs Barbara S. McCrady

CHAPTER OUTLINE Introduction Utilization of AA Factors Associated with Successful Affiliation with AA AA and Population Subgroups The Effectiveness of AA and Treatments Based on AA Mechanisms of Change in AA Case Study and Recommendations for Primary Care Medical Practitioners Future Directions Conclusions

INTRODUCTION Alcoholics Anonymous (AA) is ubiquitous, both in the United States and around the world. Worldwide, there are an estimated 109 872 groups and 1 962 499 members (1). The formal structure of AA is similar across nations, though there is some variability in emphasis on different parts of the AA program, and differences in the demography of membership are apparent, depending on the cultural context in which AA occurs (2). Though most addiction professionals have some familiarity with AA and other self-help groups based on 12-step principles, professionals’ scientific knowledge about AA often is more limited. The past 25 years has witnessed an explosion of research on AA and on treatments designed to facilitate involvement in AA, with close to 400 articles appearing since 2002. Despite earlier skepticism about the possibility of conducting research on AA, researchers have used a range of methodologies, including ethnographic methods, epidemiologic studies, longitudinal studies of treatment-seeking and non–treatment-seeking populations, controlled clinical trials, and meta-analyses, to develop a body of new research about AA that has some coherence, confirms some previous findings and beliefs, and challenges others. This chapter provides a selective review of earlier research on AA and a more comprehensive review from 2002 through 2017. It addresses several major topics, including patterns of utilization of AA, the unique experiences and views of AA among specific population groups, the effectiveness of AA and treatments designed to facilitate AA involvement, and mechanisms of change associated with involvement with AA and other 12-step programs. The chapter concludes

with methodologic comments and directions for future research.

UTILIZATION OF AA AA members enter the program by a number of routes, including self-referral or referral by family or friends, referral from treatment centers, or through coercion from the legal system, employers, or the social welfare system.

Population Studies Population surveys provide information on utilization of AA in the general and alcohol problem populations. Using data from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), Dawson et al. (3) reported that AA attendance among respondents with a history of DSM-IV defined alcohol dependence was 20.1%. Additional analyses of NESARC data (4) found, among persons who had developed alcohol dependence at least a year before the survey, that 25.5% had sought treatment. Among those seeking assistance, 88.9% attended a 12-step program, including 12.1% who attended only a 12-step program and 66.7% who attended both formal treatment and a 12step program.

Help-Seeking Populations A different perspective on the utilization of AA is provided by studies of patterns of help seeking among individuals seeking assistance for an alcohol problem. Dawson et al. (4), also using NESARC data, reported that among individuals with alcohol dependence who sought help, 78.5% had used AA and other 12-step programs (11.7% using only AA, 66.8% using AA in combination with formal treatment), compared to 88.7% who used professional services (21.9% using only professional treatment, 66.8% using treatment in combination with AA). In a 16-year longitudinal study, Timko et al. (5) examined treatment utilization among individuals who first contacted an information and referral center or who underwent alcohol withdrawal management. One year later, 75% had sought treatment: 18% had attended only AA or another self-help group (24% of help seekers), 25% had sought only outpatient treatment (33% of help seekers), and 32% had sought only inpatient/residential treatment (43% of help seekers). AA involvement was high among treatment seekers, with 66% of outpatients and 68% of inpatients also attending AA. By the time of an 8-year follow-up (6),

17% still had sought no treatment and 14% had attended only AA. The majority (53%) participated in both formal treatment and AA. Study participants who attended AA (either AA alone or in conjunction with treatment) showed a pattern of remarkably steady and consistent involvement over time: 66-91 meetings in the 1st year, 68-97 meetings per year in the subsequent 2 years, 63-71 meetings per year in years 4-8, and 46-52 meetings per year in years 9-16 (7).

Mandated Populations Though there has been considerable controversy about the current criminal justice practice of mandating individuals to attend AA, little research has examined the actual process of criminal justice referral to AA. Speiglman (8) selected four counties in California that varied in the degree to which they used presentencing screening strategies to deal with repeat offenders through the use of driving under the influence (DUI) statutes. Two of the four counties referred cases to AA, referring 37%-40% of cases. Offenders represented by private attorneys were more likely to be referred to AA than those who had public representation. However, among offenders also mandated to parole or to participation in probation-defined treatment, the vast majority (88%-97%) were required to attend AA. Frequency of attendance also was specified and typically involved two to three required meetings per week. Mandating attendance at AA requires the cooperation of the groups that the offender attends. Information at the AA website indicates that …some groups, with the consent of the prospective member, have the AA group secretary sign or initial a slip that has been furnished by the court together with a self-addressed court envelope. The referred person supplies identification and mails the slip back to the court as proof of attendance. Other groups cooperate in different ways. There is no set procedure. The nature and extent of any group’s involvement in this process [of verifying attendance] is entirely up to the individual group. (9) Recent qualitative research (10) explored the views of mandated AA attendance among African American participants in a drug court program. Participants expressed negative opinions about the required frequency of attendance and that the culture of AA, which encourages public sharing, was incompatible with their cultural values about privacy.

Patterns of Utilization of AA Both cross-sectional and longitudinal studies provide information about patterns of utilization of AA. Data from the Epidemiologic Catchment Area Study (11) suggest that individuals who attend AA or other self-help groups make about twice as many visits to meetings as to professional treatment. Persons with DSM-IV defined alcohol dependence who attend AA averaged 44.8 visits/person/year, or just under one meeting per week. Data from Timko and Moos’ 16-year longitudinal study also showed variability in AA utilization. In the 1st year of help seeking, 24.9% attended AA for more than 26 weeks, 19.1% attended for 9-26 weeks, and 14.3% attended for only 1-8 weeks (12). Regular attendance was remarkably stable over time—in years 4-8, 28% had attended AA for more than 26 weeks. However, infrequent attendance dropped off, with only 8.1% of the sample attending for 48 g may lead to a loss of this insulin sensitivity (43), resulting in a U-shaped relationship. Increases in adiponectin have been suggested as a cause for this decrease in insulin resistance (44). Ting and Lautt (29) have suggested increases in hepatic gluthathione, a hepatic insulin-sensitizing substance, as a possible etiology for chronic alcohol’s effects on insulin resistance. Knott et al. indicate that there are gender-specific differences in alcohol consumption and the risk of type 2 diabetes mellitus. They reported no reduction in type 2 diabetes mellitus in men regardless of alcohol consumption level, whereas in women there was decreased risk of type 2 diabetes in the setting of low amounts of alcohol consumption. The discrepancy may be linked to differences in the effects of alcohol on insulin sensitivity in men compared to women, as well as the prevalence of comorbidities and diabetes mellitus risk factors in women, or it may be due to inadequately measured confounding factors (45). The effects of different types of alcohol on diabetes risk and control have recently been reviewed and suggest that if the effect is causal, wine may have more protection than does beer or spirits. It was proposed that resveratrol extract in wine may contribute to its glucose-lowering properties (46).

Reproductive Consequences The reproductive effects of alcohol use are gender specific. Alcohol use has long been known to cause sexual dysfunction and hypogonadism in men, particularly in those with alcoholic cirrhosis (47). Even in men without liver disease, alcohol use leads to a decrease in testosterone (48), which may be the result of a combination of direct effects on the testicular synthesis of testosterone and hypothalamic–pituitary function (49) or on increases in sex hormone-binding globulin, which can lead to a decrease in bioavailable testosterone (50). The incidence of gynecomastia is increased in alcoholic cirrhosis, primarily because of increased levels of androstenedione, a precursor for estrogen synthesis (51). Increased prolactin levels have been found in patients with alcoholic cirrhosis (52), though it may not be present in those with alcohol use disorders who do not have severe liver disease (53). In women, the effects of alcohol use depend on menopausal status and hormone therapy use. In premenopausal women, alcohol consumption was

associated with increase in estradiol levels, and the effect was increased during times of gonadotropin elevation such as luteinizing hormone (LH) surge and early pregnancy. This increase in estrogen level may explain why alcohol use is associated with an increased risk of breast cancer (54) and why alcohol can be associated with a delay in menopause. Premenopausal women on hormonal contraceptives who consumed alcohol had higher levels of estradiol. In premenopausal women and postmenopausal women taking estrogen, acute alcohol consumption leads to an increase in estradiol levels through reduced metabolism of estradiol in the liver. It is thought that due to the accumulation of NADH from alcohol consumption, there is decreased conversion from estradiol to estrone, which results in estradiol excess (55–57). In postmenopausal women not on hormonal therapy, the effects of alcohol on estrogen levels have been inconclusive (58). Women with high or frequent alcohol intake were found to have higher rates of menstrual disorders, including amenorrhea, dysmenorrhea, and irregular menstrual periods. Pregnant women with high alcohol intake have a higher incidence of miscarriages, placental abruption, preterm deliveries, and stillbirths than do controls (59). An increased risk of infertility was associated with as few as one to five alcoholic drinks a week in a Danish study (60) and with as little as 12 g of alcohol a week (about one drink) in an American study (61). There may be an increase in prolactin levels and a decrease in oxytocin levels in lactating women (62) and premenopausal women who are exposed to alcohol (approximately two drinks) (63). Despite the increase in prolactin levels, lactating women may have a slight decrease in milk production (64).

Bone Health Consequences Postmenopausal women who drink low amounts of alcohol may have an increased bone mineral density and a decreased risk of fractures (59). Similar effects have been found by others (65–67) with some finding differences in the type of alcoholic beverage, with wine or beer being associated with more benefit than spirits or liquor (68,69). Alcohol use disorder is associated with decreased bone mass and an increased risk of skeletal fractures (70–73). African American men may be less susceptible to this bone loss (74). Authors have described this phenomenon as a J-shaped association, where there is a threshold at which alcohol use transitions from conferring a protective effect on bone health to having a deleterious effect on bone density and fracture risk (75). Alcohol consumption can increase the risk of fractures independent of bone density (76). In addition to increased risk of falls while inebriated, other indirect factors such as lean body mass, decompensated liver disease, vitamin D deficiency, and poor

nutritional status contribute to the increased risk of fractures, especially rib fractures in heavy alcohol drinkers (77). In addition to alterations in sex hormones and the type of fat malabsorption and vitamin D deficiency associated with liver disease, alcohol use can reversibly impair bone formation by osteoblasts (78–80). Therefore, alcohol consumption affects bone remodeling imbalance and preferentially decreases bone formation (81). It has been postulated that alcohol-induced oxidative stress suppresses Wnt/Dkk1 signaling pathways, thereby decreasing the formation of osteoblasts (82). Malnutrition and low body mass and decreases in IGF-I, a bone growth factor, may play a significant role in the decreased bone mass (83,84). Reductions in leptin with alcohol use (85,86) may also play a role in decreasing bone mass although there is some controversy about exactly what that role is (87). In animal studies, the parathyroid hormone (PTH) may help reverse some of the bone loss although continued alcohol use impairs the response (88). Heavy alcohol use is associated with osteonecrosis of the bone (89). Alcohol-associated osteonecrosis of the femoral head may be due in part to lipid or cortisol changes (90), and, in fact, alcohol may be responsible for up to onethird of cases of femoral head osteonecrosis (91).

Other Endocrinological Consequences Alcohol use increases triglyceride synthesis, leading to hypertriglyceridemia and hepatic steatosis. The increased NADH/NAD ratio leads to increases in alphaglycerophosphate, which favors hepatic triglyceride accumulation by trapping fatty acids. The excess NADH enhances fatty acid synthesis. Alcohol increases the high-density lipoprotein (HDL) fraction of cholesterol, which may be associated with reduced cardiovascular morbidity and mortality (92). Though glucocorticoid response to hypoglycemia can be impaired by alcohol use, patients with chronic heavy alcohol use have elevated adrenocorticotropic hormone (ACTH) and cortisol production. This response is mediated by corticotropin-releasing hormone (CRH) and the interaction with stress. This may be related to a person’s genetic propensity to developing an alcohol use disorder. These effects are dose dependent (93). Rarely, patients with alcohol use disorder may develop the clinical stigmata of glucocorticoid excess, such as central obesity, moon facies, “buffalo hump,” and biochemical evidence of nonsuppressible glucocorticoid excess that is difficult to distinguish from Cushing syndrome. This condition, which has been termed pseudo-Cushing syndrome, reverses with abstinence from alcohol for at

least 1 month (94,95). There are no clear clinical features or lab test results that distinguish pseudo-Cushing’s from Cushing’s syndrome (95), and a period of alcohol abstinence and reversal of the syndrome may avoid the search for a nonexistent pituitary or adrenal tumor. Alcohol may influence hormones regulating feeding behavior. Leptin levels are decreased acutely after low amounts of alcohol use (85) and in malnourished people with an alcohol use disorder (86). Ghrelin secretion is similarly reduced, without effects on peptide YY, soon after moderate alcohol intake (96,97). This is somewhat paradoxical given that these hormones suppress appetite and alcohol is believed to stimulate appetite. Alcohol use has effects on plasma volume and blood pressure status. It transiently decreases vasopressin release, leading to water diuresis (98). This condition can be problematic in patients with partial diabetes insipidus. Acute alcohol use also increases blood pressure, possibly through an increase in norepinephrine (99). Low amounts of alcohol consumption appear to increase plasma renin activity, though such increases are believed to result from a secondary response to changes in fluid and electrolyte balance (100). Though alcohol by itself does not affect mineralocorticoid levels, alcoholic cirrhosis leads to elevations of aldosterone in response to decreased effective plasma volume. Acute alcohol use does not produce thyroid dysfunction in patients with previously normal thyroid function (101). Alcoholic cirrhosis of the liver can produce decreases in serum triiodothyronine (T3) because the liver is a major site for the conversion of thyroxine to T3, without producing clinical hypothyroidism in those without preexisting autoimmune thyroid disease (102,103). Alcohol use was reported to suppress melatonin secretion through increased norepinephrine levels, and this increase may be implicated in disturbances in sleep and performance (104).

DISORDERS RELATED TO TOBACCO The adverse effects of tobacco on the cardiopulmonary systems are well known. Tobacco smoke contains a myriad of chemical compounds—most notably nicotine; tar; thiocyanate; 2,3-hydroxypyridine; and carbon monoxide—which may have multiple endocrine effects. Many of these effects have been reviewed in detail (105).

Disorders Related to Tobacco Thyroid Consequences Cigarette smoking increases the risk of Graves disease and Graves ophthalmopathy and can lower thyroid-stimulating hormone (TSH) levels (106–112). Smoking cessation seems to be associated with reduction in the risk for Graves disease (113). Passive smoke exposure may increase resting metabolic rate and thyroid hormone secretion (114,115). The increased risk of ophthalmopathy with cigarette smoking may be related to increased fibroblast adipogenesis associated with increased interleukin-1 levels and interleukin-6 levels and up-regulation of adipocyte-related immediate early genes (116,117). Smoking can adversely influence response to treatment modalities for Graves disease and Graves ophthalmopathy. Smoking cigarettes can dampen the response to glucocorticoids or orbital radiation in patients with Graves ophthalmopathy (118). Smoking may also be associated with decreased levels of serum thyroid autoantibodies (110,119–122), with stopping smoking increasing the risk for these antibodies (123). Smoking appears to protect smokers from hypothyroidism (110,121) and goiter (124,125). However, older studies have associated smoking with goiter and hypothyroidism (126,127). This may be a consequence of the thiocyanate present in cigarette smoke, which is a goitrogen that inhibits iodide uptake and hormone synthesis and increases iodine exit from the thyroid (128,129). Smoking may cause hypothyroidism only in those with preexisting thyroid dysfunction, and there may be impaired peripheral action of thyroid hormone (130). Smoking appears to lower the risk of thyroid cancer (131,132).

Insulin Resistance and Dyslipidemia Cigarette smoking (133), as well as nicotine gum use (134), is associated with an increase in insulin resistance and an increased risk of developing impaired glucose tolerance and diabetes mellitus (35,135–138). Stopping smoking does not seem to eliminate the risk of diabetes mellitus as both former smokers and current smokers have an increased risk for type 2 diabetes mellitus, affecting men more than women (139). Secondhand smoke exposure similarly increases diabetes risk (140). Mild decreases in HDL cholesterol and mild elevations in triglycerides, consistent with this insulin resistance, are associated with cigarette

smoking (133), though these changes may be due to components of cigarette smoke other than nicotine (141). Both passive smoke exposure and active smoking have been associated with the metabolic syndrome in adolescents (142). Insulin resistance and dyslipidemia may be responsible, in part, for the elevated rates of cardiovascular and atherosclerotic disease associated with cigarette use.

Reproductive Function In women, cigarette smoking is associated with decreases in estrogen levels (143) and, in fact, can enhance estrogen degradation (144). It also is associated with early menopause (145,146) and increased ovarian age and follicularstimulating hormone (FSH) levels (147,148). A meta-analysis by Waylen and colleagues found that patients who smoke had poorer outcomes with assisted reproduction, with significantly lower odds of clinical pregnancy per cycle, higher odds of spontaneous miscarriage, and higher odds of ectopic pregnancy (149). In men, cigarette smoking is associated with quantitative and qualitative decrements in sperm (150–152) and with increases in serum estrogen (153). Unfortunately, public knowledge of the risk of smoking for these reproductive issues is low, ranging from 17% to 39% (154), and educating patients about these unrealized dangers is paramount.

Bone Health Cigarette smoking is associated with decreased bone mineral density and increased bone loss in postmenopausal women and elderly men (155) and is an independent risk factor for osteoporotic fracture (156,157). This fracture risk appears, in part, due to a decrease in intestinal calcium absorption (158,159), resulting in a negative calcium balance. Brot et al. (160) found an association between smoking and decreased serum 25-hydroxyvitamin D, 1,25dihydroxyvitamin D, PTH, and osteocalcin levels, suggesting a more complex effect of smoking on calcium and bone metabolism. Cigarette smoking can negate the protective effect of estrogen therapy on the risk of hip fracture in postmenopausal women (161). It also is associated with femoral head osteonecrosis (89), possibly through impairment of vascular function or changes in blood lipids.

Other Endocrinological Effects

Cigarette smoke stimulates antidiuretic hormone release from the pituitary through an airway-mediated mechanism that does not depend on circulating nicotine (162,163). This antidiuretic effect may cause or exacerbate hyponatremia in susceptible patients (164,165). The nicotine found in cigarette smoke can increase the release of catecholamines from the adrenal medulla, which may precipitate a hypertensive crisis for those with pheochromocytoma. In addition, smoking is associated with hypertension and poorly controlled hypertension, apparently through stimulation of the noradrenergic nervous system (166); such hypertension is not angiotensin II dependent (167). Nicotine increases ACTH release and cortisol release in a dose-dependent fashion (168–170) and may have some role in tobacco addiction. Cigarette smoking is associated with activation on the HPA axis, leading to elevated cortisol levels and loss of diurnal variation in cortisol secretion. Stopping smoking may restore the diurnal variation, thus suggesting that smoking likely has a short-term effect on cortisol levels (171). However, moderately elevated cortisol throughout the day, as can be seen with cigarette smoking, may have clinical implications such as increased insulin resistance (172). Cigarettes also may increase prolactin secretion. In a study of men randomized to 0.2 or 2 mg nicotine cigarettes, in the higher dose nicotine group, prolactin levels were measured to be more than 150% above the baseline by 30 minutes and remained elevated 1 hour after smoking; however, there was no significant increase in prolactin in the low nicotine group. Whether this translates into clinical manifestations of hyperprolactinemia is unclear (168,170). The use of electronic cigarettes (e-cigarettes) has become a popular alternative to tobacco smoking; however, the long-term health effects have not been well studied. E-cigarettes are not regulated by the FDA as an option to achieve abstinence from tobacco (173). Furthermore, due to inconsistent labeling and variability of nicotine content in the cartridges, the level of nicotine exposure remains unclear (174). In a study on rats administered electronic cigarette refill liquid, decreased sperm density and viability as well as testosterone levels were observed in rat testes and thought to be due to impaired oxidative balance and steroidogenesis (175). Currently, there is a dearth of studies evaluating other endocrinological manifestations of electronic cigarettes.

Disorders Related to Opioid Use The endocrine effects of acute administration of opioids occur primarily in the hypothalamus and pituitary. Gonadotropins (FSH and LH) are suppressed by

inhibition of gonadotropin-releasing hormone secretion. Prolactin secretion is stimulated, while ACTH and cortisol secretion are suppressed (176). Chronic administration of opioids can produce partial tolerance to many of the endocrine effects. Vuong et al. (177) have exhaustively reviewed the endocrine effects of opioids, and readers are directed to this review for further in depth treatment of this topic.

Male Gonadal Function Male gonadal function in patients with opioid disorder and those maintained on methadone maintenance has been primarily diminished but not in all studies. In men, methadone use has been associated with a decline in serum testosterone levels in several early studies (178–180). Cushman and Kreek did not find changes in testosterone levels among people with opioid use disorder resulting from heroin maintained on methadone maintenance (181,182). Another study looking at methadone, methadone/heroin, and heroin use found normal levels of testosterone, FSH, LH, and prolactin in all but the individuals who used heroin who had elevated prolactin levels (183). However, individuals who used only heroin, individuals who used heroin and methadone, and 45% of the individuals who took methadone in that study had diminished sperm motility. Lafisca et al. (184) looked at short-term methadone use in 30 men and found no abnormalities of estrogen, progesterone, or LH, whereas FSH showed lower values than normal, and androstenedione, dehydroepiandrosterone, and prolactin noticeably increased in many subjects. Modest variations were noted for testosterone and dihydrotestosterone. Other investigators found a decrease in basal FSH and LH levels, with a decrease in pituitary response to gonadotropin-releasing hormone, suggesting a hypothalamic cause for hypogonadism in people with opioid use disorder (185). While Brown et al. (186) found sexual dysfunction associated with methadone dose in 14% of men attending a methadone maintenance clinic, they did not find it associated with a decrease in testosterone level. Daniell (187) found that men being treated with sustained-action opioids for chronic pain had decreasing testosterone levels in a dose-dependent fashion, with overtly low levels with a daily methadone dose equivalent of >70 mg. Many were overtly symptomatic with erectile dysfunction. Bliesener et al. (188) found that people with opioid use disorder on buprenorphine maintenance had higher testosterone levels, comparable to normal healthy controls, than did those on methadone maintenance suggesting that hypogonadism may be mediated through mu opioid receptor since methadone is a pure mu opioid receptor

agonist and buprenorphine is a mu opioid receptor agonist with high affinity but low intrinsic activity. Hallinan et al. (189,190) confirmed that male hypogonadism and sexual dysfunction were more common with methadone maintenance therapy than with buprenorphine. The variability in opioid-induced male hypogonadism may be due in part to the presence of other components, as well as variable doses of opioids, in street preparations of heroin, continued use of heroin in methadone-treated individuals, and the possible effect of malnutrition on the reproductive system. A study of the endocrine effects of long-term intrathecal opioid administration for pain relief found diminished testosterone and LH levels in men but normal FSH and prolactin levels in comparison to control patients with a comparable pain syndrome but who were not treated with opioid (191), suggesting that these are the “pure” opiate effects on the male reproductive system. A systematic review and meta-analysis by Bawor and colleagues concluded that both methadone and nonmethadone opioids are associated with a 165 ng/mL reduction in total testosterone in men (192). There is likely some individual variation, depending on baseline testosterone and sex hormone–binding globulin levels, with regard to whether this has clinical relevance. The male hypogonadism resulting from opiate use may increase pain sensitivity. In the Testosterone and Pain (TAP) trial, Basaria and colleagues studied 84 men on at least the equivalent of 20 mg of hydrocodone daily for 4 weeks for noncancer pain and found to have a morning serum total testosterone 5000 occasions) had reduced bone density Z-scores, associated with increased bone turnover markers, lower 25-hydroxyvitamin D levels, and increased risk of fractures. Most of the bone density reduction was explained by differences in body mass index, which was lower in individuals who use cannabis, and mitigated by dietary calcium intake (241).

Cocaine Cocaine acts primarily by blocking the reuptake of norepinephrine, dopamine, and serotonin at the synaptic junctions, resulting in increased neurotransmitter concentrations. In animal studies, cocaine can stimulate the adrenal medulla to release epinephrine and norepinephrine. By increasing catecholamines, counterregulatory hormones that antagonize insulin, stimulate glucose production and inhibit glucose clearance, hyperglycemia can result as can diabetic ketoacidosis or hyperosmolar nonketotic hyperglycemia without any other identified precipitants (242,243). Diabetic ketoacidosis appears to occur more frequently in individuals who use cocaine, resulting from a combination of omission of insulin therapy and cocaine effects on glucose metabolism (243). Dopamine is an important physiological regulator of prolactin and TSH secretion. Acute cocaine use suppresses prolactin secretion with increases in dopamine levels, but with chronic use, dopamine levels become depleted, and hyperprolactinemia results (244–246). This hyperprolactinemia persists even after cocaine withdrawal (247). The clinical significance is unclear, but it may be a cause of hypogonadism. Though acute cocaine use produces rises in ACTH, FSH, and LH (244,248,249), abnormalities of testosterone, cortisol, LH (245), or thyroid function tests (250) have not been found in individuals with chronic cocaine use.

Amphetamines Amphetamines, such as dextroamphetamine and methylamphetamine, have not been well studied with regard to the endocrinological effects of chronic use. They act primarily by stimulating the release of norepinephrine and dopamine. Well-described acute endocrine effects of amphetamine administration include increased corticosteroid release and increased growth hormone release (251–253), each of which can be influenced by the presence of depression (254–258) or other psychoactive medications (259). Though increased salivary cortisol response to D-amphetamine has been associated with personality traits of aggression and thrill-seeking (260), the clinical implications of these findings remain unclear. The cortisol response to social stressors in chronic methamphetamine use has been variable (261–263). Pre-existing hyperthyroidism may increase the risk of death due to ecstasy (3,4methylenedioxymethamphetamine) (264). Ecstasy has also been associated with severe hyponatremia related to SIADH (265,266). Both cocaine and amphetamine have well-known effects on appetite suppression. In 1995, Douglass et al. (267) first described the up-regulation of a peptide in response to the acute administration of cocaine and amphetamine. This peptide is now known as cocaine- and amphetamine-regulated transcript and has been shown to have a role in feeding behavior, interacting with neuropeptide Y, leptin, and cannabinoid (CB-1) receptors. Interested readers are referred to a useful review (268).

Caffeine Caffeine is one of the world’s most widely used drugs. The many forms in which it is delivered and prepared, including tea, coffee, and caffeinated soft drinks, may contain other bioactive substances such as flavonoids (269) and the diterpene cafestol (270,271). Add to this the marked range of caffeine content of a particular beverage, from a can of cola (37 mg) to a specialty coffee shop 16oz regular coffee (330 mg) (272), and there are multiple confounds to its study. Caffeine is a neuroendocrine stimulant with action mediated by central adenosine receptor antagonism (273). Ingestion of 250 mg (approximately three cups of coffee) produces a rapid release of epinephrine from the adrenal medulla, which can increase blood pressure (274). Immediate ingestion of 250-500 mg caffeine (equivalent of three to six cups of coffee) has little effect on circulating cortisol, TSH, growth hormone, prolactin, T3 (275), or norepinephrine levels.

However, the ingestion of 250 mg caffeine produces an increased epinephrine and norepinephrine response to tilt-table testing (274) and increased epinephrine, norepinephrine, cortisol, and growth hormone response to hypoglycemia or lownormal glucose levels in normal healthy adults (276) and in patients with insulindependent diabetes (277). Tolerance to caffeine can develop with chronic use so that these neuroendocrine changes do not become clinically relevant except after a period of abstinence. It has been suggested that caffeine can be a useful treatment for patients with diabetes without autonomic neuropathy who have hypoglycemic unawareness (277). Caffeine may have acute effects on glucose metabolism. Four hundred milligrams of caffeine daily for 1 week decreased insulin sensitivity in caffeinetolerant young adults (278). Five hundred milligrams of caffeine daily increased average glucose, and exaggerated postprandial glucose increases in caffeinetolerant type 2 diabetics (279). Chronic coffee consumption, however, is associated with a decreased risk of type 2 diabetes mellitus, and this subject was reviewed (272,280). The effects appear to be consistent across diverse populations, with a dose-dependent response, and also found with decaffeinated coffee and tea. For every additional cup of coffee, there is an estimated 7% reduction in the excess risk of type 2 diabetes mellitus (280). Caffeine is associated with increased urinary calcium excretion (281) and with decrements in serum-free estradiol (282,283) and serum insulin-like growth factor 1 levels (284), both of which are important in maintaining bone mass. As such, it is not surprising that caffeine use is associated with an increased risk of fracture (285,286) and an increased risk of reduced bone mass (287,288). However, other studies do not support this increased risk (289,290). One report from Lu and colleagues found that a high physiological dose (~5 cups of coffee) may directly suppress PTH release from parathyroid cells in vitro, which might increase bone density but impair bone formation/quality (291). Add to this mixture the studies that show that tea can protect against hip fractures (292) and is associated with increased bone density (269), and the overall situation becomes more confusing. If there is an effect of caffeine intake on bone health, it is not likely to be clinically significant. The effects of caffeine intake on reproductive health and fertility have been conflicted, but the current data do not show any significant effect on fertility (293), male sperm quality (294), pregnancy outcomes, or outcomes of assisted reproduction (295). Caffeine, by inducing CYP1A2 and CYP2C8 which also are implicated in metabolism of tamoxifen, may decrease the risk of early events in

estrogen receptor (ER)-positive breast cancers at a dose of ≥2 cups of coffee daily and may also modulate ER status (296). Coffee impairs the intestinal absorption of L-thyroxine and may alter the management of hypothyroidism (297).

Benzodiazepines Benzodiazepines act by stimulating gamma-aminobutyric acidergic (GABAergic) neurons, which usually are inhibitory in function. Many researchers have found that benzodiazepines, such as diazepam (Valium), alprazolam (Xanax), and temazepam (Restoril), suppress basal serum levels of cortisol (298–301) and also suppress the body’s cortisol and ACTH response to metyrapone (302), insulin-induced hypoglycemia, CRH (303), metabolic stress (304), and exercise (305). Such changes potentially could lead to a hypoadrenal crisis or prolonged hypoglycemia in users with preexisting adrenal disease. Suppression of cortisol response persists despite chronic benzodiazepine use (306); however, this finding may not apply to all benzodiazepines. Ambrosi et al. (307) found that triazolam and flurazepam did not influence cortisol release in women with insulin-induced hypoglycemia. Chronic diazepam use may lead to greater decrease in basal cortisol levels among elderly patients compared to younger patients (308). Benzodiazepines may variably stimulate the release of growth hormone (309), though not all investigators have confirmed this finding (310). This growth hormone response is blunted with long-term benzodiazepine administration (311) and hyperglycemia (312), suggesting that significant clinical effects are unlikely. One case report described a syndrome involving inappropriate antidiuretic hormone secretion associated with the use of lorazepam (313). Hedrington and colleagues studied the effect of alprazolam on counterregulatory responses to hypoglycemia in healthy subjects finding a significant blunting of catecholamine release, glucagon, growth hormone, and pancreatic polypeptide but a neutral effect on cortisol release, with decreased lipolysis and glycogenolysis in response to insulin-induced hypoglycemia. In addition, there was a reduction in hypoglycemic adrenergic symptoms after alprazolam (314). This same group found not only a similar reduction in catecholamines, glucagon, and growth hormone but also a reduction in cortisol, among healthy exercising patients (315) as well as exercising patients with type

1 diabetes mellitus (316). As such, there may be an increased risk for severe hypoglycemia in those on hypoglycemic agents.

Barbiturates Barbiturates are known to induce the cytochrome P450 enzyme system, leading to enhanced metabolism of many substances. Among these substances are thyroid hormone, hydrocortisone, vitamin D, and methadone. Barbiturate use or misuse can lead to increasing thyroid hormone requirements (317), hydrocortisone requirements, osteomalacia, or opioid withdrawal. Overt hypothyroidism or hypoadrenalism is not likely in the absence of underlying thyroid or adrenal disease.

Inhalants The inhalation of volatile solvents, such as toluene, is known to cause multiple medical complications, such as heart, liver, lung, nerve, and kidney damage (318,319). No specific endocrine consequences have yet been described. However, these solvents can cause renal tubular dysfunction, leading to hypophosphatemia and acidosis, which can affect calcium and bone metabolism. Though recurrent nephrolithiasis was described (320,321), no case of tolueneinduced osteomalacia has been described as yet. Cohen et al. reported a case of rapid-onset diffuse skeletal fluorosis, presenting as debilitating hip pain associated with diffuse osteosclerosis and heterotopic bone formation, from inhalant use of dust cleaner containing the refrigerant 1,1-difluoroethane (322). Occupational exposure to inhalants is associated with infertility, increased risk of spontaneous abortion, and multiple birth defects. In addition, case reports of children born to those who use inhalants have led to the term fetal solvent syndrome, reflecting its similarity to fetal alcohol syndrome. Interested readers are referred to the review by Jones and Balster (323).

Anabolic Steroids The anabolic steroids, which are testosterone derivatives, include nandrolone, oxandrolone, oxymetholone, and stanozolol. Male and female athletes often use these substances in efforts to improve athletic performance. The adverse endocrine consequences are a direct result of androgenic effects and suppression

of the hypothalamic–pituitary–gonadal axis. These effects include testicular atrophy; decreases in testosterone, LH, and FSH; increases in estrone; and suppression of spermatogenesis in men (324,325), leading to infertility (326). Gynecomastia can result from aromatization of the androgens to estrogen in endogenous androgen suppression. In women, there can be menstrual disturbances, deepening of the voice, and development of acne and male-pattern body hair (327). Interested readers are directed to the recent Endocrine Society scientific statement about the adverse health consequences of performanceenhancing drugs (328). Anabolic steroids can affect other hormones by decreasing hepatic synthesis of proteins, such as thyroid-binding globulin, sex hormone–binding globulin, vitamin D–binding protein, and HDL cholesterol (325,329). There can be mild thyroidal impairment, as measured by TSH and T3 response to thyrotropinreleasing hormone (TRH) (330). Clinically relevant sequelae are not present without underlying hyperthyroidism. Other lipid changes include increases in low-density lipoprotein cholesterol and decreases in Lp(a) (331). There are conflicting reports regarding insulin resistance and anabolic steroid use (332,333). Those with preexisting coronary artery disease may be at increased risk because of decreased HDL and increased low-density lipoprotein cholesterol. Hypertension, ventricular remodeling, myocardial ischemia, and sudden cardiac death each have been temporally and causally associated with anabolic steroid use (334). Work from Basaria et al. (335) has shown an increased risk for coronary events in elderly men with heart disease treated with testosterone replacement therapy. Basaria, writing about the Testosterone’s Effects on Atherosclerosis Progression in Aging Men (TEAAM) multicenter trial of testosterone replacement in men 60 years and older with low or low-normal testosterone levels, found no significant changes in carotid artery intima-media thickness or coronary artery calcium (336). Budoff and colleagues found a significantly increased noncalcified coronary artery plaque in 65 years and older men with low testosterone levels on testosterone replacement therapy (337). Contradicting reports, however, have suggested that androgens may have antiatherogenic and antianginal effects (338–340) in both supraphysiological and physiological doses. No significant changes in adult bone metabolism (PTH or vitamin D metabolites) have been reported in patients treated with nandrolone (341). Anabolic steroid use in children, however, may prematurely close epiphyseal growth plates, leading to growth stunting. Growth hormone levels can rise with anabolic steroid use; resolution of the hypothalamic–pituitary–gonadal

suppression can take several months (342) and is a common cause of hypogonadotropic hypogonadism.

Other Drugs Lysergic acid diethylamide acutely increases blood pressure, heart rate, and plasma levels of cortisol, prolactin, oxytocin, and epinephrine (343). The clinical significance of these changes is not clear. No endocrinological consequences have been described with phencyclidine use; further research is required.

CONCLUSION Alcohol and other drugs have complex effects on the endocrine system, with a subsequent broad range of effects on energy metabolism, electrolytes, reproduction, blood pressure control, and bone health. They can cause derangements in glucose, lipids, sodium, fertility, blood pressure, and osteoporosis. Many effects may not have clinical relevance due to development of tolerance, and these effects are reversible with cessation of the offending drug. Their broad-reaching effects should be considered in the care of patients who use these drugs.

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CHAPTER 90

Alcohol and Other Drug Use during Pregnancy: Management of the Mother and Child Michael F. Weaver, Hendrée E. Jones and Martha J. Wunsch

CHAPTER OUTLINE Approach to the Pregnant Woman Neonatal Abstinence Syndromes Tobacco Alcohol and Sedatives Opioids Cannabis Stimulants Maternal SUD Treatment Labor and Delivery Breast-Feeding Legal Issues Postpartum Care Conclusions

APPROACH WOMAN

TO

THE

PREGNANT

While the potential consequences of substance use disorders (SUDs) during pregnancy for the health and well-being of the mother, fetus, and neonate are concerning, SUDs during pregnancy must be viewed in context and in relation to multiple other factors that can compromise healthy pregnancies. Women who use substances during pregnancy often do so in the context of intricately complex individual, social, and environmental factors, including poor nutrition, extreme stress, violence of multiple forms, poor housing conditions, exposure to environmental toxins and diseases, and depression, all of which can impact postnatal outcomes (1,2). While the odds are often stacked against women who have an SUD during pregnancy, each patient is unique, and each patient must be viewed in the context of her own risk and protective factors to optimize her treatment and outcomes for herself and her child. For the health and well-being of mother and child, all health care providers should be able to recognize perinatal SUD, address this medical problem, and thus reduce potential complications for the mother and her child. The prevalence of substance use during pregnancy is substantial. Women using tobacco, alcohol,

prescription medications, and illicit substances may have irregular menstrual cycles yet still have the ability to conceive. Several months may lapse before a woman realizes that she is pregnant (3). Perinatal SUD affect women of all races, ethnicities, and socioeconomic levels (4,5). In the 2015 National Survey on Drug Use and Health, 9.3% of pregnant women 15-44 years of age reported they consumed alcohol, while 4.6% reported binge drinking, and 0.8% reported heavy drinking (5). The prevalence of illicit substance use during pregnancy varies by type of psychoactive substance, with 10.1% reporting cannabis use and 1.7% using opioids and around 1% using cocaine (5). Pregnancy motivates some, but not all, women to quit using tobacco, alcohol, nonmedical use of prescription medications, and/or illicit psychoactive substances. Others may have difficulty stopping due to the severity of their SUD or fear of withdrawal. The clinician’s role is to begin to support pregnant women who use substances (PWUSs) in changing their behavior to stop or substantially reduce substance use and to assist with addiction treatment referral. Whether or not she continues to use, every PWUS should be encouraged to engage in prenatal care. Pregnant women who use psychoactive substances experience more prejudice and are much more stigmatized than nonpregnant women, so they may deny their drug use, its harmful effects, and the need to seek help (6). Clinicians who provide health care to PWUS should be sensitive to the cultural background, family context, and the patients’ feelings. Thus, clinicians need to provide care in a supportive and nonjudgmental manner. Clinicians should be sensitive and explicitly discuss with their patients the need for and limits around confidentiality regarding SUD, because of stigma and potential legal ramifications. In many cases, a woman may have used alcohol or drugs during a previous pregnancy, experiencing the negative consequences of stigmatization and perhaps loss of custody of her other children. PWUS may be wary of health care providers owing to previous experiences. The availability of a physician within a prenatal clinic setting able to make the determination of severity of SUD and with skills in facilitating a referral to treatment is advantageous. This process will increase access for pregnant women to these services. Such a strategy helps to decrease the stigma attached to specialized SUD treatment services. However, if an addiction medicine specialist physician is not available within the prenatal clinic setting, then it is well worthwhile to have other clinicians within that setting who are familiar with the principles of addiction medicine. Encouragement and consistency in approach, expectations, and messages to PWUS are important and will maximize engagement and retention in treatment

(7). Effective treatment for these patients and their newborns requires collaboration among multiple providers and agencies. It is essential that there be clear and direct communication among the mother’s SUD specialist physician, obstetricians, pediatricians, neonatologists, primary care physicians, nurses, anesthesiologists, psychiatrists, psychologists, social workers, and legal agencies.

SCREENING Estimates vary, but 30%-50% of women in the general population have unintended pregnancies. For pregnant women with opioid use disorder, the rate is estimated to be 86% (8). Prevalence estimates for pregnancies exposed to other psychoactive substances are less known, but one could expect that the overwhelming majority of PWUSs did not intend to become pregnant. Thus, comprehensive care for women who may become pregnant and are using substances should include reproductive health education and access to methods to give women control over their reproductive options. Drug and alcohol use during pregnancy is substantially underreported for most major drug classes, with both amount and frequency of use being underreported by PWUS who use frequently compared to those who only use occasionally (9). PWUS may not fit the usual stereotype of a person with an SUD, making early identification difficult. Although a number of questionnaires have been validated to detect alcohol use, few instruments have been validated for detection of illicit drug use—including prescription medications—during pregnancy. Screening women in a prenatal clinic with specific questions about tobacco, alcohol, and drug use holds the promise of identifying, intervening, and reducing substance use during pregnancy (10). Screening followed when appropriate by brief intervention and referral to treatment (SBIRT), especially for alcohol and tobacco, is recommended in obstetric settings by the American College of Obstetrics and Gynecology (ACOG) and the US Preventive Services Task Force and has been shown to be effective to reduce alcohol and tobacco use (11–14). Asking directly about current substance use can identify the risk of use and of SUD to inform and educate women planning conception or who are currently pregnant. The combination of screening questions and urine toxicology has been shown to be more effective for detection of perinatal SUD than the use of either one alone (15).

Screening of pregnant women for substance use should be done at the first prenatal visit and repeated every trimester if necessary (16). Options include standardized interview questions, validated screening instruments, or the Quick Screen from the National Institute on Drug Abuse (17). Validated screening instruments for pregnant women include the T-ACE, the TWEAK, and the AUDIT-C for alcohol and the 4Ps, which is used for any substance. A survey of Maryland hospitals revealed that 97% do universal screening of pregnant women for substance use, but only 6% use a validated instrument (18). Screening is used to determine the risk level of a pregnant woman for problems related to substance use during pregnancy. Those at low risk can simply receive brief advice, and those at high risk should be referred for definitive SUD treatment. Women at moderate risk benefit most from a brief intervention delivered by the clinician. Women at moderate risk are those who have a history of SUD with high quantities, who have recent SUD treatment, who stopped using during pregnancy, and who continue sporadic low-level use during pregnancy. The purpose of screening is to allow for treatment of the SUD, not to punish or prosecute the pregnant patient (19). In an effort to normalize this process, it may be useful to standardize the approach to screening and set expectations with the patient at the outset of the visit. Information from a thorough history (including medical problems and social stressors) and a physical examination can provide clues to the use of specific substances during pregnancy. Certain facets of a patient’s history, such as a family history of SUD, may alert the clinician to the possibility of substance use during pregnancy. Frequent encounters with law enforcement agencies may also indicate active SUD (20). Women are often introduced to and supplied with drugs by a male partner; therefore, substance use by a current significant other should increase the index of concern (21). Given that ~90% of drug treatmentenrolled pregnant women smoke cigarettes, the use of nicotine and/or cannabis may be an important indicator of other SUD (22). If any of these risk factors are present, there is increased likelihood of perinatal use and/or an SUD, and the expectant mother should be asked about the spectrum of substance use. Although limitations in assessing the extent of physical abuse and differing definitions of what constitute physical abuse create difficulties in precisely estimating the extent of physical abuse in pregnant women, estimates suggest a prevalence rate of around 6% in the general population of pregnant women (23). In contrast, it is estimated that 34% of PWUS report physical abuse, usually intimate partner violence (24). This rate is similar to rates of victimization among nonpregnant women with SUD, so pregnancy is not a protective factor

against domestic violence (25). Physical, sexual, and verbal abuse by a partner is also common among women with alcohol use disorder, so eliciting a thorough social history adds information about consequences of addiction. These high rates of domestic violence among PWUS should prompt clinicians to ask all pregnant women about the possibility of physical or sexual abuse, violence, or injury, especially when substance use is also identified in the woman or her partner. There is no single recommended way to address this. Clinicians are encouraged to implement screening with whatever method is comfortable and opportune (written form in waiting room, asking as part of other screening questions on a list, or working into a general interview at an appropriate time based on clinician judgment). There are three screening tools available—Women Abuse Screen Tool (WAST), Abuse Assessment Screen (AAS), and Humiliation, Afraid, Rape, and Kick (HARK)—that are identified as having strong psychometrics and validation for women and could be useful for identifying pregnant women at risk for intimate partner violence (26). Cognizance and discussion of risks and/or indications of use or SUD with women can help enhance honest communication about substance use throughout pregnancy. Once identified, options for treatment of acute withdrawal syndromes or other pharmacotherapy and behavioral treatments can be offered to PWUS, if applicable. Routine office visits for prenatal care provide an opportunity to screen for depression and other mental health issues, as co-occurring psychiatric disorders are not uncommon in this population. Appropriate obstetric care also includes evaluation for sexually transmitted infections with treatment of the woman and ideally treatment of her partner. Office visits allow ongoing evaluation of the woman’s psychosocial support system and may include referral to appropriate community services, if not available in the prenatal clinic setting. Prenatal education about labor, delivery, and care of the newborn may prevent misunderstandings. Discussions with the PWUS should include details of the birth plan, including the treatment of her pain during labor and postpartum, education about the potential need for treatment of neonatal withdrawal due to maternal medications, and appropriate contraceptive methods postpartum. When possible, involvement of the patient’s significant other and support system, with maternal consent, is helpful.

Laboratory Testing For the PWUS in treatment, and for any pregnant women with evidence of

substance use or an SUD identified at the time of labor and delivery, the physical examination, social and legal history, and a maternal history of psychoactive substance use, including previous treatment episodes and substance-related obstetrical or medical problems, may indicate the need for laboratory screening and then confirmatory testing for substances in mother and newborn. Infant urine, meconium, and cord tissue as well as maternal urine are biological matrices that have been tested for use of legal and illegal drugs. As with any medical diagnostic evaluation, laboratory evaluation should be accompanied by a review of maternal records, maternal medical and psychiatric history, and, for those PWUS identified at the time of the birth, a complete evaluation for substance use and SUD during pregnancy (7). In addition to helping in a diagnostic evaluation of the newly identified PWUS, negative results are helpful in validating a mother’s history of engagement in treatment, recovery, and abstinence. However, it is important to remember that a positive biological test does not (1) diagnose a current SUD, (2) provide a result of parenting ability, or (3) indicate amount, frequency, or route of substance use. The decision to perform drug testing on a pregnant woman is often determined by the suspicion of the physician (27), which is subject to bias. A recent survey showed that women of reproductive age are very supportive of laws mandating universal verbal screening and urine drug testing of pregnant women and newborns and that pregnant women should not be able to decline such screening (28). However, the same population was not supportive of targeting low-income women for testing. A survey of hospitals showed that 45% do universal maternal drug testing and only 7% do universal newborn drug testing; of those, only 32% obtain maternal consent prior to testing (18). Initially, immunological assays are used to screen urine, blood, and meconium for psychoactive substances. Positive results should be confirmed with gas chromatography/mass spectroscopy since cross-reacting chemicals may be read initially as a “positive” for a drug. Substances routinely tested vary by laboratory, so the clinician should request assays keeping in mind medications prescribed or misused, drugs commonly used in the community, and relevant maternal SUD history. For example, an assay for “opiates” will typically identify heroin, morphine, hydrocodone, hydromorphone, and codeine. If the patient is using a prescription pain medication such as methadone, buprenorphine, oxycodone, and other synthetic and semisynthetic opioids, they will likely not be detected (false negative). Immunoassay tests may also have problems with crossreactivity to unintended substances (false positive) (29). Thus, it is helpful to communicate with the lab that the reader utilizes to better understand drug

testing issues such as these, as they can vary greatly in accordance with lab or test utilized. The advantage of testing urine is ease of collection; however, results only reflect use and fetal exposure shortly before delivery due to the short window of detection for most substances in urine. Meconium, a dark-green odorless substance produced by the fetal gastrointestinal tract beginning at 13-14 weeks of gestation, may also be tested for medications, alcohol, and other drugs. Meconium is passed by the newborn in bowel movements most often shortly after birth. The advantage of testing meconium is information about a long window of prenatal exposure, beginning in the second trimester (30). Unfortunately, meconium may be passed in utero, thus not available at birth, or may take days to collect. These difficulties and the lag time in receiving meconium results make collection of infant urine easier and more feasible. In addition, meconium may reflect iatrogenic exposure to medications administered to the neonate. Cord tissue sampling can be used to test for in utero exposure. An academic hospital transitioning from meconium to cord tissue samples compared 2072 neonatal samples using both techniques. They reported no significant difference in detection rates of nonmedical substances (amphetamines, cannabis, and opiates) between meconium and cord tissue and did not detect medications administered to the neonate after birth (31). Cord tissue sampling avoids detection of iatrogenic exposure to medications as they can be absorbed in meconium not passed at the time of birth (32). The cost of umbilical cord blood drug testing is similar to that of meconium. For any tests used, it is important to consider cost and reimbursement issues. Alcohol use often accompanies illicit substance use and/or nonmedical use of prescription medications in pregnancy; the biomarkers ethyl glucuronide (EtG), ethyl sulfate (EtS), and fatty acid ethyl esters (FAEE) in urine have been validated in outpatient settings (33). Biomarker positive evidence of alcohol use may be present from 72 hours to 7 weeks after use. Variations in results depend upon chosen lower limits for reporting positive results. EtG and FAEE are correlated in pregnancy (34). Among pregnant nurses using alcohol-containing mouthwash and hand cleansers during hospital shifts, there were no falsepositive results for EtG and EtS (35). Clinician judgment in interpretation is necessary, as results indicate exposure to alcohol throughout pregnancy, which is an indicator of maternal risk, but not an assessment of parenting ability. Confirmed or suspected history of SUD in the mother should lead to infant

and maternal screening for hepatitis B or C, human immunodeficiency virus (HIV), or other sexually transmitted diseases. Infants born to PWUS are at higher risk for these infections because of the association of drug use with highrisk sexual behaviors and intranasal and parenteral routes of administration. Screening facilitates early treatment and may help prevent further transmission or other complications of infection.

Teratogenicity A teratogen is a substance that may produce an alteration in the offspring’s physical structures and/or behavior when used during gestation. The time of exposure and amount of chemical will affect whether congenital malformations or neurobehavioral problems that persist into later lifetime will occur. In many cases, a “subthreshold exposure” will not lead to malformations, whereas in others, a small dose during critical embryogenesis can lead to significant teratogenicity. In the human, it is difficult to attribute causation to exposure when there are confounding variables such as malnutrition, severe stress, and concurrent use of other substances. Alcohol and tobacco, alone and in combination with other substances, are known to have the most potential to cause teratogenicity in the human, but any psychoactive substance use in pregnancy, whether illicit or medicinal, always involves some degree of risk of some form of teratogenicity to the developing embryo. It is not necessary for a pregnant woman to meet diagnostic criteria for an SUD for disruption of fetal growth and development to occur. Exposure in the first trimester can result in significant problems, including pregnancy loss. The majority of development and organogenesis occurs in the first 12 weeks of pregnancy; however, exposure can cause problems during any trimester of pregnancy. Even when maternal history of substance used, amount and mode of use (injection vs. oral), and the timing of use are known, there are multiple factors that affect determination of fetal substance exposure. Substances are often used in combination, confounding the effects of exposure (36). Additionally, recall bias may impact the validity of a retrospective maternal history. Finally, PWUS may feel guilty, ashamed, and overwhelmed when faced with problems in the newborn that are secondary to their SUD and may either under- or over-report their use of substances.

NEONATAL ABSTINENCE SYNDROMES

Rates of neonatal abstinence syndrome (NAS) have been increasing in the United States, primarily due to the growing epidemic of opioid use. The overall incidence of NAS has tripled in the United States from 1999 to 2013, and rural areas have experienced higher growth rates of NAS compared to urban areas, although residents of urban communities typically have access to more SUD treatment services (37,38). Polysubstance use is the norm rather than the exception in substanceexposed pregnancies; thus, it is often difficult to determine specific effects of exposure to individual psychoactive substances other than alcohol. In the newborn, signs of intoxication as well as withdrawal from illicit and legal psychoactive substances are all characterized by autonomic instability, central nervous system (CNS) irritability, and feeding difficulties. The substanceexposed newborn may have poor weight gain, instability in heart rate, respiratory rate, and temperature, as well as hyperactivity, irritability, hypertonia or hypotonia, difficulty sucking or excessive sucking, sleep disturbance, and high-pitched cries (39). The duration and severity of intoxication and the onset of withdrawal syndrome will depend upon the time of the last drug exposure, the combination of substances, and the metabolism and excretion of the drug. For example, an infant exposed to cocaine will be irritable, have sleep/wake cycle disruption, and feed poorly, but if the infant has also been alcohol exposed, symptoms may be more severe, as alcohol and cocaine form cocaethylene, a potent stimulant (40). Timing of withdrawal also varies. In the case of the infant exposed to heroin, withdrawal signs will generally emerge in the first 24 hours of life for the newborn if use occurred shortly before birth. In contrast, if methadone is prescribed or used illicitly, signs of withdrawal usually present later than with heroin, after 24-72 hours post-birth, while signs of withdrawal from buprenorphine usually present later than with methadone, after 48-96 hours postbirth (41,42). When the diagnosis of substance use or maternal SUD is under consideration, there is known use of tobacco products (including electronic cigarettes), or a urine drug screen has been positive for psychoactive substance(s), newborns should have regular assessment for withdrawal or intoxication beginning at birth or as soon as possible. Additionally, an infant born to a mother currently prescribed opioid agonist treatment for treatment of her addiction should be monitored closely. Initial treatment of the neonate experiencing NAS should be primarily supportive, as pharmacotherapy may prolong hospitalization and subject the neonate to exposure to medications that

may not be indicated (43,44). The substance-exposed neonate is easily overstimulated, so ambient light exposure and noise should be minimized. Quieting the infant with swaddling, frequent small feedings, and intravenous replacement of fluids and electrolytes may be required. Indications for pharmacotherapy include seizures; poor feeding, diarrhea, or vomiting resulting in dehydration or excessive weight loss; inability to sleep; or significant autonomic instability with bradycardia or tachycardia, apnea or tachypnea, or temperature instability not due to infection. Pharmacotherapy should be considered if the infant is too ill to assess possible withdrawal signs, if comorbid medical problems dictate that the infant will not tolerate NAS, or if the infant is not eating well and not thriving as expected. Vomiting and diarrhea associated with dehydration and poor weight gain, in the absence of other diagnoses, are relative indications for treatment, even without high total withdrawal scores (43). See page 1317 for assessment of NAS. Clinical signs and symptoms should not be attributed solely to drug withdrawal or intoxication without appropriate assessment and diagnostic tests to rule out other causes. The differential diagnosis for NAS includes sepsis, hypoglycemia, perinatal anoxia, intracranial bleed, and hyperthyroidism (45). Consultation with a neonatologist may be indicated in cases where presentation is not straightforward, the course is difficult, or the infant is not responding to pharmacotherapy and supportive measures. Neonates with intrauterine drug exposure should be followed up in the hospital for at least 72-96 hours after birth to monitor for signs of a neonatal intoxication or a withdrawal syndrome. If an infant is discharged prior to this time, the mother and her support network should be well informed about signs of NAS. She will need clear instructions about how to reach a physician to assess the newborn should signs emerge. If more than 7 days has elapsed between the last maternal use and delivery, the incidence of NAS is low (46).

TOBACCO Forty percent of women who smoke and become pregnant quit during pregnancy (47). All pregnant women should be asked directly about tobacco (all forms) or use of nicotine via electronic cigarettes and any quit attempts. ACOG recommends clinicians strongly advise all pregnant women who use tobacco/nicotine to quit (48). Nicotine replacement has not been found to be successful with pregnant women, and the US Preventive Services Task Force has

indicated that there is insufficient information regarding its safety and efficacy (49). Varenicline and bupropion are alternative pharmacotherapies for stopping smoking. However, varenicline has limited safety data for use in pregnancy, although one study of varenicline-exposed pregnancies showed no significant safety issues (50). A small study of bupropion for tobacco/nicotine treatment in pregnancy showed no significant improvement in abstinence rates at the end of pregnancy (51). However, both medications can be found in breast milk. Thus, it is suggested that health care providers focus on brief office-based interventions coupled with referral to tobacco/nicotine treatment programs specifically developed for pregnant women. Finally, PWUS should be reminded that quitting at any time during their pregnancy is advantageous to themselves, their fetus, and their other children (52). Cigarette use exposes the fetus to carbon monoxide, nicotine, and tar, which contains multiple chemicals including cyanide and lead. Disruption of growth has been demonstrated in the animal model and is due to intrauterine hypoxia, a result of carbon monoxide and other metabolites causing reduced uterine blood flow (53). Nicotine is quickly absorbed, crosses the placenta, and is active in the developing CNS, causing developmental neurological problems (54). An inverse relationship exists between birth weight and the number of cigarettes smoked per day. Neonates born to mothers who smoked during pregnancy weigh an average of 200 g (range, 100-400 g) less and have lower birth lengths than neonates born to mothers who did not smoke during pregnancy (55). Fortunately, a period of accelerated growth occurs during the first year of life, and generally, no differences in body weight or length are observed among these infants at 1 year of age. Because nicotine is a stimulant, infants born to women who smoke or otherwise use tobacco/nicotine may also be irritable and difficult to calm. When assessed with the Neonatal Intensive Care Unit Network Neurobehavioral Scale (NNNS), infants exposed to tobacco were more excitable and hypertonic with indications of disturbance in the CNS, gastrointestinal system, and visual response (56). Some investigators have proposed development of a scoring system to describe a nicotine withdrawal syndrome (57). Neurobehavioral abnormalities have been identified in the newborn period in infants exposed to tobacco in utero (56). Multiple studies have examined the causal link between sudden infant death syndrome (SIDS) and smoking. Given the confounding effect of postnatal exposure to cigarette smoking, an analysis of more than 60 studies concluded that nearly one-third of SIDS deaths may be prevented with cessation of smoking in pregnancy (58).

ALCOHOL AND SEDATIVES More than 60% of women who use alcohol and become pregnant quit during pregnancy (48). The US Surgeon General’s office advises that women who are pregnant or considering pregnancy should not drink alcohol. The majority of women with a sedative use disorder will take multiple drugs, including benzodiazepines, barbiturates, and other sleeping pills, as well as drink alcohol. The smell of alcohol on the breath indicates recent ingestion but not necessarily acute intoxication. Palpation of the abdomen may reveal an enlarged or shrunken liver due to alcoholic hepatitis. Even a minimal neurological evaluation can reveal altered mental status due to intoxication or acute alcohol withdrawal. Hyperreflexia and tremulousness may also prompt consideration of acute alcohol withdrawal. Progression to severe withdrawal from alcohol or sedatives carries a significant mortality risk, so early recognition and treatments are essential. However, the normal physiological changes that accompany pregnancy can make it difficult to recognize early withdrawal. Table 90-1 displays similarities and differences between sedative withdrawal syndrome and pregnancy. Treatment for acute withdrawal from sedatives (including alcohol) in PWUS should be accomplished in an inpatient setting that allows for medical supervision in collaboration with an obstetrician. Uncontrolled withdrawal symptoms may be life-threatening to both the mother and fetus. Benzodiazepines and barbiturates can adversely affect the fetus when given during pregnancy, so this should be taken into account when beginning treatment for acute withdrawal symptoms. However, the risk to both mother and fetus from untreated sedative withdrawal is usually greater than the potential risk to the fetus from exposure to these medications in a controlled setting.

TABLE 90-1 Pregnancy and Sedative–Hypnotic Withdrawal

In the pregnant woman, when alcohol is consumed, it is absorbed into the maternal bloodstream, quickly crosses the placenta, and enters fetal circulation. Alcohol is found in significant levels in the amniotic fluid even after a single moderate dose. As fetal hepatic circulation does not metabolize alcohol as efficiently as in the adult, alcohol is not eliminated from the amniotic fluid as rapidly as it is from maternal circulation.

Neurobehavioral Disorder Associated With Prenatal Alcohol Exposure The effects of consuming alcohol during pregnancy vary depending upon the amount used, timing of exposure during gestation, concurrent use of other psychoactive substances, and maternal factors such as nutrition and life circumstances. For example, there are negative effects of binge drinking during pregnancy on child cognition (59). The effects of low to “moderate” average weekly alcohol consumption on child neuropsychological behavior up to 5 years are less clear (59,60). To date, the conclusion remains that there is no known safe amount of alcohol to consume while pregnant. Fetal alcohol syndrome (FAS) was described in the United States in 1973 (61). In the ensuing years, multiple diagnostic criteria and schemata have described the spectrum of structural anomalies and neurocognitive disabilities associated with teratogenic exposure

to alcohol. As the diagnostic criterion of FAS excludes individuals with more subtle effects of alcohol exposure, fetal alcohol spectrum disorder (FASD) was introduced (62,63). While FASD adequately describes the varying effects of in utero alcohol exposure, this categorization is an umbrella term and not a recognized diagnostic term. A new diagnostic classification is proposed in the DSM-5, Neurobehavioral Disorder with Prenatal Alcohol Exposure (ND-PAE). This categorization addresses the spectrum of neurodevelopmental and mental health problems and symptoms experienced by affected adults and children. The diagnosis of NDPAE includes impairments and deficits in neurocognitive, self-regulatory, and adaptive functioning (64,65). Multidisciplinary research teams, using rigorous diagnostic criteria, evaluated elementary age children in predominantly white and middle class areas in the Midwest and Rocky Mountain Region. Their goal was to describe the prevalence of alcohol-exposed pregnancies in these communities. These studies predate the DSM-5 introduction of ND-PAE and use FAS, partial FAS, and FASD terminology. In the Midwestern city, FAS was reported in 6-9 per 1000 children (midpoint, 7.5), PFAS from 11 to 17 per 1000 children (midpoint, 14), or an estimation of the rate of FASD of 24-48 per 1000 children or 2.4%-4.8% of the population (midpoint, 3.6%) (66). Prevalence rates were similar for children in the Rocky Mountain City (FAS is 2.9-7.5 per 1000, PFAS is 7.9-17.7 per 1000, and combined prevalence is 10.9-25.2 per 1000 or 1.1%) (66). Addiction treatment is an opportunity to intervene with the current pregnancy and prevent further alcohol affected pregnancies. There may have been significant alcohol use during prior pregnancies, and the addiction physician specialist may be the first professional with whom a mother shares concern about her other children’s development. Formal diagnosis of ND-PAE is made through evaluation by a multidisciplinary team including geneticists, psychologists, physicians, and allied health professionals. Families and patients will find information about ND-PAE and support through the National Organization of Fetal Alcohol Syndrome (NOFAS; www.nofas.org). The use of benzodiazepines during pregnancy appears to have a low teratogenic risk. Maternal misuse of sedatives near term has resulted in poor muscle tone and respiratory depression in the neonate (67). Neonatal sedative withdrawal syndrome usually resolves spontaneously and does not require specific treatment.

OPIOIDS The use of heroin or nonmedical use of prescription opioid medications may continue into pregnancy because attempts to quit lead to obvious withdrawal symptoms, but PWUS may be reluctant to disclose information about their opioid use. Constipation from opioid use may be apparent on abdominal examination, although this is nonspecific and may be related to pregnancy. Opioids may be used by injection, especially heroin, so clues during the history and physical examination that indicate injection use may be evident. Infections such as endocarditis, recurrent cellulitis, or thrombophlebitis should raise suspicion for injection drug use. Some PWUSs hide needle marks by injecting under the tongue, in the axillae, under the breasts, into the legs, between fingers or toes, and under the nails. Track marks are wormlike scars from repeated injection that follow the courses of veins. Look for healed abscess scars from subcutaneous injection.

Maternal Pharmacotherapy Opioid withdrawal syndrome during pregnancy can lead to fetal distress and premature labor owing to increased oxygen consumption by both mother and fetus. Even minimal symptoms in the mother may indicate fetal distress, as the fetus may be more susceptible to withdrawal symptoms than the mother. Methadone is frequently used to treat acute withdrawal symptoms from illicit opioids. Methadone may be used by a clinician for temporary maintenance when a patient with an opioid use disorder is admitted to a hospital for an illness other than opioid use disorder that may be complicated by opioid withdrawal. This includes admission for evaluation for preterm labor, which may be induced by acute opioid withdrawal. Naloxone should not be given to a pregnant woman maintained on an opioid agonist medication or using opioid agonists illicitly except as a last resort in life-threatening opioid overdose, as withdrawal precipitated by an opioid antagonist can result in spontaneous abortion, premature labor, or stillbirth. Medically assisted withdrawal of the pregnant woman with an opioid use disorder is not recommended because of high rates of relapse to illicit prescription opioid and heroin use and the increased risk to the fetus of intrauterine death (68). Therefore, opioid agonist maintenance pharmacotherapy with methadone has served as the long-time standard of treatment (69). Buprenorphine has now emerged as a first-line medication alongside methadone

(70). Being on an adequate and stable dose of opioid agonist medication decreases fluctuations in maternal opioid level, which is thought to reduce stress on the fetus related to rapid cycles of intoxication and withdrawal. Fluctuations between opioid intoxication and withdrawal result in adverse fetal effects, such as premature labor and spontaneous abortion. Illicitly bought heroin is likely adulterated with other compounds that may be harmful to the fetus, and access to illicit prescription opioids may be unpredictable, so elimination of any opioid use with adequate doses of an opioid agonist medication prevents harm to the fetus from exposure to these other compounds. Engagement in opioid agonist pharmacotherapy improves maternal health and nutrition, reduces obstetric complications, and improves the health of the infant at delivery. Other advantages of opioid agonist pharmacotherapy over illicit opioid use are reduction of criminal activity and decreased disruption of the maternal–child dyad (71). Opioid agonist pharmacotherapy enhances the ability of PWUS to participate in prenatal care and SUD treatment, thus giving the woman and her family the opportunity to adequately prepare for the arrival of the infant. Pregnant women with opioid use disorder should be referred to a local addiction treatment program, if available. Most programs assign high priority to pregnant women, so the patient may be able to enter treatment sooner than if she were not pregnant. Pregnant women maintained on methadone or buprenorphine should have their dose monitored regularly throughout the pregnancy and the postpartum period and their dose adjusted as necessary. Certain factors need to be considered when treating PWUS with methadone. Maternal methadone dose does not correlate with neonatal abstinence symptoms, so maternal benefits of methadone are not offset by harm to the newborn (72). Effective daily methadone dose in pregnant women with opioid use disorder may vary (73). It is reasonable to expect the methadone dose requirement to increase during the third trimester of pregnancy. This increase is due to larger plasma volume, decreased plasma protein binding, increased tissue binding, increased methadone metabolism, and increased methadone clearance in the mother. As a result, the half-life of methadone is shortened as pregnancy progresses, and the woman may experience mild withdrawal symptoms unless adjustments are made to her methadone dose. Splitting the total daily requirement into two doses, given in the morning and evening, is preferred, if possible (74,75). This splitdose procedure provides a more even blood concentration throughout each day. Sublingual buprenorphine, a partial μ agonist and κ antagonist prescribed for the treatment of opioid use disorder, like methadone has been used successfully for the treatment of opioid use disorder in pregnant women and should not be

considered “off-label” use (76). It is available in an office or opioid treatment program from a certified provider that has a DEA waiver to prescribe buprenorphine. Induction onto buprenorphine is not more complex than methadone, and the initial dose may need to be divided into two or three doses, and it may take a few days for dose stability to occur. This medication has been well tolerated by pregnant women, and newborns have had a similar incidence of NAS compared to mothers on methadone yet appear to require less morphine to treat and shorter duration of treatment for NAS than with methadone (73). The onset of treatment for NAS may be longer compared to methadone but still within 4 days of hospital observation (42). Opioid agonist pharmacotherapy as part of comprehensive care for pregnant women who use heroin and/or illicit prescription opioids improves maternal psychosocial function and birth outcomes (77).

Neonatal Withdrawal Neonatal opioid withdrawal syndrome occurs in 60%-80% of infants with intrauterine exposure to heroin or prescription opioids, including methadone and buprenorphine (78). The incidence of the syndrome is best described in those cases where PWUSs are prescribed an opioid while in treatment. In these cases, historical and laboratory information for most of the pregnancy is available and may assist in treatment of the newborn (79). Assessment and pharmacological management of opioid-exposed infants vary across nurseries (80). Perhaps the most comprehensive assessment is provided by the Maternal Opioid Treatment: Human Experimental Research (MOTHER) NAS Measure (Fig. 90-1 and Table 90-2) (73). This modified Finnegan scale with specified item-by-item definitions assesses signs and symptoms with weighted scores, which are evaluated at 2 hours after birth and then every 4 hours. In scoring an infant, considerations of other factors, such as comorbid exposure to tobacco or other stimulants, a noisy environment and overstimulation, or whether the infant is hungry or not, may impact upon results. Pharmacotherapy is usually initiated when the total score is 9 or greater for 2 consecutive evaluations or 13 or more on a single evaluation, with dose escalation if scores climb rather than drop; however, some nurseries will utilize a lower score to initiate pharmacotherapy in an infant with comorbid medical problems or a higher score if the infant is feeding well and thriving. After initiation of treatment, the clinician should evaluate and score the infant every 4 hours until the score remains at 8 or below for 48 hours.

Figure 90-1 Maternal Opioid Treatment: Human Experimental Research (MOTHER) Neonatal Abstinence Measure. *See Table 90-2 for scoring. †Code Status of Treatment as follows: N, no treatment; I, initiation; M, maintenance; W, weaning; R, reescalation. (Reproduced from Jones HE, Kaltenbach K, Heil S, et al. Neonatal abstinence syndrome after methadone or buprenorphine exposure. N Engl J Med. 2010;363:2320-2331. Copyright © 2010, Massachusetts Medical Society.)

TABLE 90-2 MOTHER NAS Scoringa

aThe MOTHER NAS scoring instrument is a revision of the Finnegan scoring system for the NAS. Reproduced from Jones HE, Kaltenbach K, Heil S, et al. Neonatal abstinence syndrome after methadone or buprenorphine exposure. N Engl J Med. 2010;363:2320-2331. Copyright © 2010, Massachusetts Medical Society.

Another scoring tool, the Lipsitz Withdrawal Score, is used in some nurseries with treatment initiated at a score of more than 4 (81). This assessment has fewer items and may be easier to administer. The NNNS is also used to assess stress

and responsiveness in the newborn. It is not used to determine opioid withdrawal medication treatment initiation, adjustments, or discontinuation (82). Recommendations regarding specific treatments of NAS are hampered by the paucity of controlled trial data supporting the efficacy of any one preparation or treatment regimen over another (83). The use of other nonopioid drugs such as alcohol and other sedative drugs is a confounder of studies. The Cochrane Database Review of NAS concluded that treatment with an opioid agonist, such as oral morphine sulfate or methadone, reduces time to regain birth weight but may increase hospital length of stay (84). In a meta-analysis, phenobarbital and diazepam were found to be less effective in the treatment of seizures, but administration of a CNS depressant did not clearly lead to poorer treatment outcomes (85). Some investigators report the addition of phenobarbital to an opioid lead to better outcomes, whereas others find the CNS depressants fare poorly when compared to treatment with opioids (86,87). The American Academy of Pediatrics no longer recommends treatment with paregoric (43,88). Moreover, they also caution that tincture of opium contains a concentration of morphine 25 times higher than oral morphine solutions, which increases the risk of morphine overdose due to dosing or pharmacy error. Treatment with buprenorphine is currently under investigation (89). In the case of PWUS prescribed methadone or buprenorphine for opioid addiction, with no indication of other drug exposure, opioid agonist treatment is appropriate when pharmacological intervention is indicated (Table 90-3).

TABLE 90-3 Pharmacotherapy for Neonatal Opioid Withdrawal Syndrome

Adapted from Desmond MM, Wilson GS. Neonatal abstinence syndrome: recognition and diagnosis. Addict Dis Int J. 1975;2:113-121. Oral morphine sulfate directions based on Berghella V, Lim PJ, Cherpes J, et al. Maternal methadone dose and neonatal withdrawal. Am J Obstet Gynaecol. 2003;189:312-317.

A review of the animal and human literature provides no evidence that prescribed and illicit use of opioids are in themselves teratogenic (90). Other than transmission of infection secondary to injection and intranasal insufflation, the most common ill effect of opioid use and opioid addiction in pregnancy is

intrauterine growth restriction (IUGR). Growth restriction is a result of poor maternal nutrition and the fluctuations of intoxication and withdrawal from the opioids inherent to the lifestyle and disease of opioid use disorder. The children of women prescribed opioids for the treatment of pain, with steady-state concentrations of opioid medications, have no increase in pregnancy complications and deliver infants of normal weight and length (91). The most common complication in these infants is emergence of neonatal opioid withdrawal syndrome. Finally, newborns exposed to opioids chronically through gestation develop physiological tolerance and rarely have CNS or respiratory depression at birth. Initial findings are that there is no greater fetal risk from exposure to buprenorphine than methadone, with some suggestion that buprenorphine may produce less suppression of fetal heart rate and less fetal heart rate reactivity than methadone (92). The use of opioids for pain at the time of delivery is addressed on page 1319.

CANNABIS The legalization of medical and recreational cannabis at the state level is increasing, which has also led to an increase in other forms of use of Cannabis such as via electronic cigarettes, edibles, lollipops, and lotions. Unfortunately, many pregnant women believe that Cannabis is relatively safe to use in pregnancy, with increasing rates of Cannabis use due to reductions in perceived risk and stigma (93,94). The amount of delta-9-tetrahydrocannabinol (THC), the active ingredient in various cannabis products, varies significantly depending on the extraction process from the cannabis plant. Women are using greater quantities of Cannabis or Cannabis products with higher THC concentrations, especially after legalization in multiple states, so that neonates in Colorado had substantially more exposure to Cannabis in the post-legalization period (95). The full impact of this exposure has yet to be determined throughout the development of the exposed children. Pregnant patients who report cannabis use are more likely to be young, single, primigravida, and Black (96). Delta-9-tetrahydrocannabinol easily crosses the placenta, and the fetus is exposed to the active chemical as well as carbon monoxide. Numerous studies have documented neurodevelopmental deficits in children prenatally exposed to Cannabis (97). The concurrent use of alcohol and tobacco in pregnancy confounds understanding of the teratogenicity of cannabis, but there does not appear to be any teratogenic pattern unique to Cannabis. However, there is a possible small reduction in fetal growth and a higher risk of stillbirth (98,99).

Neonatal effects take the form of impaired regulatory control, including irritability, and tremors and sleep disturbances (100,101). Preteen children exposed in utero have demonstrated behavioral problems and reduced attention span (102). During adolescence, studies have shown that children exposed to Cannabis in utero had lower scores on tests of visual problem solving, visualmotor coordination, and visual analysis compared to unexposed children (103,104). Cannabis is neither regulated nor evaluated by the U.S. Food and Drug Administration, so there are no approved indications and no standardized formulations, dosages, or delivery systems. As a result, there are no safety precautions or recommendations regarding use during pregnancy or lactation.

STIMULANTS Previous pregnancy complications such as preterm labor, premature rupture of membranes, placental abruption, or IUGR may indicate prior complications of stimulant use, especially cocaine or methamphetamine. A meta-analysis of 31 studies including subjects who used cocaine during pregnancy revealed that birth outcomes included higher odds of preterm birth, shorter gestational age at delivery, and small for gestational age neonates (105). Respiratory problems in the mother may be a current consequence of intranasal insufflation (snorting) or smoking stimulant drugs such as cocaine and amphetamines (105). Atrophy of the nasal mucosa or perforation of the nasal septum indicates snorting of drugs, most often cocaine or methamphetamine (106). A cough productive of black sputum may be indicative of crack smoking (107). The withdrawal syndrome from stimulants is subtle and complex and consists primarily of depression and craving. As abrupt discontinuation of stimulants does not cause gross physiological sequelae, they are not tapered off or replaced with a cross-tolerant drug during medically supervised withdrawal treatment (108). Pregnant women withdrawing from stimulants should not receive medication except in cases of extreme agitation. Low doses of a benzodiazepine may be used if necessary. An abstinence syndrome for intrauterine cocaine exposure has not been clearly defined, although effects of cocaine intoxication on neurobehavioral status have been identified (43). Intoxicated newborns may be irritable, be difficult to quiet, and have feeding difficulties (109). Stimulant exposure may worsen the appearance of opioid withdrawal syndrome because of increased

irritability in the newborn with stimulant intoxication. When cocaine is used, the active drug and its metabolites readily cross the placenta. As fetal pH normally is lower than maternal pH and the fetal liver does not metabolize cocaine efficiently, cocaine is more highly concentrated in amniotic fluid. The effects of cocaine are thought to be through direct neurotoxicity by disrupting monoaminergic pathways and causing vascular damage (110). Multiple studies over the last decade have identified neurological, developmental, and behavioral deficiencies in the infant, toddler, and young child exposed prenatally to cocaine (110,111). Cognitive differences, motor delays, language delays, and fine-motor problems have been identified across multiple studies, and there may be a dose–response effect of cocaine on newborn head circumference (112). However, many confounders of these effects have been identified, not the least of which is the use of alcohol by women using cocaine (113). Additionally, the teratogenic effects of cocaine on the CNS, heart, and genitourinary system are debated as results of large controlled population studies provide contradictory findings (114). The National Toxicology Program Center for Evaluation of Risks to Human Reproduction evaluated the potential for reproductive problems with the therapeutic and nontherapeutic use of amphetamines (115). One of the major concerns of this group was the effect of other factors, including concurrent exposure to other drugs. The report concludes there is some concern about neurobehavioral alterations occurring with prenatal exposure to amphetamines. Additionally, the group expressed some concern about growth, and an effect of methamphetamine on growth was found in the multicenter, longitudinal infant development, environment, and lifestyle study, with these exposed infants showing higher rates of IUGR (116). Finally, ACOG has suggested that newborns exposed to methamphetamines in utero may be small for gestational age and at risk for neurodevelopmental abnormalities (117).

MATERNAL SUD TREATMENT Simple admonitions to stop using are sometimes helpful if substance use or a SUD is identified early but in most cases of moderate to severe disorder are insufficient (118). SUD treatment is more likely to be effective when begun during pregnancy than afterward (119). In certain cases, therapy for PWUS who are actively using illicit substances begins with management of withdrawal, but this is merely a first step in overall treatment. Women are likely to benefit from

different types of treatment programs, depending on the primary drug used and severity of SUD, as well as the patient’s life context, including her past experience in treatment or recovery. The ability of PWUS to follow through with treatment may be compromised by guilt, lack of supportive significant others (including family), and uncertainty about the success of treatment. However, the possibility of being reunited with children that may have been placed with another family member or in temporary foster care is often an incentive for a mother to enter treatment. This reduces the burden on the foster care system by assuring the safety of the child in a therapeutic environment. Unique factors and problems must be considered when providing treatment to pregnant women. Access to treatment for PWUS may be limited by lack of treatment program openings, transportation problems, lack of childcare, or poverty (120). SUD treatment programs must provide child care to be effective, but few do so (121,122). Twelve-step self-help group attendance and/or formal treatment programs, whether inpatient, residential, or outpatient, must address these unique challenges to be optimally effective. Specialty residential treatment programs for PWUS, specifically those that provide care for their infants, are economically justified because comprehensive treatment programs for this population are successful (123). Pharmacotherapy may be an option for some PWUS, though some medications are contraindicated in pregnancy. Women prescribed medication for an alcohol use disorder should inform their health care provider if they are planning to become pregnant. Some forms of long-term SUD pharmacotherapy are not appropriate in pregnancy. Disulfiram (Antabuse) is contraindicated during pregnancy because of the association with specific birth defects, and the effects of acamprosate (Campral) and naltrexone (Revia, Depade or Vivitrol) have not been studied in pregnancy (124). Clinicians should discuss options regarding whether to start or continue acamprosate or naltrexone and the preferences of the mother. Due to limited data on safety and efficacy of nicotine replacement therapy or prescribed medication (varenicline, bupropion) for tobacco/nicotine use treatment for PWUS, clinicians should focus on officebased brief interventions. Buprenorphine or methadone treatment is first-line therapy for pregnant women using opioids and requires dose monitoring throughout pregnancy. Maintenance until after delivery is recommended as opposed to tapering off during pregnancy.

LABOR AND DELIVERY

One of the most common complications of substance use and SUDss during pregnancy is preterm labor with occurrence varying according to the substance. Rates from opioid use may be as high as 29%-41% (7,125). Rates for other illicit drugs are generally lower, with around 6% attributable to cocaine (126). Women may relapse as they near the end of pregnancy. They may confuse early signs of labor with signs of acute withdrawal, so may use illicit prescription opioids and/or heroin during the early hours of labor and arrive at the hospital in labor with high concentrations of drugs from recent use. This increases the chances of fetal stress and distress. Some PWUSs may use heroin or illicit prescription opioids immediately before presenting for delivery in anticipation of the pain and stress of labor. Reassuring the woman that she will have access to adequate analgesia may help to allay some fears. The delivery method should be selected based solely on obstetric considerations. The staff on a labor and delivery unit should be aware that women who use stimulants may display bizarre and potentially abusive behavior (7). Delivery is a clinical situation with nearly universal acute pain and a reasonably defined onset and resolution (127). Patients who use illicit drugs are subject to pain in the same manner as any other patient, so can benefit from appropriate treatment for pain (if the drug used is an opioid, they may have tolerance and thus require higher doses of opioids for pain relief) (128). PWUS should be assessed for appropriate analgesia, and anesthesia options and adequate pain management should be provided at the time of delivery. Regional anesthesia may be the procedure of choice during delivery and for postpartum pain. Placement of an epidural catheter with infusion of a local anesthetic such as bupivacaine can reduce or eliminate the need for opioid analgesics. Pain medication should not be withheld based on the presence of current or past SUD. There is no reason to withhold or alter the dose or timing of the dose of opioid agonist therapy given to women with opioid use disorder in labor and delivery or postpartum. Adjust the pain medication dose based on the patient’s reported pain level using a pain scale. Splitting the daily dose of buprenorphine in four (ie, administering every 6 hours) may take advantage of the analgesic properties of the medication (129). One study found that women stabilized on methadone or buprenorphine experienced adequate pain control postpartum with the use of other opioids in combination with acetaminophen and a nonsteroidal antiinflammatory drug. Methadone-maintained women may need additional pain control that can be managed with nonsteroidal anti-inflammatory drugs (130). These results suggest that routine pain management protocols are effective in reducing pain in buprenorphine- or methadone-maintained patients following a

vaginal delivery. A second study showed that women on methadone maintenance during pregnancy had similar analgesic requirements and response during labor but required more opioid analgesic after cesarean delivery when compared to women not on methadone maintenance (127). Women who are using heroin or prescription opioids or are prescribed chronic opioids (including methadone maintenance) should not receive opioid agonist/antagonist pain medications (such as pentazocine or butorphanol) for acute pain because these medications may cause an acute opioid withdrawal syndrome (131).

BREAST-FEEDING Women actively engaged in recovery, including those in SUD treatment, should be encouraged to breast-feed as long as urine drug screens are negative and the mother is negative for HIV (132). Women infected with either hepatitis B or hepatitis C may also breast-feed as long as the nipple and surrounding areola are not cracked and/or bleeding to avoid direct contact with maternal blood (133). In such cases, women should be encouraged to pump and discard breast milk and to resume nursing after the skin has healed. Breast-feeding builds a strong mother– infant bond while providing optimal nutrition and passive immunization for the child. Women with SUD may struggle with the responsibilities and role of parenthood, sometimes having lost custody of infants and children or having been exposed to SUD in their own families as children. Therefore, successful establishment of breast-feeding by a recovering woman is particularly empowering. Women can breast-feed while on methadone maintenance (132). The American Academy of Pediatrics lists methadone as a medication compatible with breast-feeding (133). Nonetheless, women in methadone maintenance programs are sometimes discouraged from breast-feeding or are told that their “dose is too high.” Such a position is contrary to the evidence that negligible amounts of methadone are excreted in human milk across the dose range; thus, there is no contraindication to nursing while prescribed methadone (134). Although little methadone is transferred in breast milk, small amounts may ease neonatal withdrawal from opioids. In a study of 190 infant–mother pairs where the majority of the mothers were prescribed methadone, those infants who were breast-fed had less severe NAS (135). Buprenorphine is likewise appropriate to be continued for a woman who becomes pregnant while on maintenance treatment. Small amounts of buprenorphine are excreted in breast milk, so breast-feeding should also be encouraged in mothers prescribed buprenorphine

(136). Insufficient information about the extent to which naloxone passes into breast milk is available to provide guidance with regard to breast-feeding. Clinicians should discuss options regarding whether to continue buprenorphine without or with naloxone and the preferences of the mother. Breast-feeding during maternal use of benzodiazepines should be discouraged. Diazepam and its active metabolite, N-desmethyldiazepam, have been found in both breast milk and infant blood. However, the relative concentrations in breast milk and infant blood plasma are not currently known. Breast-feeding should likewise be discouraged during any period of maternal cocaine use (137). Cocaine is present in breast milk, which the newborn easily absorbs. Moreover, metabolism of cocaine in infants is quite slow, and it may be several days before cocaine does not appear in urine assay of the newborn. Breast-feeding during any period of maternal Cannabis use should also be discouraged. Cannabinoids have been shown to pass through breast milk (138). The active metabolite of Cannabis, tetrahydrocannabinol, is found in breast milk at levels elevated to maternal blood plasma levels. ACOG discourages clinicians from prescribing or suggesting the use of Cannabis for medicinal purposes during preconception, pregnancy, and lactation (19). An infant may be exposed to psychoactive drugs through breast milk if the mother relapses or is not yet in recovery from SUD. The substance-exposed nursing infant will display signs not dissimilar from those seen in the adult using a substance. Exposure to nicotine may cause irritability and poor feeding and disrupt sleep in the infant. Similarly, infants can become intoxicated and irritable with exposure to other stimulants such as cocaine and amphetamine. The infant may feed and sleep poorly, have gastrointestinal disturbance with vomiting or diarrhea, and may present with a seizure. Infants exposed to opioids may display intoxication with sedation and poor feeding or may exhibit withdrawal signs and become tremulous, restless, and feed and sleep poorly. Finally, the infant exposed to alcohol may feed and grow poorly, become diaphoretic, and have poor muscle tone. A mother ingesting more than 1 g/kg of alcohol each day may have decreased milk letdown, belying the conventional wisdom that alcohol consumption increases letdown and milk production (139).

LEGAL ISSUES Patient history or physician examination may lead a physician to request laboratory screening for substances in a pregnant woman and/or newborn child,

in the interest of both the woman’s and the child’s health. Testing should not be done without the patient’s (woman’s) knowledge. A request for bodily fluid testing must be accompanied by informed consent, because testing without this violates the constitutional rights of the mother and child and the patient’s autonomy (140). The physician must balance the maternal right to privacy with the imperative to protect the fetus (141). Most physicians favor mandatory screening for any alcohol use, although there is concern that fear of prosecution and potential loss of custody of the child or her other children would cause women to avoid prenatal care (142). Some states have laws that present terrible dilemmas to clinicians because they equate positive drug testing with child abuse or criminal offenses, which can interfere with successful treatment of SUD (143). However, in many cases across the nation, legislators and the courts have ruled that SUD in pregnancy is not a criminal matter and there is no evidence that punitive approaches work (140,142). A positive toxicology screen in mother or infant warrants a Child Protective Services (CPS) evaluation of the situation. The federal Child Abuse Prevention and Treatment Act requires states to have policies and procedures to notify CPS of substance-exposed newborns (144). The mandate to report varies significantly, and thus, clinicians should be familiar with legislation in their state and community. Fortunately, CPS workers are responsible for further investigation of the risk to the child, thus relieving the clinician from the task of optimizing the home postpartum environment. Many states require hospitals to report pregnant women suspected of heavy alcohol or other drug use to local public health authorities or the criminal justice system when they present for delivery, whether she has or has not sought treatment for her SUD. The threshold for amount of alcohol or other substances such as Cannabis that triggers reporting to authorities may not be specified by state legislation and left up to the judgment of the clinician. This reporting may cause PWUS to be even more wary of acknowledging that they have a problem. For this reason, it is very important for a physician who recognizes perinatal SUD to address this issue with the patient in a compassionate, nonjudgmental manner, thus advocating for both mother and child. Mandatory reporting of positive maternal drug screens or aggressive prosecution of PWUS may cause women to avoid disclosure of SUD during pregnancy. Some PWUS avoid prenatal care and hospital delivery, particularly if they have other children in the custody of CPS or living with relatives, because they fear the loss of their children. However, mandatory reporting legislation may provide an incentive for PWUS to enter treatment prior to delivery in order to avoid potential

prosecution. Continued custody of the child may be contingent upon adherence to a treatment plan determined by the CPS. The use of the criminal justice system for coercion to initiate SUD treatment is supported by improved outcomes when PWUS are allowed to retain custody of their infant (117). Every effort should be made to coordinate appropriate placement of the infant (with the mother, another family member, or in foster care) when a mother is in need of SUD treatment. With such support, the mother can continue to build her bond with the infant, and it provides positive motivation for the mother to attend treatment and enter recovery. Laws vary greatly across the United States and are often unclear regarding charges of child abuse for PWUS (142). Education and support of PWUS about applicable state legislation can help enhance motivation to enter SUD treatment prior to delivery.

POSTPARTUM CARE SUD is not sufficient to determine at-risk parenting; however, it is within a cumulative risk framework. Identifying children who were exposed in utero to substances can be a launching point to help optimize the health and well-being of the mother and child (145). Further, the link between parental SUD and child maltreatment has been known for many years and has been recently affirmed in the Adverse Childhood Experiences Study (146,147). Effectively treating a parent is the most important intervention for the child exposed to substances, both prenatally and during their childhood (148). Particularly in the case of PWUS, the additional stresses of meeting the developmental needs of a newborn, possibly together with rearing older children, lack of family and social support, depression and other psychiatric problems, inadequate housing or homelessness, exposure to violence, and financial difficulties, may pose as much risk to successful child rearing as an SUD (146). Comprehensive ongoing maternal SUD treatment, tailored to help the woman address other stressors besides SUD, reduces the chance of an adverse outcome for both mother and child. Otherwise, these factors can hamper the recovering woman’s effectiveness as a parent, thus contributing to the risk of relapse to SUD (149). If a mother is successful in treatment, she may be able to retain custody of her children. For the woman whose children have been removed from her home, a goal of treatment and recovery should be reunification of her family. Prolonged hospitalization of newborns or foster care for children born to PWUS is an economic burden on society (108). Effective treatment and intervention is costeffective in the short and long term and becomes the first and most effective

prevention intervention for children. For PWUS without an SUD, the goal of brief counseling is to prevent a return to hazardous substance use, particularly during a subsequent pregnancy. Following birth, maternal treatment plans should be expanded to address newborn medical problems such as infection and developmental problems due to substance exposure. Bonding with the infant may be more difficult, so the mother may need to be taught specific skills to calm and feed her infant. Older children may need to be evaluated for developmental problems if the mother is concerned or gives a history of substance use in earlier pregnancies. Communication links developed during the pregnancy should be expanded to include physicians, social workers, and allied health professionals caring for the infant and older children. Such interventions can have a positive impact on development of every child in the family and prevent another substance-exposed pregnancy (146).

CONCLUSIONS Screening with brief intervention for substance use along with laboratory testing should be performed for all pregnant women at the initial prenatal visit and repeated if necessary. Several validated screening tools are available. Screening for co-occurring disorders and domestic violence is also valuable. Clinicians must be aware of mandated reporting requirements in their jurisdiction during pregnancy or after delivery, which may help motivate PWUS to consider appropriate treatment for substance use during pregnancy. Once identified, PWUS should be offered appropriate pharmacotherapy for maternal withdrawal syndromes, especially for alcohol, sedatives, and opioids. Pregnant women should also be offered appropriate options for pain management at delivery and education about breast-feeding as well as postpartum care and support.

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CHAPTER 91

Perioperative Management of Patients with Alcohol- or Other Drug Use Daniel P. Alford and Zoe M. Weinstein

CHAPTER OUTLINE Introduction Perioperative Care of the Patient With Unhealthy Alcohol Use Perioperative Care of the Patient With an Opioid Use Disorder Perioperative Care of the Patient With Benzodiazepine Use Disorder Perioperative Care of the Patient With Nicotine or Cannabis Use Perioperative Care of the Patient With Stimulant Use Disorder Organ Transplantation in Patients With Substance Use Disorders Conclusions

INTRODUCTION Surgery may be required for complications of alcohol and other drug use such as the management of traumatic injuries, infections of the skin, soft tissue, bones, and joints, infective endocarditis, and certain cancers. It is estimated that in the perioperative setting, one in five patients has an alcohol use disorder, one in three has a nicotine use disorder and one in ten patients has a drug use disorder (1). Because of the high prevalence of substance use, patients who use substances will be among those who are planning to undergo surgery that is unrelated to alcohol and other drug use complications. Substance use and its associated chronic medical conditions can increase the risk of postoperative complications. In an older retrospective study of patients presenting with traumatic mandibular fractures in which two-thirds reported current or past alcohol or drug use disorders, postoperative complications including wound infections and poor healing were up to five times more likely in groups with substance use compared to individuals who did not use substances (2). Orthopedic surgery in patients with an active opioid use disorder was associated with an increased inpatient mortality and morbidity including respiratory failure, surgical site infection, pneumonia, myocardial infarction, and postoperative ileus or other gastrointestinal complications (3). Hospitalization for surgery may be the first time that a patient with a substance use disorder does not have access to alcohol or other drugs, putting him or her at risk for withdrawal. Acute withdrawal syndromes may complicate surgery and the postoperative course presenting as tachycardia, hypertension, anxiety, delirium, pain, and seizures. Therefore, providers of perioperative care must identify substance use disorders

and be comfortable with the management of substance withdrawal syndromes. The care of patients with substance use disorders is also complicated by a potential mutual distrust that exists between patients and their medical team, with physician fear of being deceived and patient fear of being mistreated and stigmatized (4). Often, preoperative evaluations can be deceivingly simple in this patient population because they are often without known chronic illnesses. However, careful evaluation may detect clinical signs of chronic diseases secondary to alcohol or drug use that increase surgical risk, such as diseases affecting the heart, lungs, kidney, liver, nervous system, and pancreas. In addition, the physiological stress associated with surgery may bring out subclinical comorbidities not obvious during routine preoperative evaluation. Treating physicians should not expect to cure the patient’s substance use disorder during the perioperative hospitalization but should focus on getting the patient through the surgery safely and then offering the patient referral to long-term addiction treatment. This chapter focuses on relevant perioperative issues in the patient with alcohol or other drug use.

PERIOPERATIVE CARE OF THE PATIENT WITH UNHEALTHY ALCOHOL USE Unhealthy alcohol use is common especially in patients seeking medical and surgical care (5). The prevalence of alcohol use disorders is as high as 40% in emergency room and various surgical inpatient settings and up to 50% in patients with trauma (6). Many chronic medical conditions that can complicate or necessitate surgery, including dilated cardiomyopathy, cirrhosis, pancreatitis, and oral and esophageal cancers, are attributable to alcohol. The incidence of symptomatic alcohol withdrawal in hospitalized patients is as high as 8% and is two to five times higher in hospitalized trauma and surgical patients (7–9). Chronic alcohol use can increase the risk of postoperative mortality (10) and morbidity through immune suppression, reduced cardiac function, and dysregulated homeostasis including alterations in platelet production, aggregation, and changes in fibrinogen levels (11,12). Preoperative alcohol use is an independent predictor of pneumonia, sepsis, superficial surgical site infection, wound complications, and longer hospital stays (13). Postoperative complications appear to show a dose–response relationship with alcohol consumption, that is, the more alcohol consumed, the higher risk for

postoperative complications (14). Therefore, preoperative screening for unhealthy alcohol use and withdrawal risk is important.

Preoperative Evaluation In addition to a complete history and physical examination, the preoperative evaluation should assess for the risk of acute alcohol withdrawal and the presence of diseases associated with heavy alcohol use. Historically, physicians failed to identify alcohol use disorders in medical patients. In one study, only 16% of people with alcohol use disorder were identified in the perioperative setting (15). The amount of alcohol consumed is a risk factor for postoperative complications (16). When screening for alcohol use disorders, it is important to remember that patients with unhealthy alcohol use are often asymptomatic and often minimize consumption. Quantity and frequency questions are essential but are generally not sensitive or specific for diagnosing an alcohol use disorder, with the exception of specific items that have been validated for this purpose. Laboratory tests such as blood alcohol levels and liver function tests are not sensitive or specific. Adults undergoing preoperative evaluation should be screened using validated questionnaires such as the single item screening question (SISQ), CAGE, Alcohol Use Disorder Identification Test (AUDIT), or the AUDIT-C. The 3-item AUDIT-C can identify patients at risk for postoperative complications but also for increased postoperative healthcare utilization (ie, hospital length of stay, more ICU days, and increased probability to return to the operating room) (17,18). It should be noted that the disadvantage of the CAGE is it may only identify disorder and not heavy drinking, and it does not focus on current use. Other historical findings suggestive of unhealthy alcohol use include traumatic injuries, marital, social and legal problems, homelessness, and a history of withdrawal and blackout episodes (19). Screening preoperatively in the surgical setting differs from screening in other settings. In the surgical setting, screening for risk of withdrawal and medical comorbidities are the priorities. Consider including one or more of the following questions regarding alcohol withdrawal in the preoperative evaluation: Have you ever gone through alcohol withdrawal, such as having tremor or the shakes? Have you ever had problems or gotten sick when you stopped drinking? Have you ever had a seizure, hallucinations, or DTs (delirium tremens), been confused, after cutting down or stopping drinking?

The spectrum of withdrawal ranges from mild tremor, hallucinosis, to seizures and delirium tremens. In the postoperative period, withdrawal can mimic many postoperative complications including acute pain and sepsis. The incidence of alcohol withdrawal is two to five times higher in hospitalized trauma and surgical patients (5). Risk factors associated with severe and prolonged alcohol withdrawal include amount and duration of alcohol use, multiple recurrent withdrawal episodes, older age, and co-morbid diseases (20). It is also important to note that sedatives (eg, benzodiazepines) and analgesics (eg, opioids) given during surgery and the postoperative period may delay, partially treat, or obscure some symptoms of alcohol withdrawal. It is important to assess for other drug use as well, because many patients with unhealthy alcohol use often use other substances such as benzodiazepines and cocaine. Physical examination should evaluate for evidence of liver, pancreatic, nervous system, and cardiac disease. The spectrum of alcoholic liver disease ranges from fatty liver with normal or mild elevations in liver function tests (ie, transaminases) to acute hepatitis and cirrhosis. Clinical evidence of cirrhosis including jaundice, palmar erythema, gynecomastia, testicular atrophy, spider telangiectasia, as well as findings consistent with portal vein hypertension, namely splenomegaly, ascites, hemorrhoids, and caput medusa (dilation of the periumbilical veins on the abdominal wall), should be looked for. Pancreatitis can present as acute and chronic abdominal pain as well as exocrine (ie, malabsorption) and endocrine dysfunction (ie, glucose intolerance to diabetes mellitus). Alcohol-associated dementia, Korsakoff syndrome, hepatic and Wernicke encephalopathy, myelopathies, and polyneuropathies are nervous system disorders associated with long-term regular heavy alcohol use. These neurological conditions can worsen during the perioperative period and may be confused with other postoperative neurological complications. Therefore, preoperative baseline mental status and cognition should be assessed and well documented. Preoperative evaluation for congestive heart failure should be considered because up to one-third of patients with long-standing heavy alcohol use have a decreased cardiac ejection fraction (21). Because of the association between heavy alcohol use/alcohol use disorders and nicotine use disorder, smokingrelated comorbidities such as coronary heart disease and chronic obstructive pulmonary disease (COPD) should also be evaluated for. Preoperative laboratory studies should include electrolytes, liver function tests, coagulation studies, and a complete blood count. Anemia is common in patients with alcohol use disorders as well as decreased platelet count from alcohol-associated bone marrow suppression and splenic sequestration. Preexisting anemia may need to

be treated preoperatively because these patients are at increased risk of perioperative bleeding secondary to coagulopathies and thrombocytopenia. It is also important to identify patients who are in recovery from alcohol or other drug use preoperatively because they may have concerns and questions about perioperative exposure to sedative–hypnotics and opioid analgesics.

Management of Alcohol Withdrawal One of the most common complications of hospitalized patients with alcohol use disorder is withdrawal. The spectrum of alcohol withdrawal ranges from minor symptoms of autonomic hyperactivity including diaphoresis, tachycardia, systolic hypertension to tremor, insomnia, hallucinations, nausea, vomiting, psychomotor agitation, anxiety, and grand mal seizures to life-threatening delirium tremens. Withdrawal symptoms may appear within hours of decreased intake; however, during the perioperative period, the administration of anesthetics, sedatives, and analgesics may delay the onset of withdrawal. Recognizing withdrawal risk and treating early withdrawal can often prevent the complications of severe withdrawal. Because alcohol withdrawal is especially dangerous during the postoperative period, asymptomatic but at-risk patients should receive prophylactic treatment to prevent withdrawal. Although many medications have been used to treat alcohol withdrawal, benzodiazepines are the medications of choice for both the prevention and management of alcohol withdrawal (22,23). Preferably, benzodiazepines with a long half-life such as diazepam or chlordiazepoxide should be chosen. However, patients with severe liver disease should receive a shorter-acting agents that are not metabolized by hepatic oxidation (often impaired in severe liver disease), such as lorazepam, to avoid excessive and prolonged sedation. Treatment of withdrawal should be based on the severity of symptoms and signs. The Clinical Institute Withdrawal Assessment Scale for Alcohol, revised, is a validated tool that can be used to rate the severity for alcohol withdrawal (24). This 10-item scale can be completed rapidly and easily at the bedside. Use of the Clinical Institute Withdrawal Assessment Scale for Alcohol, revised, may be difficult to use in the postoperative period in patients unable to verbally communicate and may be less reliable in patients with acute medical or surgical illnesses. Alternatively, for patients who are in severe withdrawal and unable to respond to questions, the Minnesota Detoxification Scale (MINDS) protocol could be used (25). The MINDS protocol is an alcohol withdrawal scoring tool which has been studied in the ICU setting. Goals for management of alcohol withdrawal include treatment of withdrawal symptoms, prevention of initial and recurrent seizures, and

prevention and treatment of delirium tremens.

Alcohol Use and Surgical Risk In addition to alcohol withdrawal, observational studies have demonstrated that heavy alcohol use even in the absence of clinical liver disease and even in the absence of alcohol use disorder per se is an independent risk factor for postoperative complications. Higher rates of postoperative complications were seen after spinal surgery, transurethral prostatectomy, colonic surgery, and hysterectomy (26–29). There is a dose–response effect, with increased alcohol consumption in grams being associated with both increased postoperative complications and prolonged hospital stay. The most dramatic differences were in groups who drank >60 g of alcohol (>4 drinks) per day (30). The postoperative complications reported were an increased rate of infection, bleeding, and delayed wound healing. Patients with alcohol use disorders also have longer intensive care unit stays, more postoperative septicemia, and pneumonia requiring mechanical ventilation as well as increased overall mortality (31). Five possible pathological mechanisms have been identified to account for the increased rate of postoperative complications including immune incompetence, subclinical cardiac insufficiency, hemostatic imbalances, abnormal stress response, and wound healing dysfunction (7). Heavy alcohol use suppresses T-cell–dependent activity and decreases macrophage, monocyte, and neutrophil mobilization, and phagocytosis. The decrease cardiac function associated with heavy alcohol use is thought to be secondary to direct alteration in the electromechanical coupling and contractility of cardiac myocytes. This alcohol-associated cardiac dysfunction may be reversible, with 50% of patients showing improvement after 6 months of abstinence (32). The hemostatic dysfunction in people with an alcohol use disorder is due to a modification in coagulation and fibrinolysis pathways as well as a decrease in the number and function of platelets. Wound healing problems seem related to poor accumulation of collagen. Abstinence before surgery decreases postoperative morbidity. A meta-analysis of two small randomized clinical trials evaluating the effect of intensive preoperative alcohol cessation interventions including pharmacological strategies showed a decrease of overall postoperative complications but no significant reduction of in-hospital and 30-day mortality rates (33). It suggests that when possible, treatment of alcohol use disorder should occur preoperatively, with treatments proven to decrease alcohol use or achieve abstinence (eg, pharmacotherapies and proven psychosocial approaches).

Alcoholic Liver Disease The spectrum of liver disease associated with the spectrum of unhealthy alcohol use (ie, risky use to alcohol use disorder) includes asymptomatic fatty liver, to acute hepatitis, and finally chronic cirrhosis. Each form of liver disease carries some degree of surgical risk and requires special preoperative considerations.

Alcoholic Fatty Liver Alcoholic fatty liver (hepatic steatosis) occurs in 90% of heavy drinkers and is often asymptomatic and reversible. It can occur after “binge” (heavy-drinking episode) or “social” drinking (excessive but without other recognized consequences). Signs and symptoms when present include nausea, vomiting, and right upper quadrant pain and tenderness. Laboratory tests often demonstrate a mild elevation in liver transaminases but with preserved liver synthetic function with normal bilirubin, albumin, and coagulation studies. These signs and symptoms usually resolve within 2 weeks of abstinence (34). Patients with fatty liver seem to tolerate surgery well; however, there are no known studies evaluating perioperative risk in these patients. It is prudent to delay elective surgery until resolution of clinical signs and symptoms, and if possible, abstinence is achieved.

Alcoholic Hepatitis Alcoholic hepatitis is a serious inflammatory disease of the liver, which occurs in up to 40% of people who drink heavily. The pathological mechanisms include hepatocyte swelling, liver infiltration with polymorphonuclear cells, and hepatocyte necrosis. These patients often present extremely ill with nausea, vomiting, anorexia, abdominal pain, fever, and jaundice. Elevated transaminases and prolonged coagulation studies are common. Surgical risk is very high in this group, with 100% mortality rates reported in older series (35). Therefore, alcoholic hepatitis should be considered a contraindication to elective surgery. It is recommended that elective surgery be delayed until clinical and laboratory parameters normalize, sometimes taking up to 12 weeks.

Alcoholic Cirrhosis Cirrhosis occurs in 15%-20% of heavy drinkers and refers to the irreversible necrosis, nodular regeneration, and fibrosis of the liver. Cirrhosis is associated with abnormal hepatic circulation, resulting in portal vein hypertension.

Clinically, patients may present with ascites, peripheral edema, poor nutritional status, muscle wasting, coagulopathies, gastrointestinal bleeding from esophageal varices, encephalopathy, and renal insufficiency as well as hypoxia secondary to hepatopulmonary syndrome and pulmonary hypertension. The need for surgery is common in patients with cirrhosis, with up to 10% requiring a surgical procedure during the last 2 years of life (36). Depending on the severity of cirrhosis, surgery can be extremely risky. The most common causes of perioperative mortality in patients with cirrhosis are sepsis, hemorrhage, and hepatorenal syndrome (36). Although currently used anesthetic agents are not hepatotoxic, surgical stress in itself causes hemodynamic changes in the liver resulting in postoperative elevations in liver function tests in patients with no underlying liver disease (37). Patients with underlying liver dysfunction are at increased risk for hepatic decompensation during surgical stress because anesthetic agents decrease hepatic blood flow by as much as 50% and therefore decrease hepatic oxygen uptake (38). Intraoperative traction on abdominal viscera may also decrease hepatic blood flow.

Effect of Cirrhosis on Surgical Risk Surgery in patients with cirrhosis is high risk. A study of patients undergoing total knee arthroplasty found that both local and systemic complications were as high as 44% in patients with cirrhosis versus 6% in a control group (39). The preoperative factors associated with increased surgical morbidity and mortality include emergent surgery, upper abdominal surgery, poor hepatic synthetic function, anemia, ascites, malnutrition, and encephalopathy (37). These patients are at increased risk for uncontrolled bleeding, infections, and delirium. Coagulopathies and thrombocytopenia result in difficult perioperative hemostasis. Ascites increases the risk of intra-abdominal infections, abdominal wound dehiscence, and abdominal wall herniation. Nutritional deficiencies result in poor wound healing and an increased risk of skin breakdown, and encephalopathy decreases the patient’s ability to effectively participate in postoperative rehabilitation. The action of anesthetic agents may be prolonged and increases the risk of delirium. Cholecystectomy is a particularly risky surgery in patients with cirrhosis and portal hypertension because of intraabdominal collateral circulation. This collateral circulation increases the vascularity of the gallbladder bed and places the patient at greater risk for severe perioperative hemorrhage. In a group of patients with cirrhosis undergoing cholecystectomy, those considered decompensated preoperatively by the presence of ascites and prolonged coagulation studies had an 83% morality rate

compared with 10% in compensated patients (40). In trying to risk stratify patients preoperatively, it is important to look for clinical signs of cirrhosis and portal hypertension. There are two scoring systems in use to predict whether patients with advance liver disease will survive surgery (41). Using a multivariable clinical assessment, the Child and Turcotte Classification made it possible to risk stratify patients with cirrhosis preoperatively. In 1964, the Child and Turcotte Classification stratified patients with cirrhosis into three classes based on “hepatic reserve” and therefore surgical risk before portacaval shunt surgery (42). Class A was the most compensated, whereas class C was the most decompensated group. Variables included laboratory values of bilirubin and albumin as well as clinical ascites, encephalopathy, and nutritional status. Garrison found good correlation between Child and Turcotte Classification and abdominal surgical mortality with class A, B, and C mortality rates of 10%, 31%, and 76%, respectively (43). Some of the limitations of the Child and Turcotte Classification scheme included the subjective nature and interobserver variation in the assessment of nutritional status, encephalopathy, and ascites. In addition, there was variability in the assigning of patients to classes A, B, and C and no accounting for the nature and urgency of the surgical procedure. In an attempt to decrease the subjective nature of the classification scheme, Pugh et al. modified the Child and Turcotte Classification (Table 91-1) (44). The Pugh modification separates hepatic encephalopathy into five grades depending on various signs and symptoms (Table 91-2). The subjective evaluation of nutritional status is changed to objective measured prolongation in prothrombin time and the assignment of class based on a total point score. Using pooled surgical data, the Pugh Classification scheme has proven to be a good preoperative risk stratifier (Table 91-3).

Table 91-1 Pugh Classification (Modified Child and Turcotte Classification)

Class A 5-6 points. Class B 7-9 points. Class C 10-15 points. Adapted from Pugh RN, Murray-Lyon IM, Dawson JL, et al. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg. 1973;60:646-649.

Table 91-2 Encephalopathy Grade

Adapted from Trey C, Burns DG, Saunders SJ. Treatment of hepatic coma by exchange blood transfusion.

N Engl J Med. 1966;274:473-481.

Table 91-3 Child Class, Operative Risk, and Operability

Adapted from Stone HH. Preoperative and postoperative care. Surg Clin North Am. 1977;57:409-419.

A second scoring system is the Model for End-Stage Liver Disease (MELD), which was designed to predict survival after transjugular intrahepatic portosystemic shunt treatment of bleeding esophageal varices (45). The MELD score is used to prioritize patients for liver transplantation and, more recently, as a predictor of survival after nontransplant surgery (46). The MELD score is calculated using the patient’s international normalized ratio (INR) and serum creatinine and bilirubin. Because the MELD formula is complex, scores can be calculated by using an online MELD score calculator at http://www.unos.org/resources/meldpeldcalculator.asp.

Preoperative Considerations in Patients With Cirrhosis Preoperative abstinence should be the goal before all elective procedures. Since coagulopathies may develop as a result of vitamin K deficiency due to malnutrition or intestinal bile salt deficiency, attempts at correction should start with the administration of vitamin K. If there is no effect in 12 hours, it is most likely secondary to decreased hepatic production of coagulation factors, and perioperative use of fresh frozen plasma should be considered. Thrombocytopenia secondary to bone marrow suppression, hypersplenism, and

splenic sequestration should be considered for preoperative prophylactic platelet transfusions when counts fall below 50,000/mm3 (47). In addition, units of packed red blood cells should be on hold in the blood bank. Ascites secondary to portal hypertension and hypoalbuminemia can impede abdominal wall healing, increase the risk of abdominal wall dehiscence and herniation, and restrict effective mechanical ventilation. Therefore, ascites should be optimally managed preoperatively with sodium restriction and appropriate diuretic therapy. In patients with peripheral edema, a more aggressive approach including largevolume paracentesis (≥5 L) should be considered. Electrolytes should be monitored closely. Perioperative hemodynamic monitoring is often needed because these patients may have large fluid shifts, especially during abdominal surgeries. Preoperative broad-spectrum antibiotics (eg, norfloxacin, ciprofloxacin) should be considered as prophylaxis against secondary and spontaneous bacterial peritonitis. Renal function should be monitored closely. Perioperative changes in volume status and hemodynamics may adversely affect renal function. These patients are at risk for renal insufficiency secondary to prerenal azotemia as well as developing hepatorenal syndrome. Any potential nephrotoxic agent (eg, aminoglycoside antibiotics) should be used with extreme caution. Because of the risk of hepatotoxicity nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen should be used sparingly and at low doses. Many perioperative conditions can exacerbate hepatic encephalopathy such as gastrointestinal bleeding, constipation, azotemia, hypoxia, and the use of sedatives. Aggressive preoperative treatment of hepatic encephalopathy using lactulose and dietary protein restriction is recommended. Patients with known gastroesophageal varices should be monitored closely for gastrointestinal bleeding and should be considered for beta-blocker prophylaxis preoperatively. The nutritional status of these patients is usually poor, and they are often deficient in thiamine, folate, vitamin C, and B vitamins. Nutritional status should be optimized with multivitamins, thiamine, folate, and nutritional supplementation preoperatively. From a pulmonary standpoint, patients with decompensated cirrhosis may desaturate because of the development of pulmonary shunts in hepatopulmonary syndrome; therefore, continuous monitoring oxygen saturation should be part of the postoperative care. General class-specific guidelines are shown in Table 91-3. There is increasing evidence that laparoscopic procedures in cirrhotic patients may be safer than open procedures regardless of Child Classification (43). Patients with cirrhosis undergoing surgery may benefit from a multidisciplinary approach including a hepatologist (and nephrologist if the patient has renal insufficiency).

Management of Patients on Naltrexone (Opioid Antagonist) Pharmacotherapy Patients with alcohol use disorder treated with naltrexone (oral daily or depot monthly) pharmacotherapy are becoming more common. Because naltrexone is an opioid antagonist and will block the effects of co-administered opioid agonists, patients requiring opioid analgesics during the perioperative period will need to discontinue naltrexone (48). The half-life of a single dose of oral naltrexone is 14 hours. The recommendation that oral naltrexone be discontinued at least 72 hours before surgery is based on experimental studies showing that 50% of the oral naltrexone blockade effect was gone after 72 hours (49). Because a degree of opioid resistance will remain, patients should be observed closely for respiratory depression and sedation. After IM depot injection of naltrexone, peak plasma levels occur within 2-3 days with a decline in plasma concentrations beginning ~14 days after dosing. For patients on depot naltrexone, elective surgery should be postponed, if possible, for a month after the last naltrexone injection. Patient requiring opioids for pain management after emergent surgery should have naltrexone discontinued and opioids analgesics administered under close observation. Animal studies have shown that naltrexone blockade can be overcome resulting in analgesia and no significant respiratory depression or sedation with either hydrocodone or fentanyl at 10-20 times the usual doses (50). An anesthesiologist should be consulted to assist with perioperative pain management including the use of nonopioid alternatives and regional analgesia. Naltrexone can be restarted when the patient no longer requires opioid analgesics. In order to avoid precipitating opioid withdrawal, patients must be opioid free for a minimum of 7-10 days before restarting naltrexone if they are physically dependent on opioids. This opioid-free time period may be longer if patients are taking extended-release/long-acting opioids. However, if patients have only been briefly on opioids in the postoperative period and are not physically dependent, providers may consider resuming naltrexone treatment within 24-48 hours after the last short-acting analgesic opioid medication. If there is concern for precipitated withdrawal, a naloxone challenge can be performed using subcutaneous naloxone before naltrexone administration (51).

PERIOPERATIVE

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The goal during the perioperative period is to get the patient with an opioid use disorder safely through the surgical period. This may also be a “teachable moment” for patients to consider entering into long-term addiction treatment at time of hospital discharge and for clinicians to better appreciate the interplay between pain and addiction. Persons with an opioid use disorder are at high risk for medical complications that often require surgical intervention. Most of these complications are a consequence of both active and past high-risk behaviors (ie, injection drug use [intravenous, intramuscular, subcutaneous “skin popping”]) and the direct toxic effects of the drug and additives being injected. Infections of the skin, soft tissue, bones, and joints are common and often require surgical drainage and debridement. Infectious endocarditis may require emergent or urgent heart valve replacement and patients with drug use are at higher risk for postoperative complications of valvular surgery including sepsis, pneumonia, kidney injury, and pulmonary embolism (52). In addition, patients with endocarditis will require antibiotic prophylaxis in the future before certain dental procedures. Functional bowel obstruction has also been described in patients with chronic opioid use and may require surgical management. Acute hepatitis B and chronic hepatitis C infections are common in patients with intravenous drug use and are the leading causes of liver transplantation (53). Chronic diseases associated with opioid misuse, such as pulmonary hypertension secondary to talc granulomatosis, renal insufficiency secondary to heroin-associated nephropathy, and congestive heart failure from valvular heart disease secondary to endocarditis, HIV syndrome, and chronic hepatitis B and C can all increase surgical risk. Acute opioid withdrawal can also complicate the perioperative period.

Preoperative Evaluation Patients with current or past injection drug use should be evaluated for past endocarditis and the need for antibiotic prophylaxis. These patients should also be evaluated for HIV/AIDS and active hepatitis B and C. Hospitalized patients with an opioid use disorder are at risk for acute opioid withdrawal. The onset and severity of withdrawal will depend on which opioid is being used and on the degree of physical dependence, which is related to the duration and amount used. Daily use for at least 2-3 weeks is generally required before significant physical

dependence (and thus clinically significant withdrawal) occurs. Heroin withdrawal typically begins within 4-6 hours of the time of last use. Withdrawal from extended-release, long-acting opioids such as methadone and sustainedrelease oxycodone and morphine may not occur for up to 24-36 hours. Active opioid use can be verified using urine drug tests, whereas injection drug use can be identified by examining the skin for “track marks.” Heroin and other semisynthetic opioids will be detected as morphine or codeine in the urine for up to 72 hours. Synthetic opioids (such as methadone and fentanyl) are not usually included in standard urine drug tests, so if synthetic opioid use is suspected, the laboratory should be asked to test for the specific synthetic opioid of concern. Depending on the opioid used, acute withdrawal usually peaks at 2-3 days and can last for up to 14 days. The Clinical Opiate Withdrawal Scale (54) and the Short Opiate Withdrawal Scale (55) are useful clinical opioid withdrawal assessment instruments. Patients who are addicted to opioids may also be using other drugs, such as cocaine, alcohol, or benzodiazepines.

Management of Opioid Withdrawal It is important for providers of perioperative care to be able to recognize and manage acute opioid withdrawal, which is likely in hospitalized surgical patients with opioid use disorder. One approach to treating opioid withdrawal in the hospital setting involves treating the physiological manifestations of acute withdrawal (including the hyperadrenergic signs and symptoms, insomnia, nausea, vomiting, diarrhea, and muscles aches) with clonidine, benzodiazepines, dicyclomine, and nonsteroidal anti-inflammatory drugs. Depending on the patient’s blood pressure, clonidine 0.1-0.2 mg orally every 4-6 hours is given for the first 48-72 hours, with a gradual taper over the next 48-72 hours. A much more effective method employs a long-acting opioid agonist such as methadone or buprenorphine (56). In general, trying to convert the dose of opioid the patient is addicted to with an equivalent dose of methadone or buprenorphine is unhelpful due to the inexact nature of estimating the actual amount of illicit opioid being used. A starting dose of 10-30 mg of methadone orally or 2-4 mg of buprenorphine sublingually lessens the signs and symptoms of withdrawal in most patients. The patient should be reassessed for continued withdrawal in 2-3 hours; if withdrawal persists, additional doses of 5-10 mg of methadone or 2-4 mg of buprenorphine may be given, up to a total dose during the hospital stay should not exceed 40 mg of methadone or 16 mg of buprenorphine in 24 hours. Because of the long and unpredictable elimination half-life of methadone, dosing higher than 40 mg should avoided in patients who are not already enrolled in an

outpatient methadone treatment program. After a stable dose has been achieved, it should be given daily to prevent the reemergence of withdrawal. For methadone doses of 40 mg or less, the patient will likely continue to “crave” opioids, but his or her acute withdrawal signs and symptoms should abate. It is important to openly discuss this treatment plan with the patient and nursing staff to avoid unnecessary anxiety and conflict between the patient and healthcare team. If the patient on methadone is unable to take oral medications during the perioperative period, methadone can be administered parenterally (IV, SQ, or IM) at 50% of the total daily oral dose administered in a divided dose every 12 hour (eg, 40 mg by mouth every day = 10 mg IV every 12 hours) (57–59). After acute withdrawal is controlled, discussions regarding continued daily dose (recommended) versus daily dose taper until the day of discharge (as well as postoperative addiction treatment aftercare and referral) should be discussed and coordinated.

Management of Patients on Medications That Treat Opioid Use Disorders (Also Known as “Medication Assisted Treatment”) Patients may be maintained on opioid agonist therapy (OAT) with methadone or buprenorphine or on opioid antagonist therapy with naltrexone. Patients on OAT should be maintained on their usual maintenance dose equivalent during the perioperative period. The correct maintenance dose should be determined by calling the patient’s addiction treatment program (eg, methadone program) or buprenorphine prescriber. Patients treated with naltrexone (oral daily and depot monthly) maintenance will need to discontinue naltrexone preoperatively in order to achieve benefit from postoperative opioid analgesics. The patient’s addiction treatment program or physician prescriber should be notified at time the patient is discharged from the hospital to assure continuity of addiction care. Some methadone-maintained patients with complicated postoperative courses who have impaired ability to ambulate (eg, limited weight-bearing) postoperatively may be eligible for “medical” take-home doses of methadone from their addiction treatment provider. However, because each methadone clinic has its own policies and procedures on take-home doses, the discharging provider should discuss this possibility with the addiction treatment program’s clinical staff.

Management of Acute Pain in Patients on Opioid Agonist Therapy Acute postoperative pain management in patients maintained on long-acting OAT can be challenging; however, recommendations have been published (Table 91-4) (60,61). The daily methadone or buprenorphine dose a patient receives is not adequate analgesia for acute pain. The lack of analgesia occurs because of the patient’s high tolerance to opioids and the pharmacodynamics of methadone and buprenorphine. All methadone- and buprenorphine-maintained patients have a high tolerance to other opioids (cross-tolerance). Cross-tolerance likely is the reason that methadone- and buprenorphine-maintained patients often require higher and more frequent doses of opioid analgesics to adequately treat acute pain. Both methadone and buprenorphine have long plasma half-lives (15-40 hours), with different durations of action for analgesia (4-8 hours) and for suppression of opioid withdrawal (24-36 hours). Because the majority of patients on methadone or buprenorphine maintenance for opioid use disorder are dosed every 24 hours, the potential for even partial pain relief is small. The appropriate treatment of acute pain in these patients includes uninterrupted OAT to address the patient’s baseline opioid requirement for addiction treatment and aggressive pain management. As with all patients suffering acute pain, nonopioid analgesics should be aggressively implemented first-line. However, severe acute pain will often require opioid analgesics. Continuing the usual dose of OAT avoids worsening pain symptoms because of the increased pain sensitivity associated with opioid withdrawal. While it has been accepted practice to continue methadone perioperatively, there has been debate about whether to continue or discontinue buprenorphine preoperatively (60). Preclinical and clinical studies now suggest that concurrent use of opioid analgesics in patients maintained on buprenorphine is effective (62,63). To decrease anxiety, patients should be reassured that their opioid use disorder treatment will continue and their pain will be aggressively treated. Because of cross-tolerance with OAT, adequate pain control will generally necessitate higher opioid doses at shorter intervals. Analgesic dosing should be continuous or scheduled rather than as needed. Allowing pain to reemerge before administering the next analgesic dose causes unnecessary suffering and anxiety and increases tension between patient and treatment team. Empiric data on the use of patient-controlled analgesia (PCA) in patients with substance use disorders are limited. One study reported that, although methadone-maintained women had higher pain scores after cesarean section surgery, there was no statistically significant difference in opioid PCA

usage compared with controls (64). Clinical experience supports consideration of PCA use in patients on OAT; increased patient control over analgesia minimizes patient anxiety over pain management. The pharmacological properties of opioids must be considered when selecting an opioid analgesic for the patient on OAT. Mixed agonist/antagonist opioid analgesics such as pentazocine (Talwin) and butorphanol (Stadol) must be avoided because they may displace the methadone or buprenorphine from the mu receptor, thus precipitating acute opioid withdrawal in these patients.

Table 91-4 Recommendations for Treating Acute Pain in Patients on Opioid Agonist Therapy (OAT)a

aThese recommendations are applicable only when opioid analgesic treatment is determined to be necessary for the treatment of acute pain. Data from Alford DP. Acute and chronic pain. In: Renner JA, Levounis P, LaRose AT, eds. Office-Based Buprenorphine Treatment of Opioid Use Disorder. 2nd ed. Arlington, VA: American Psychiatric Association Publishing, Inc, 2018 (Chapter 12); Alford DP, Compton P, Samet JH. Acute pain management for patients receiving maintenance methadone or buprenorphine therapy. Ann Intern Med. 2006;144:127-134.

Management of Acute Pain in Patients on Opioid Antagonist Therapy Patients with opioid use disorder treated with naltrexone (oral daily and depot monthly) maintenance therapy are becoming more common. See section above entitled “Management of Patients on Naltrexone (Opioid Antagonist) Pharmacotherapy” for guidance on acute pain management in patients maintained on naltrexone.

PERIOPERATIVE CARE OF THE PATIENT WITH BENZODIAZEPINE USE DISORDER Benzodiazepines, which are commonly prescribed to treat panic attacks, anxiety, and insomnia, have a high potential for misuse. Patients who misuse benzodiazepines often are addicted to multiple drugs (65). Therefore, patients with substance use disorders should be asked about benzodiazepine use. Benzodiazepine use has been associated with higher rates of postoperative mechanical ventilation among trauma surgery patients, and the use of multiple substances has been associated with increased length of stay (66). Chronic benzodiazepine use, taking around the clock doses over weeks to months, results in physical dependence, with an acute withdrawal syndrome that can be life threatening. The withdrawal syndrome ranges from severe anxiety, insomnia, and autonomic hyperactivity (including tachycardia and hypertension) to seizures and delirium. Patients with physical dependence to prescribed benzodiazepines should be maintained on their usual dose during the perioperative period to prevent acute withdrawal and subsequent postoperative complications. Patients physically dependent on illicit benzodiazepines should be maintained on an equivalent dose of long-acting benzodiazepine (eg,

diazepam, chlordiazepoxide) during the perioperative period with psychiatric and addiction specialist consultation for guidance on a safe benzodiazepine taper during the postoperative period, noting that physically patients dependent on long-acting benzodiazepines may not exhibit withdrawal symptoms for 5-7 days after the last dose.

PERIOPERATIVE CARE OF PATIENT WITH NICOTINE CANNABIS USE

THE OR

According to an evaluation of the American College of Surgeons National Surgical Quality Improvement Program database (67), current smokers had a 1.38 times higher likelihood of 30-day postoperative mortality compared to never smokers. Current smokers also had greater odds of postoperative cardiovascular events (ie, cardiac arrest, myocardial infarction, stroke), infections (ie, pneumonia, incision infections, sepsis, septic shock), and unplanned intubation. Asymptomatic smokers are at risk for pulmonary infections due to abnormalities in their respiratory epithelium leading to retained secretions and abnormal lung immune responses (68). A 20-pack-year history and smoking >20 cigarettes a day seem to be the threshold of this increased risk. In observational studies of patients undergoing cardiothoracic surgery, the increased risk decreases only after 8 weeks of smoking cessation and was unrelated to pulmonary function test results (69). Healing is impaired because of decreased tissue oxygenation and inhibition of normal immune responses. Preoperative evaluation should include assessment of physical dependence on nicotine and risk of withdrawal. In addition, preoperative evaluation should include assessment for evidence of cardiovascular disease and COPD. Patients with COPD have increased risk of postoperative pulmonary complications, including pneumonia bronchospasm, respiratory failure with prolonged mechanical ventilation, and COPD exacerbations (70). Other possible risk factors for pulmonary complications include increased age, duration, and anatomic location of surgery and preoperative sputum production. It is important to assess for upper respiratory infections and to treat with preoperative antibiotics as indicated. Elective procedures should be delayed until any pulmonary infection is resolved. Intensive preoperative interventions for nicotine/tobacco use have been shown to reduce the incidence of postoperative complications (71). Pharmacotherapy, including nicotine replacement,

bupropion, and varenicline, consistently increases abstinence rates and should be considered preoperatively. Aggressive perioperative treatment of airflow obstruction should be achieved with inhaled steroids and beta agonists. Preoperative patient education regarding postoperative incentive spirometry use decreases the incidence of postoperative pulmonary complications (70). Nicotine replacement therapy also should be offered postoperatively to patients at risk for nicotine withdrawal. Compared with nicotine cigarettes, the airway effects of smoking cannabis are mild, but with acute use, upper airway edema can occur and a chronic cough and mild airflow obstruction can develop with long-term use (72).

PERIOPERATIVE PATIENT WITH DISORDER

CARE OF STIMULANT

THE USE

Cocaine and methamphetamine may be ingested, snorted, smoked, or taken intravenously. Intravenous stimulant use may result in all the complications attributable to injection drug use such as endocarditis, pulmonary hypertension, hepatitis B and C, and HIV/AIDS. Stimulant use reduces sexual inhibition that also increases the risk of contracting sexually transmitted infections. Acute stimulant intoxication can be a life-threatening condition because of excessive adrenergic stimulation resulting in acute psychosis, hypertensive crisis, cardiac arrhythmias, sudden cardiac death, seizures, intracranial hemorrhage, myocardial infarction, and cerebrovascular accident. Stimulant users may require surgical interventions due to the acute and chronic effects of these drugs. Cocaine and methamphetamine use can cause bowel ischemia and gangrene resulting from mesenteric vasoconstriction requiring emergent bowel resection. Methamphetamine users may require acute surgical care for traumatic injuries and chemical burns and skin abscesses from compulsive skin picking. They may require elective surgery for severe periodontal disease. The period of cocaine intoxication is generally brief (~60 minutes) and should not increase the risk of most surgery. However, methamphetamine’s longer half-life of 12 hours could adversely affect emergent surgical procedures. Intoxicated patients should be placed in a calm and quiet environment and managed with sedatives such as benzodiazepines. Smoked stimulants can increase surgical risk by causing pulmonary edema. Long-term stimulant use can result in chronic medical conditions, which increase surgical risk such as cardiac dysfunction from prior

myocardial infarction or dilated cardiomyopathy. Up to 7% of asymptomatic chronic cocaine users have left ventricular systolic dysfunction (73), while young methamphetamine users were found to have a 3.7-fold increased odds ratio for cardiomyopathy (74). In addition, long-term stimulant use causes left ventricular hypertrophy, a known risk factor for ventricular arrhythmias (75,76). Therefore, it is critically important to identify stimulant use during preoperative assessment and to evaluate carefully for clinical evidence of cardiac disease. Concurrent use of cocaine and alcohol is common, because alcohol prolongs the effects of cocaine through the metabolite cocaethylene. Cocaethylene increases the rate of cardiac complications. Therefore, all patients who use cocaine should be screened for concurrent heavy alcohol use. Depression and hypersomnolence are common in stimulant withdrawal and may mimic or be confused with other postoperative neurological complications.

ORGAN TRANSPLANTATION IN PATIENTS WITH SUBSTANCE USE DISORDERS Hepatitis B and C infections from injection drug use and alcoholic liver disease are the most common causes of end-stage liver disease requiring liver transplantation in the United States. In the past, patients with a history of substance use disorder have been kept off of transplantation lists because of fears of posttransplant nonadherence, with subsequent loss of graft but also because of moralistic arguments that the patients had “self-inflicted” diseases. In fact, some studies have demonstrated posttransplant relapse rates as high as 49%, with lower overall survival rates in patients who failed to complete addiction treatment (77). Other studies found no difference in 1-year survival rate between patients with alcohol use disorders who maintained sobriety and patients who had no history of an alcohol use disorder (78). Among people with alcohol use disorders selected for liver transplant, most (71%) abstain or nearly completely abstain (79). However, a European study found postoperatively up to 20%-25% of these patients return to heavy alcohol use (80). This has resulted in the widely used “6-month abstinence” rule despite a lack of evidence validating its use in predicting relapse. A study identified preoperative risk factors that were predictive of relapse after transplantation that included shorter length of abstinence before transplantation, greater than one episode of alcohol withdrawal before transplantation, younger age at time of transplantation, and an alcohol use

disorder in first-degree relatives (81). It is clear that patients with a current or past substance use disorders need to be assessed for risk of relapse and social support systems before being accepted for transplantation. Because organ transplantation in patients with substance use disorders is unusually complex, medical centers often add addiction specialists to the transplant team.

CONCLUSIONS Patients with substance use disorders have high rates of hospitalization and surgery. The underlying history of addiction may not be apparent initially, but thorough history taking and the use of effective screening tools can elicit information about past or current drug and alcohol use disorders. Because of the high prevalence of the use of more than one drug, patients who acknowledge an addiction to one substance should be asked about their use of all other substances with misuse potential. Careful evaluation also can detect clinical signs of chronic diseases of the heart, lungs, and liver related to drug and heavy alcohol use. The importance of identifying addiction preoperatively cannot be overstated. Perioperative morbidity associated with acute abstinence syndromes can be prevented with proper preoperative treatment. If possible, elective surgery should be postponed to allow time for complete substance withdrawal. Sedative– hypnotics and opioid analgesics should be used as indicated perioperatively; however, these drugs have a significant misuse potential in patients with addiction, so they should be prescribed with caution. Management of patients with addiction going for surgery often requires consultation with addiction and pain specialists. All patients with current addiction should be encouraged to engage in addiction treatment postoperatively.

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SECTION 11

Co-Occurring Addiction and Psychiatric Disorders

CHAPTER 92

Substance-Induced Mental Disorders Christine Yuodelis-Flores, R. Jeffrey Goldsmith and Richard K. Ries

CHAPTER OUTLINE Introduction Diagnosis of Substance-Induced Mental Disorders Prevalence of Substance-Induced Mental Disorders Specific Substances: Substance-Induced Symptoms

INTRODUCTION The focus of this chapter is to help clinicians understand, differentially diagnose, and treat a person with substance-induced psychiatric syndromes that mimic traditional psychiatric disorders such as depression, anxiety, and psychotic disorders. Because there is often overlap between the pharmacodynamics of potentially addictive substances as well as many psychiatric disorders, it should not be surprising that many patients with substance use disorders (SUDs) (including withdrawal) may appear to have a free-standing psychiatric disorder or at least appear to have significant psychiatric symptoms. The revised chapter of “Substance-Related and Addictive Disorders” in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) of the American Psychiatric Association (1) includes changes to grouping of the disorders so that substance-induced disorders are discussed in general terms in the chapter “Substance-Related and Addictive Disorders,” while the specific substance-induced psychiatric disorder is discussed in the chapter discussing that specific disorder (ie, Substance-Induced Depressive Disorder [SIDD] is found in the chapter on Depressive Disorders). In addition, there are two additional substance-induced psychiatric disorders in DSM-5: SubstanceInduced Bipolar and Related Disorder (SIBD) and Substance-Induced Obsessive–Compulsive and Related Disorder (SIOCD). This chapter describes the diagnostic criteria in the DSM-5, reviews the epidemiological data, and discusses the clinical strategies needed to manage these disorders. Eleven substance-induced mental disorders (SIMDs) are outlined in the DSM-5: Substance/Medication-Induced Delirium Substance/Medication-Induced Major or Mild Neurocognitive Disorder Nonamnestic-Confabulatory Type

Amnestic-Confabulatory Type Substance/Medication-Induced Persisting Amnestic Disorder Substance/Medication-Induced Psychotic Disorder Substance/Medication-Induced Depressive Disorder Substance/Medication-Induced Bipolar and Related Disorder Substance/Medication-Induced Anxiety Disorder Substance/Medication-Induced Obsessive–Compulsive and Disorder Hallucinogen Persisting Perception Disorder Substance/Medication-Induced Sexual Dysfunction Substance/Medication-Induced Sleep Disorder

Related

Here, we will focus on those that are most confounding in terms of differential psychiatric presentation (substance-induced psychotic, depressive, bipolar, obsessive–compulsive, and anxiety disorders and hallucinogen persisting perceptual disorder). These will be referred to as substance-induced mental disorders. Substance-induced disorders that are not the focus of this chapter include Substance/Medication-Induced Delirium, Substance/Medication-Induced Major or Mild Neurocognitive Disorder (previously known as Substance/Medication-Induced Persisting Dementia and Substance-Induced Persisting Amnestic Disorder in DSM-IV), Substance-Induced Sexual Dysfunction, and Substance-Induced Sleep Disorder.

DIAGNOSIS OF SUBSTANCE-INDUCED MENTAL DISORDERS According to DSM-5 (1), there are several classes of substances that may induce mental disorders as well as a variety of toxins and medications. The addictive substances that can induce mental disorders are alcohol, cannabis, phencyclidine (PCP) and other hallucinogens, inhalants, opioids, sedative–hypnotic/anxiolytic drugs, stimulants, caffeine, and tobacco (nicotine). Quoted from DSM-5 (1), there are five (A-E) criteria for diagnosis of all substance/medication-induced mental disorders: A. The disorder represents a clinically significant symptomatic presentation of a relative mental disorder. B. There is evidence from history, physical examination, or laboratory findings of both of the following:

1. The disorder developed during or within 1 month of a substance intoxication or withdrawal or taking a medication. 2. The involved substance/medication is capable of producing the mental disorder. C. The disorder is not better explained by an independent mental disorder. Such evidence of an independent mental disorder could include the following: 1. The disorder preceded the onset of severe intoxication or withdrawal or exposure to a medication. 2. The full mental disorder persisted for a substantial period of time (eg, at least 1 month) after the cessation of acute withdrawal or severe intoxication or taking the medication. This criterion does not apply to substance-induced neurocognitive disorders or Hallucinogen Persisting Perception Disorder, which persist beyond the cessation of acute intoxication or withdrawal. D. The disorder does not occur exclusively during the course of a delirium. E. The disorder causes clinically significant distress or impairment in social, occupational, or other important areas of functioning.

PREVALENCE OF SUBSTANCEINDUCED MENTAL DISORDERS Prevalence of Substance-Induced Depressive Disorder and Anxiety Disorder Prevalence rates of SIMD vary considerably depending on the study subjects (treatment-seeking populations vs. epidemiological surveys) and the research diagnostic criteria used to define the disorders (eg, how long is a substanceinduced syndrome defined to last).

Substance-Induced Depressive Disorder Brown and Schuckit (2) reported that 42% of males with alcohol use disorder (AUD) presenting for treatment displayed depressive symptoms in a range comparable to that seen in individuals hospitalized for affective disorder (more than 19 points, which is in the moderate to severe range of the Hamilton Depression Rating Scale). The symptoms abated rapidly over the first 2 weeks of

abstinence, with only 12% of the subjects still depressed at the end of the 2nd week. In light of this rapid abatement of depressive symptoms, it is significant that the subjects averaged more than 9 days of abstinence before the study began. In a study of similar subjects with AUD who had been sober for an average of 8 days, Brown et al. (3) reported that 33% of the primary AUD (with or without secondary affective disorder) scored in the moderate to severe range for depression, whereas 81% of the subjects with primary affective disorder did so at the end of week 1. By week 4 of the study, none of the patients with primary AUD were in the moderate to severe range, whereas 67% of the subjects with primary affective disorders were. This finding suggests that all of the subjects with primary AUD had SIDD, a number quite comparable to the 30% reported in the earlier study by the same researchers. Schuckit et al. (4) studied nearly 3000 patients with AUD to test three hypotheses related to substance-induced depression. They hypothesized that there would be more SIDD than major depressive disorder (MDD), that those with SIDD would have more severe alcohol and drug histories, and that those with independent depression would have more first-degree relatives with affective disorder. All three hypotheses were supported by their findings. Among the study population, 15% had independent depression and 26% reported information consistent with SIDD. Subjects with SIDD drank more alcohol per occasion, drank on more days per week, sought treatment more often, were more likely to have attended Alcoholics Anonymous meetings, and used more marijuana and stimulants than did those with co-occurring or no depression. Women were more likely to have co-occurring than substance-induced depression and less likely to not have depression. Subjects with co-occurring depression also had more anxiety disorders than did those with SIDD (8.4% vs. 4.8%) and the same percentage of mania (1.6% vs. 1.0%). More recent studies using the DSM-IV criteria and structured clinical interviews show a wider variety of results depending largely on the study population used. Kahler et al. (5) looked at SIDD and independent MDD in patients with AUD seeking treatment and found that out of 166 AUD patients with elevated levels of depression 122 met the Structured Clinical Interview for DSM-IV criteria for MDD. Of this group, 61.6% were found to have “pure” SIDD and 15.2% were found to have independent MDD. The remaining 23.2% had the diagnosis of SIDD with a history of independent MDD.

Substance-Induced Anxiety Disorder (SIAD) As with depressive symptoms, anxiety symptoms show similar changes over the

early sobriety phase. Several studies have reported high rates of anxiety symptoms among patients with AUD in withdrawal, with 80% of alcoholdependent male subjects experiencing repeated panic attacks during alcohol withdrawal (6). In the same study, 50%-67% of the alcohol-dependent subjects had high scores on the state anxiety measures, which resembled generalized anxiety and social phobia (6). Brown et al. (7) reported that 40% of recently detoxified men with AUD scored above the 75th percentile on the state anxiety subscale of the State Trait Anxiety Inventory. At discharge after 4 weeks, 12% scored that high, whereas at 3-month follow-up, only 5% remained above the 75th percentile. This finding suggests that 35% had SIAD. In contrast to treatment-seeking populations, Grant et al. (8) in a major epidemiological study found the prevalence of SIDD and SIAD to be extremely low in the general population (1.05% for current SIDD and 0.22% for SIAD). However, the prevalence of those with current independent mood disorders who reported having both independent and substance-induced mood disorders in the prior year was 7.35%. Of those with current independent anxiety disorders, 2.95% reported having both substance-induced and independent anxiety disorders in the prior year. Using the Psychiatric Research Interview for Substance and Mental Disorders (PRISM-IV) (9), which was designed to distinguish between substance-induced and independent psychiatric disorders in co-occurring populations, Langås et al. (10) interviewed first-time consecutively admitted patients aged 16 years or older who were admitted to addiction clinics and psychiatric outpatient or inpatient facilities. In this study, among those with comorbid addictive and psychiatric disorders (n = 54), 41% had psychiatric disorders considered to be independent of their substance use, 7% had substanceinduced disorders only, and 38% had both independent and substance-induced disorders. It can be very difficult to differentiate between SIDD and independent depressive disorders, and the diagnosis may change if the patient is followed over time. Ramsey et al. (11) studied AUD patients with SIDD and found that over a course of a year, 26.4% of those diagnosed with SIDD were reclassified as having an independent MDD because of meeting full criteria for the diagnosis of MDD after 1 month of sobriety. In this study, those with a history of past independent MDD were five times more likely to be reclassified from SIDD to independent MDD. Patients who had lower severity of DSM-IV alcohol dependence were also more likely to be reclassified as having independent MDD. Nunes et al. (12) studied depressive disorders in patients with AUD admitted to an inpatient psychiatric unit using the PRISM-IV and found that

51% of patients had SIDD; however, after following them for a year, 32% of these patients were reclassified as having independent depression. Regarding cocaine-induced depressive disorders, Rounsaville et al., (13) in a study of patients with cocaine use disorders (CUD), examined the current and lifetime prevalence of research diagnostic criteria disorders. They used both strict and less strict criteria in evaluating the depression diagnostic data from the Schedule for Affective Disorders and Schizophrenia—Lifetime. The less strict criteria allowed a diagnosis if the symptoms ever had been present, whereas the strict criteria allowed a diagnosis only if symptoms had persisted for 10 or more days after cessation of cocaine use. Using the less strict criteria, major depression was diagnosed in 59% of the subjects, whereas the more strict criteria yielded a 30% prevalence rate. This finding conservatively suggests a lifetime prevalence of about 30% for cocaine-induced depressive disorder in those with CUD. Further, the current rate of MDD was 4.7%, hypomania was 2%, and minor mood disorder was 38% (mania was 0%) (13). (The current diagnoses of minor mood disorders appeared to use the strict criteria, but this was not clarified in the report.) Rounsaville et al. (13) also reported a 16% current rate and a 21% lifetime rate of anxiety disorders, but the investigators did not disclose what criteria were used to diagnose anxiety unrelated to cocaine use. People with methamphetamine use disorders are also reported to have high rates of depressive symptoms and suicidal behavior during active use as well as during withdrawal and early abstinence. A large study of psychiatric symptoms among 1016 methamphetamine users presenting for treatment revealed that depression was the most common symptom reported and 27% had attempted suicide in the past (14).

Prevalence of Substance-Induced Psychotic Disorders Psychosis during intoxication is common among those using psychotomimetic substances, which include cannabis, cocaine, amphetamines and related stimulants, hallucinogens, and dissociative drugs such as PCP, ketamine, and dextromethorphan. Regarding the prevalence of SIPD, Brady et al. (15) evaluated individuals admitted for treatment of CUD and found that 53% reported transient cocaine-induced psychosis. Caton et al. (16) evaluated individuals with psychosis and SUDs presenting to a psychiatric emergency department in New York using PRISM-IV and reported a prevalence of 44% for

SIPD, while the other 56% had primary psychotic disorder (PPD) with concurrent substance use. In a later study by Fraser et al. (17), the PRISM-IV differentially diagnosed 56% of first-episode psychosis patients with SIPD and 44% with PPD. An Australian study using PRISM-IV was done by Hides et al. (18) to investigate the rates of PPDs and SIPD compared to no psychotic disorder among methamphetamine users accessing needle and syringe programs. More than half of the study subjects met DSM-IV criteria for a lifetime psychotic disorder including 80% with SIPD and 20% with PPD. Although SIPD is thought to have a better prognosis than PPD, a recent study documents that SIPD transitions to a permanent schizophrenia spectrum disorder in about 10.9%-24.3% of cases followed in Taiwan (19). In a Finnish register-based study of over 18 000 inpatients with SIPD, the 8-year cumulative risk of SIPD converting to a diagnosis of schizophrenia spectrum disorder was 46% for those diagnosed with cannabis-induced psychosis and 30% for those with amphetamine-induced psychosis (20).

Substance-Induced Bipolar and Related Disorder According to DSM-5, this disorder is defined as a prominent and persistent disturbance in mood characterized by elevated, expansive, or irritable mood with or without depressed mood or markedly diminished interest or pleasure in almost all activities. The ICD-10-CM codes for specific SIBDs list substances such as alcohol, PCP, hallucinogens, steroids, sedative–hypnotics/anxiolytics, and stimulants as inducing this disorder as well as medications such as dexamethasone. The prevalence of SIBD is unknown as there are no epidemiological studies. DSM-5 specifically mentions that antidepressant or electroconvulsive-induced mania is not included in this diagnosis as they are indicative of true bipolar disorder.

Substance/Medication-Induced Obsessive– Compulsive and Related Disorders Obsessions, compulsions, skin picking, hair pulling, and other body-focused repetitive behaviors can occur during substance intoxication or withdrawal, use of a medication, or exposure to heavy metals or toxins. Stimulants such as

methamphetamine, amphetamine, cocaine, and substituted cathinones are associated with this diagnosis (ie, methamphetamine-induced excoriation [skinpicking] disorder). The prevalence of SIOCD is considered rare; however, one study of amphetamine-induced obsessive–compulsive disorder (AIOCD) in Iran showed the prevalence of AIOCD to be 6.9% in patients with amphetamine use disorder presenting for treatment (21).

Substance-Associated Suicidal Behavior SIDD can dissipate rapidly, but it is as dangerous as MDD in terms of the risk of suicide and self-injurious behavior. When completed suicides are investigated, the rate of comorbidity is high. Henriksson et al. (22) reported that nearly half (43%) of a group of suicide victims in Finland had the diagnosis of AUD and that 48% of those with AUDs had comorbid depression, 42% had a personality disorder, and 36% had a significant Axis III medical disorder. Salloum et al. (23) studied patients who had been hospitalized psychiatrically and found that more than half of the subjects in all three groups studied (with AUD, CUD, or AUD plus CUD combined) had a history of suicide attempts. Zweben et al. (14) also found a high prevalence of prior suicide attempts (27%) in patients with methamphetamine use disorders presenting for treatment. Elliott et al. (24) found that patients who made medically severe suicide attempts had a statistically higher rate of SIDD than did patients who made less severe suicide attempts. There was no difference between the two groups in the prevalence of DSM-IV alcohol abuse or dependence or in the prevalence of polysubstance abuse or dependence. Moreover, most of the patients with substance-induced mood disorder did not meet the criteria for substance dependence. This finding is consistent with the findings of Asnis et al. (25) and Murphy and Wetzel (26), who argued that alcohol dysregulates mood independent of use patterns, suggesting that some individuals are at risk of severe depression regardless of the chronicity of their alcohol use. Conner et al. (27) analyzed suicidal behavior in 3729 individuals with AUD and concluded that both independent and substance-induced depression are associated with suicidal ideation and planning, whereas alcohol-related aggression is correlated with suicide attempts. Aharonovich et al. (28) studied depressed substance-dependent patients who had attempted suicide and found that patients with SIDD were as likely as those with independent MDD to have attempted suicide. Ries et al. (29) studied acutely suicidal psychiatric inpatients with SIDD and found that this subgroup had higher severity of suicidal ideation but improved more quickly than other patients and tended to have shorter lengths of stay. Among individuals with

schizophrenia, however, Bartels et al. (30) found that it was the severity of the depression, not the substance use, which explained suicidal behavior. In contrast, Seibyl et al. (31) reported that patients with schizophrenia who had used cocaine before admission exhibited increased suicidal ideation. In summary, it is clear that SIMDs are common, and it is logical that clinical intervention for substance-induced disorders should focus on different issues (eg, entering into treatment and recovery) than independent psychiatric disorders (medications and psychotherapy).

SPECIFIC SUBSTANCES: SUBSTANCEINDUCED SYMPTOMS The occurrence of psychiatric symptoms as a result of legal and illegal drug use has been well documented. It is common medical knowledge that hallucinogens and dissociative agents cause hallucinations, stimulants cause euphoria, and chronic sedative use can result in depression. It is common medical knowledge that in acute withdrawal, alcohol, and sedative–hypnotics cause anxiety. It is less obvious that a distinct set of symptoms appear when psychoactive substances are used over a long period. Symptoms reported for each of the major psychoactive substances are reviewed below to establish a basis on which to understand the syndromes that can arise. Caffeine, the most commonly used stimulant, is considered a benign drug by many consumers and professionals and is very popular worldwide. However, the use of high caffeine content “energy drinks” is increasing (32). Energy drinks can contain anywhere from 80 to 500 mg of caffeine (33). Symptoms of caffeine intoxication include anxiety, restlessness, insomnia, gastrointestinal upset, tremors, tachycardia, psychomotor agitation, and even death due to arrhythmias. It enhances dopaminergic actions indirectly via potentiation of dopaminergic neurotransmission through competitive antagonism at the adenosine receptors (33). Caffeine withdrawal occurs frequently, although it is usually mild and is characterized by headaches, fatigue, drowsiness, impaired concentration, and depressed mood, which occur 12-24 hours after cessation of consumption and reach a peak after 20-48 hours. Withdrawal symptoms disappear shortly after ingestion of caffeine. Tolerance to the psychoactive effects of caffeine is also reported (32,33). Nicotine is the deadliest psychoactive drug, and the prevalence of depression

among smokers has been estimated at three times that of nonsmokers (34). This may arise from association, as opposed to causation, as tobacco does have MAOI-like antidepressant effects and thus depressed people may be more at risk to progress from trying tobacco to regularly using tobacco, to developing nicotine/tobacco use disorder. Some smokers experience relapse of depressive episodes during quit attempts (35). Alcohol use is common among American adolescents and young adults. Although light consumption of alcohol is associated with a slight euphoria or “buzz,” moderate to heavy consumption may be associated with depression, suicidal feelings, or violent behavior in some individuals. With prolonged drinking, the incidence of dysphoria and anxiety rises, much to the distress of the drinker. In those who are physiologically dependent, one usually sees a hyperadrenergic state that is characterized by agitation, anxiety, tremor, malaise, hyperreflexia, mild tachycardia, increasing blood pressure, sweating, insomnia, nausea or vomiting, and perceptual distortions. After acute withdrawal from alcohol, some persons suffer from continued mood instability, with moderate lows, fatigability, insomnia, reduced sexual interest, and hostility. Chronic heavy drinkers can experience hallucinations, delusions, and severe anxiety during acute withdrawal, and some have grand mal seizures. Brain damage of several types is associated with alcohol-induced neurocognitive disorder, persistent amnestic disorder, and delirium. With sedative–hypnotics and anxiolytics, particularly the benzodiazepines, acute use can produce a “high” similar to that seen with alcohol. The drug effects are perceived as relaxing, producing a social ease, but sedatives also can induce depression, anxiety, and even withdrawal-induced psychosis with prolonged use. Withdrawal symptoms include mood instability with anxiety or depression, sleep disturbance, autonomic hyperactivity, tremor, nausea or vomiting, transient hallucinations or illusions, and grand mal seizures. A protracted withdrawal syndrome has been reported to include anxiety, depression, paresthesia, perceptual distortions, muscle pain and twitching, tinnitus, dizziness, headache, derealization and depersonalization, and impaired concentration. These symptoms can last for weeks, and some (such as anxiety, depression, tinnitus, and paresthesia) have been reported for a year or more after withdrawal (36). Stimulants: Cocaine, amphetamine/methamphetamine and other stimulant use often is associated with an intense euphoria or “rush,” with hyperactive behavior and speech, racing thoughts, hypersexuality, anorexia, insomnia, inattention, anxiety, and manic/labile mood swings. The route of administration and the dose alter the intensity of the experience. Depressive symptoms and

cognitive problems as well as hypersomnia, decreased energy, and increased appetite commonly occur during a stimulant withdrawal phase. After a methamphetamine binge of several days, individuals will often be hostile and agitated, which is referred to as “tweaking” as they stop their use, or they may use other drugs such as benzodiazepines or alcohol to moderate the agitation. Up to 40% of methamphetamine users become paranoid and delusional after prolonged heavy use (37). Once abstinence is maintained for several weeks to months, the psychotic symptoms usually attenuate and resolve but many of those with SIPD go on to develop a persistent psychotic disorder (20). Persons with stimulant use disorders report a prolonged withdrawal state that is dysphoric and prominently marked by anhedonia and/or anxiety, but which does not meet the symptom severity criteria to qualify as a DSM-5 disorder. This anhedonic state can persist for weeks to months. Individuals with stimulant use disorder frequently report hallucinatory symptoms that are visual (“coke snow”) and tactile (“meth mites” or formication). Sleep disturbances are prominent in the intoxicated and withdrawn states, as is sexual dysfunction. Methylenedioxymethamphetamine (MDMA), more commonly known as “ecstasy,” intoxication produces stimulant effects similar to cocaine and amphetamine as well as empathogenic effects such as empathy, a sense of wellbeing, and sociability due to serotonergic activity (38). Withdrawal states are characterized by depression, hypersomnia, poor concentration, and fatigue. Chronic MDMA users may develop more severe longer-term problems such as dysphoric states and cognitive impairments in memory, concentration, and executive functioning, which are thought to be due to serotonergic neurotoxicity (38). Opioid use is characterized by a “high” or “rush” when the drug is used intravenously or smoked. Unlike the stimulants, opioid-induced euphoria usually is associated with some sedation and manifests as a mellow, sleepy state. If opioids are used for a long period, moderate to severe depression is common. Symptoms of opioid withdrawal include irritability, accompanied by craving, anxiety and agitation, muscle aches, a flu-like syndrome, and gastrointestinal symptoms early in withdrawal from drugs such as heroin and morphine. More drug subdues the craving. In withdrawal, some opioid users are acutely anxious and agitated, whereas others report depression and anhedonia. Anxiety, depression, and sleep disturbance, in a milder form, can persist for weeks to months as a protracted withdrawal syndrome that gradually subsides. Classical hallucinogens such as lysergic acid diethylamide (LSD), mescaline, psilocybin, and dimethyltryptamine (DMT) produce visual distortions

and frank hallucinations. All hallucinogens are associated with drug-induced panic reactions that feature panic, paranoia, and even delusional states in addition to the hallucinations. However, they are not associated with a withdrawal syndrome. A few hallucinogen users experience chronic reactions, involving (a) prolonged psychotic reactions; (b) depression, which can be life threatening; (c) flashbacks; and (d) exacerbations of preexisting psychiatric illnesses. A flashback is the re-experiencing of hallucinogen-induced perceptual distortions, despite no recent hallucinogen use. The DSM-5 refers to these flashbacks as “Hallucinogen Persisting Perception Disorder” and requires that they be distressing or impairing to the patient. Marijuana (cannabis) and hashish or hash oil contain tetrahydrocannabinol (THC). Intoxication with THC augments appetite and causes sedation with euphoria. Some users experience a marked sense of time distortion and feelings of depersonalization. A cannabis withdrawal syndrome is described (39) that is generally mild and consists of anxiety, irritability, physical tension, depressed mood, decreased appetite, restlessness, and craving. Recent literature has emerged that early use of cannabis is a risk factor for the later development of schizophrenia-spectrum disorders (40) and the cumulative 8-year risk of cannabis-induced psychosis converting to permanent psychosis is 46% (20). PCP, an arylcyclohexylamine, and ketamine are N-methyl-D-aspartate (NMDA) antagonists and dissociative drugs that cause hallucinations and dissociative states. Dextromethorphan is a codeine-like drug that when metabolized is converted to dextrorphan, which is also an NMDA antagonist. All three are known for their dissociative and delusional properties. PCP is also associated with violent behavior and amnesia of the intoxication (41). Over the last decade, PCP use has increased in combination with cannabis. Novel psychoactive substances also known as designer drugs and other emerging substances often found on the Internet and advertised as “legal highs” have been appearing with increasing frequency over the past few years. Synthetic cathinones popularly known as “bath salts” are all synthetic analogs of cathinone derived from leaves of the khat plant (Catha edulis), a stimulant chewed for centuries in Yemen, Somalia, Eritrea, and Ethiopia (42). The cathinone derivatives found in bath salts are primarily 3,4-methylenedioxypyrovalerone (MDPV), mephedrone, and methylone, which are structurally similar to methamphetamine and MDMA and produce similar stimulant effects as well as psychotic effects in susceptible individuals (42). Other new psychoactive substances of which we have as yet little medical knowledge include methoxetamine, a “legal” ketamine analog that is an NMDA receptor antagonist

that causes hallucinations (42), and the piperazine derivatives that have central serotonergic and amphetamine-like effects (42). These recently emerging substances are becoming popular in Europe and other parts of the world such as New Zealand and Eastern Europe and are often advertised as “research chemicals” that can be bought on the Internet. Salvia divinorum, an herb in the mint family that has become more popular of late, is native to Southern Mexico and is used for its mind-altering effects. The plant can be chewed, smoked, or vaporized and is not controlled under the United States Controlled Substances Act. Salvia divinorum is, however, controlled by a large number of states and had been widely available via the Internet or local “head shops.” Psychotropic properties are due to the chemical salvinorin A, a kappa opioid receptor agonist. Effects include hallucinations, visual distortions, perceptual disturbances, anxiety, confusion, and dysphoria (42). Some users describe synesthesia (where one sensory perception takes on the appearance of another, ie, hearing colors or smelling sounds), while others endorse a dissociative or “out of body experience.” Effects can last as long as 24 hours (43). Synthetic cannabinoids such as “Spice” and “K2” consist of inert plant material sprayed with chemical compounds originally designed by pharmaceutical companies as research drugs with cannabinoid receptor agonist activity (42,43). In early 2011, the U.S. Drug Enforcement Agency gave Schedule I status to several of the synthetic cannabinoids including JWH-018, JWH-073, CP 47, 497, and homologues (44), and a comprehensive national ban was enacted in July 2012 (44). However, new analogues are still being released and synthetic cannabinoids continue to be popular particularly among people who do not want to have a urine toxicology screen positive for cannabinoids. Psychotropic effects that occur when “Spice” is smoked include alterations in mood, perception, as well as anxiety, agitation, nausea, vomiting, tachycardia, elevated blood pressure, tremor, seizures, hallucinations, paranoid behavior, and unresponsiveness to external stimulation (45).

Differential Diagnosis and Treatment Diagnosing and treating SIMDs is very much dependent on the attitude and training of the clinician. Is he or she attuned to the prevalence of substance use, such as those outlined above? Without this awareness, there is less inclination to search for the problem. Does the clinician think that it is relevant to the current problem to take the time to elicit a substance use history? Has the clinician

received adequate training to counteract therapeutic nihilism that may be acquired during medical school, residency, or independent practice? Is he or she adversely affected by the distortions and denial that are exhibited by many individuals with SUDs? Does the clinician routinely seek independent thirdparty substance use history from family or friends of the patient? Will the clinician order a drug screen? All of these questions hint at behaviors that can make the diagnosis more apparent or allow it to elude identification. Making the diagnosis of an SUD is the first step in the differential diagnosis and treatment of SIMD. In the second step, the substance-induced symptoms must be differentiated from the symptoms of independent psychiatric disorders. Finally, the SIMD must be differentiated from a co-occurring disorder: SUD combined with a comorbid, nonsubstance Axis I disorder.

Substance-Induced Depressive and Anxiety Disorders These may be the most common substance-induced disorders that clinicians need to consider in arriving at a differential diagnosis. It is important to consider and make the substance use diagnosis whenever it is pertinent. There are some guidelines that can help with these diagnoses. Because of denial, the patient may not understand what is happening in his or her life. If the clinician is aware of the prevalence of addictive disorders and the ways in which such disorders typically present, he or she is more likely to take a careful history and to seek confirmation of the history from collateral informants, especially family and friends but also other healthcare professionals. Establishing whether there is a relationship between the use of psychoactive substances and the symptoms prominent at the moment is a crucial step. Chronic use of alcohol, sedatives, and opioids can cause depressed mood, as can withdrawal from stimulants and sedatives. Exploring the mood during periods of sustained abstinence from all substances is critical. In making a diagnosis of SIMD, it is important to order a toxicology screen. Even if the results come back hours after the clinical decision is made, they can be used to confirm the presence of a substance despite the patient’s denial. Such a screen also can clarify the history in some future episode. Sometimes, patients report part of their history but not all. For example, it may be useful to know that both alcohol and cocaine were used by a depressed patient. Although either substance can induce symptoms of anxiety or depression, a slightly different treatment plan may be necessary for a patient addicted to both.

Substance-Induced Psychotic Disorders A drug screen may be critical to the diagnosis of SIPD especially since the subject may not have accurate knowledge of what substances were ingested. Hallucinations or delusions must be prominent and are not counted if the individual has insight into the substance-induced nature of his or her psychiatric symptoms. Among young people, substance use is common in first-episode psychosis, and the differentiation of SIPD from PPD is challenging and requires a careful psychiatric and substance use history, drug screen, and collateral information from family and friends. The differential diagnosis of methamphetamine psychosis and PPD is difficult, and a recent multisite international study has concluded that the severity of psychotic symptoms observed in patients with methamphetamineinduced psychosis and patients with schizophrenia is almost the same (46). Fraser et al. (17) using the PRISM-IV–studied individuals with first-episode psychosis admitted to a psychiatric ward and found that 56% had SIPD. Those with SIPD had higher rates of substance use and SUD, had higher levels of insight, were more likely to have a forensic and trauma history, and had more severe hostility and anxiety symptoms compared to those with non–druginduced psychosis. They reported that after logistic regression analysis, a family history of psychosis, trauma history, and current cannabis use disorder were significant predictors for SIPD (17). Ali et al. (47) in a recent Multisite World Health Organization–sponsored study on SIPD reported on non–evidence-based treatment recommendations for SIPD and concluded that benzodiazepines should be used to manage acute agitation during intoxication followed by atypical antipsychotic administration should the psychosis be severe or not resolve within 1-2 weeks after cessation of drug use. Most cases of SIPD are short-lived and resolve within a few days to 2 weeks with the exception of methamphetamine and synthetic cannabinoid-induced psychosis since persistent psychotic symptoms after heavy and/or long-term use has been well documented in several studies (18–20).

Case 1 Mr. B is a 46-year-old divorced Caucasian man who works as a house painter. He came to the emergency department because of suicidal ideas, which frightened him. He had become increasingly depressed over the preceding month and was afraid that he was “going crazy.” He had experienced episodes of

depression over the preceding 7 years (since his divorce), but the episodes had not lasted more than a day or two. He also had experienced fleeting suicidal ideas but had not hurt himself. In the past year, he occasionally had sat with his gun and considered ending it all. At those times, he felt momentarily hopeless. The suicidal and hopeless thoughts lasted for an evening but were not continuously present for more than a day. He had never been treated psychiatrically for depression. The clinician gathers information suggestive of a depressive syndrome of some kind and must determine whether there are any secondary causes, the most common of which would be SIDD. Mr. B has been hospitalized once, 4 years ago, to be detoxified from alcohol, but he received no treatment for AUD after the withdrawal management. Recently, his drinking has increased to about a case of beer a day. He reports that the alcohol use is the only way he can cope with his depression. He denies any loss of control, but admits to two arrests for driving under the influence (DUI) over the preceding 10 years. He is experiencing difficulty in getting to work on time since becoming depressed and is in trouble with his supervisor. He denies morning tremors and says that he never has experienced seizures, delirium tremens, or hallucinations when withdrawing. Mr. B admits that his ex-wife complained about his drinking. He has had only one period of abstinence for more than a year, while on probation for his second DUI. He felt well during that time. He developed the depressive symptoms in his late 30s, whereas his heavy drinking began in his early 20s. He denies any ongoing medical problems or thyroid problems. He has had some weight loss in the past month because he has not been eating regularly with his heavy drinking, and he has experienced some nausea in the mornings, which made eating breakfast difficult. He denies any use of sedatives, barbiturates, cocaine, or opioids, but he does endorse daily tobacco use. On mental status examination, Mr. B is found to be a middle-aged white man, who looks more like 55 than 46 years old. He is thin, looks depressed, and smells of alcohol. He is vague about some details and specific about others. He is oriented to person, place, date, and purpose. He is tearful at some times and anxious at others. He seems bewildered about his predicament. He denies having problems with alcohol. He has suicidal ideas about shooting himself but does not seem motivated to do so. He denies hallucinations and obsessions. He denies any manic episodes. His blood alcohol concentration is 200 mg/dL. A drug toxicology screen is negative for benzodiazepines, opioids, barbiturates, and cocaine.

Diagnostic Issues

Is there a reason to consider a diagnosis of AUD for Mr. B? Is depression a prominent symptom? Is there a reason to connect the depressive symptoms to alcohol or drug use or withdrawal? Is the intensity of depression more severe than is usually found with alcohol intoxication alone? Is the depressive mood better explained by a primary mood disorder? Did the depressed mood occur during a delirium?

Diagnostic Considerations At this point, the clinician has enough information to diagnose AUD. Mr. B exhibits tolerance, alcohol withdrawal symptoms, use despite adverse consequences, impairment of personal relationships, and, possibly, impairment of occupational function: all related to his use of alcohol. His mood disturbance is prominent and is more severe than that experienced by social drinkers and most persons with AUD. His depressive symptoms seem sufficiently severe to suggest major depression; however, there is no evidence of depression at the times that Mr. B is not drinking heavily, suggesting alcohol-induced depressive disorder. The AUD seems to be primary; that is, it began before the depressive symptoms. This sequence of symptoms also suggests SIDD. It is possible that Mr. B has two independent disorders: AUD and MDD; however, there is no evidence of that at present. Finally, there is no evidence of a delirium.

Treatment Issues Safety issues involve ongoing evaluation of the diagnosis, a risk-stratification regarding suicidal ideation with a gun, use of medications, and psychosocial therapy. A trial of abstinence is called for in a safe and supportive environment. The clinical challenge is to find a safe environment. The risk of alcohol withdrawal delirium and seizures is minimal, suggesting that Mr. B could be managed as an outpatient. However, there are other considerations in this decision. The ASAM Criteria (48), which provides a guideline for multidimensional assessment and criteria for treatment of addictive, substancerelated, and co-occurring conditions, encourage the physician to evaluate the patient’s status in six different dimensions. The first is the potential for withdrawal. The second and third consider the presence of medical and psychiatric comorbidities. (The seriousness of Mr. B’s suicidality, as well as the degree of his anergia and inability to mobilize because of depression, is relevant in this case.) Risk stratification for suicide must be accomplished, including identification of the gun location, offering a gun lock or other means to secure

the weapon, etc. The medical comorbidity is minor (possibly gastritis) and should improve with abstinence. The fourth dimension is the patient’s readiness for change. Mr. B appears to seek treatment; however, he may balk at inpatient or outpatient treatment, making his cooperation a major issue. The final two dimensions—the potential for relapse and the presence or absence of a supportive recovery environment—are very pertinent to this patient. If Mr. B has no supportive friends or family who can remove his gun, watch over him and be sure that he gets to therapy sessions or to the emergency department if his condition worsens, then outpatient therapy becomes risky, particularly given the patient’s suicidal ideas. The patient’s potential for relapse, including his motivation for abstinence, craving for alcohol while abstinent, and history of prior attempts to quit, is crucial in determining the viability of outpatient treatment. Alcohol-induced depression should remit over the first 2-3 weeks of abstinence. Careful follow-up during this period is very important with outpatient treatment because of the severity of Mr. B’s symptoms and the possibility that the correct diagnosis is not alcohol-induced depression. However, if he cannot or will not stay sober as an outpatient, it is likely that he will remain depressed or become even more depressed. At this point, residential treatment is essential to break the cycle of addiction and allow the patient’s mood to improve. If his mood does not improve with abstinence, the diagnosis of MDD is likely, and the patient should be given appropriate antidepressant treatment. FDAapproved medications for AUD such as naltrexone, acamprosate, and injectable naltrexone can be very helpful when the patient is cooperative, open to the idea of abstinence from alcohol, and willing to engage in some kind of psychosocial treatment. The same is true of disulfiram. Various off-label medications may also have effectiveness for AUD (such as topiramate, gabapentin, etc.). Patients with a firm commitment to recovery may not need the assistance of such medications. Patients with a strong connection to Alcoholics Anonymous may not be motivated to take such medications because they believe that medications are not appropriate for recovery from an SUD; however, Alcoholics Anonymous produces a pamphlet that is quite supportive of both psychiatric care and the use of psychiatric medications.

Case 2 Mr. M is a 64-year-old African American veteran who is divorced and unemployed. He presented to the evaluation area at 9:00 AM because of a longstanding problem sleeping that has worsened over the past 2 months. He has been drinking more alcohol to fall asleep but has been waking after only a few

hours of sleep. He experiences hand tremors in the mornings, which resolve with a few shots of whiskey. He has become jumpy and irritable and tends to isolate himself from his friends.

Option A Mr. M has no history of withdrawal seizures, hallucinations, or delirium tremens. He has no history of panic attacks, chronic anxiety, or traumatic life events. His vital signs include blood pressure 148/90, pulse 96, temperature 98.6°F, and respirations 16. Mr. M was detoxified from alcohol within the past year but refused to enter outpatient treatment. He complained that he was “not going to let the doctors treat him like a ‘guinea pig’ on the withdrawal management unit” and that “they just try to lock up a Black man these days.”

Diagnostic Issues Is there a prominent symptom? If so, is this symptom related to drinking? Is there any evidence of other drug use? Is this explained better by another DSM disorder? Did the symptoms occur during a delirium? Has this disorder caused symptoms beyond what normally is experienced during alcohol intoxication or withdrawal?

Clinical Considerations At this point, the information available suggests alcohol withdrawal. There also is information suggesting a sleep disturbance that may be alcohol induced or related to alcohol withdrawal. Because of the cultural tensions already reported, an effort should be made to rule out an anxiety disorder, as Mr. M may be reluctant to report anxiety symptoms. Efforts should be made to rule out other causes of his anxiety and agitation, such as hyperthyroidism, stimulant intoxication, caffeinism, or medication-induced anxiety. A drug toxicology screen would be helpful to rule out stimulant intoxication, benzodiazepine withdrawal, and opioid withdrawal. A phone call to a family member or friend may add confidence to the diagnosis and rule out chronic anxiety and psychotic disorders. The symptoms do not seem excessive for alcohol withdrawal, which is the likely diagnosis, given the available information.

Option B Mr. M has no history of delirium tremens, withdrawal seizures, or withdrawal

hallucinations. He has a history of panic attacks, which began after he returned from military service in Vietnam in 1971. He had been in combat for 6 months and had seen a lot of action, which he does not wish to discuss. He becomes more agitated as he talks about combat, eventually cutting off the conversation. He is angry about the way he was treated when he returned to the United States and reports a difficult transition to civilian life. He demonstrates recent heavy drinking, nightmares about combat, flashbacks, relationship problems, and a significant startle reaction to loud noises. He complains of racist treatment by white soldiers and officers in Vietnam and claims that his white superiors sent him on suicide missions.

Diagnostic Issues Is there a prominent symptom? Is there a causal relationship with the drinking? Is there any drug use that could account for the disorder? Is this better explained by another DSM disorder? Did the symptoms occur during a delirium? Are the symptoms excessive for alcohol intoxication or withdrawal?

Diagnostic Considerations The patient certainly evidences anxiety as a prominent symptom. However, it still is important to look for a substance-induced depressive and anxiety disorders. It is necessary to clarify the diagnosis of alcohol withdrawal. This patient seems to have posttraumatic stress disorder (PTSD), AUD, alcohol withdrawal, and, possibly, SIAD. Because the engagement of this patient in treatment may depend on which combination of problems he has, it is important for the clinician to obtain collateral information and a toxicology screen. Because the patient’s denial may be convincing, it is not sufficient to dismiss SUD or SIMD based on his history. If the patient’s report is the only information available, the clinician must make a treatment decision, while remaining aware that new information could change the diagnosis and treatment plan. Mr. M’s vital signs should be monitored to pick up signs of severe alcohol withdrawal. A toxicology screen should be obtained to check for drugs that can cause agitation or anxiety. A chronic history of anxiety, tension, and nightmares is excessive for alcohol-induced anxiety or alcohol withdrawal alone. With this information, the clinician may consider both PTSD and alcohol withdrawal. It will be difficult to diagnose alcohol-induced anxiety disorder in combination with PTSD unless there is a clear history of anxiety that recently has worsened without a psychosocial trigger for the PTSD. More commonly, the clinician will see an

acute improvement with abstinence as a sign that there was an alcohol-induced anxiety component.

Treatment Issues Mr. M needs to be engaged in a withdrawal management setting (followed by a rehabilitation setting), and his denial needs management in order to expand his awareness beyond the PTSD symptoms. His claims of racism should be addressed as part of the engagement and assessment processes. While benzodiazepines or gabapentin may be effective for alcohol withdrawal, Mr. M’s postwithdrawal anxiety should be managed without using benzodiazepines. His sleep disorder should be managed and the process of relapse prevention initiated.

Treatment Considerations Treatment must be conceptualized in stages. The first stage is withdrawal management from alcohol (and any other drugs that may be present). With this patient, withdrawal management can be managed through a careful outpatient regimen if he is able to remain abstinent. If abstinence seems unlikely, if the patient fails at outpatient withdrawal management, or if a comorbid problem arises that cannot be monitored safely on an outpatient basis, then residential or inpatient withdrawal management must be considered. The next stage is the maintenance of sobriety, a stabilization phase. During this stage, the clinician should monitor Mr. M’s abstinence and observe the course of the anxiety symptoms. A relapse can increase his anxiety symptoms (or vice versa), which would interfere with attainment of the treatment goals. Such a relapse would require a treatment strategy that focuses on management of denial, motivation, and relapse prevention. Once withdrawal management is complete, if anxiety symptoms persist and support a diagnosis of PTSD, then medication may be indicated. If the anxiety symptoms diminish or are manageable without medication, then psychotherapy may be sufficient. The use of benzodiazepines in patients with AUD after withdrawal management is achieved is controversial, even in the face of severe anxiety. The anxiolytic properties of benzodiazepines are sustained over time; however, many patients with AUD are susceptible to developing subsequent sedative–hypnotic use disorder. Moreover, craving for drugs is greatest when the drug, or a similar drug, is being used. Thus, there always is a concern that benzodiazepines will stimulate the desire for alcohol. Drinking in addition to benzodiazepine use can lead to an “out of control” binge, as well as intoxicated behaviors, which could exaggerate the PTSD symptoms of

anxiety and agitation. Disulfiram is a possible safeguard to prevent alcohol use during outpatient treatment, but the patient must be willing to collaborate (ie, take it regularly) if it is to be effective. As well, a “disulfiram reaction” (characterized by anxiety) from drinking alcohol may then catalyze worsening of PTSD. Thus, other medications for AUD may be preferred. The use of FDAapproved medications for PTSD in combination with evidence-based psychotherapy should be considered; however, selective serotonin reuptake inhibitors (SSRIs) have been suggested to increase relapse risk for AUD in certain patients (49). Akin to the use of benzodiazepines in AUD, similar concerns exist when considering sedatives for insomnia. Use of sedating antidepressants without addiction potential may be advised.

Option C Mr. M has no history of delirium tremens, withdrawal seizures, or withdrawal hallucinations. He has had an episode (the day before coming to the emergency department) in which he became frightened, felt short of breath, felt his heart pounding, and worried that he was having a heart attack. This episode was not the first time he has experienced such an attack; he had one 6 months earlier when he quit drinking. He had gone to the emergency room the first time this happened, 5 years ago. The physician then had checked his heart and told him that he was having a nervous attack, not a heart attack. Although Mr. M feels stressed at times, he does not have these attacks regularly. When he stopped his drinking for a year, he felt well and does not recall having a spell during that time. He denies any major, traumatic life events. He was embarrassed to be worried about these anxiety spells but also fearful that he might have been having a heart attack.

Diagnostic Issues Is there a prominent symptom? Is this symptom related to drinking? Is the symptom better explained by another DSM diagnosis? Is the symptom in excess of the symptoms normally encountered during intoxication or withdrawal?

Diagnostic Considerations There is a prominent symptom of anxiety in this case, and it appears to occur only with drinking. The clinician must think about AUD, alcohol withdrawal, and alcohol withdrawal–induced panic disorder. The major anxiety disorders should be ruled out, as should PTSD (although certain events, like sexual abuse,

may be denied initially). Some attempt to rule out cardiac disease as a cause of the chest pain would be important. Other causes of anxiety also should be ruled out.

Treatment Issues Mr. M should be engaged in a withdrawal management program and his level of denial and motivation for treatment evaluated. The denial needs to be evaluated and the problem redefined as AUD, not panic or heart disease. The possibility of a comorbid anxiety disorder should be explored. The patient then needs to be engaged in an addiction treatment program. Medications that will enhance the likelihood of abstinence should be considered. The patient should be evaluated for relapse triggers and referred for relapse prevention as appropriate.

Treatment Considerations Treatment should be designed to help Mr. M safely withdraw from alcohol, to explore other possible substance use, and to keep him abstinent long enough to determine whether the anxiety disorder abates as an alcohol withdrawal–induced anxiety disorder would. The patient’s denial and motivation are important because he must understand the connection between his drinking and his panic. If his awareness of this connection is minimal, then the treatment may have to occur in a setting in which chest pain and panic are integrated into the understanding of his AUD and its impairment of his functioning. He may not accept the focus on his drinking and therefore decline all referrals for rehabilitation. Ongoing monitoring and working with his denial would be necessary (such as via evidence-based motivational enhancement techniques) before he may move past his ambivalence for help. Benzodiazepines would be appropriate only during withdrawal management; medications that promote abstinence, such as disulfiram, acamprosate, or naltrexone, would be appropriate if Mr. M is willing to comply with them. If panic disorder is confirmed after abstinence has been achieved, then FDA-approved pharmacotherapy may be considered.

Case 3 Mr. S, a 20-year-old gay man, was brought by the police to the local emergency department after threatening his partner with a knife. He presented with acute agitation, hostility, paranoia, and delusions of reference. He expressed fear that

his partner was a “necrophiliac” and a serial murderer. Over the past month, Mr. S had begun to arm himself with a knife in order to protect himself and others from possible attack. Other symptoms included frequent anger episodes, increased libido, insomnia, tachycardia, weight loss, and anxiety. On physical exam, he was found to have scattered scarring and sores on his face, arms, and legs. The patient reported having used methamphetamine on many occasions over the past year, smoked, and later injected over weekends to “party with friends.” During his partying experiences, he related repeated unsafe sexual practices including receptive anal intercourse and he requested an HIV test. He described frequent withdrawal effects after a weekend of partying that included hypersomnia, increased appetite, poor concentration, and dysphoria that would last several days and culminate in craving until his next methamphetamine binge. In addition to methamphetamine use, the patient also reported frequent alcohol and marijuana use but denied a history to support an SUD including withdrawal from those substances. He denied all other drug use including tobacco.

Diagnostic Issues Is this SIPD or is it the onset of a PPD? What is the course and prognosis? Is this condition better explained by a delirium or another DSM disorder?

Diagnostic Considerations This case appears to be methamphetamine-induced psychotic disorder. However, given his young age, the possibility of a PPD cannot be ruled out. A drug toxicology screen should be obtained to rule out other drugs despite his denial of use since street drugs are often contaminated with other compounds. He appears delusional and dangerous with very poor insight as he has armed himself with a knife over the last month and believes his partner may be trying to kill him. Hostility is a frequent symptom of methamphetamine psychosis (50) but is also common in untreated paranoid psychosis. He does not appear to have negative symptoms of schizophrenia, but there may have been a prodromal period of increasing delusional and paranoid thoughts, which is common for people who become psychotic from frequent use of methamphetamine. He also appears to have manic-like agitation, mood lability, and excessive sexual behavior accompanying his insomnia alternating with depressive periods and hypersomnia. This is characteristic of chronic stimulant users who binge and then withdraw. His weight loss, tachycardia, and mild hypertension are probably

effects of the stimulant, but a thyroid disorder should be ruled out. His skin lesions are likely due to “meth mites” or formication and the chronic skin picking frequently seen in those who use methamphetamine. In DSM-5, this is diagnosed as stimulant-induced excoriation disorder and is consider stimulantinduced obsessive–compulsive-related disorder. However, the lesions may also represent a parasitic infestation such as lice, scabies, or bed bugs or a sexually transmitted disease (STD) such as a rash or chancre associated with syphilis since he has had indiscriminate and unsafe sexual behavior that is frequently associated with recreational methamphetamine use. An HIV test, as well as other STD tests, should be done.

Treatment Issues This patient is frightened but also hostile and delusional with poor insight and threatening behavior. He also has intense craving associated with his withdrawal periods, which likely will prompt him to leave against medical advice. If he declines admission for stabilization, then involuntary psychiatric hospitalization is required as well as acute treatment of the agitation and psychosis with benzodiazepines and atypical antipsychotics. Mr. S will need extensive education about the origin of his psychosis followed by inpatient and then outpatient addiction treatment for relapse prevention. His partner should be warned if homicidal ideation is present and advised to seek a protective order. He will also need close follow-up after hospitalization to ensure that his paranoia attenuates with abstinence and antipsychotic treatment.

Treatment Considerations Prognosis will depend primarily on his motivation and success in addiction treatment, and it is essential that he understand the role methamphetamine has played in his decompensation and the likelihood of worsening and prolonged psychosis should he relapse. If psychosis persists despite a month of abstinence, a PPD must be considered. Subspecialized culturally appropriate addiction treatment for sexual minorities with methamphetamine dependence is available in most large urban areas and can include education about unsafe sexual practices and harm reduction. Twelve-step groups such as “Crystal Meth Anonymous” and “Strength Over Speed” are very helpful if available, but “gay friendly” AA and NA groups will also suffice. As yet, there is no FDA-approved pharmacological treatment for methamphetamine use disorder.

Case 4 Ms. A is a 35-year-old woman who was brought to the emergency department (ED) after overdosing on heroin and clonazepam. She was revived by bystanders using naloxone. When evaluated in the ED, she reported severe anxiety, panic attacks, and feeling very despondent over the past few weeks with suicidal ideation. She reported her overdose was an attempt to “escape the pain” but not necessarily to end her life, rather, end her suffering. She endorsed chronic pain due to past trauma from domestic violence and had been on prescription opioids for several years. Over the past year, she began to use heroin after her physician retired, and the new provider did not want to continue prescribing opioids. She related that she has had untreated depression and anxiety in the past but her symptoms began to worsen when she started injecting heroin and using clonazepam to supplement her “highs.” Ms. A reported that she would use 1-3 mg daily of clonazepam that she bought on the streets to “help” with withdrawal and symptoms of anxiety and panic but she took 5 mg on the day of her overdose.

Diagnostic Issues Is there a prominent symptom? Is this symptom related to drug use? Is this situation better explained by another DSM diagnosis? Did this situation occur exclusively during a delirium? Is this symptom more severe than usually is encountered with intoxication or withdrawal?

Diagnostic Considerations Ms. A made a suicide attempt that brought her to the emergency department. She also endorsed prominent anxiety and depression, which is consistent with opioid and benzodiazepine use disorders and withdrawal symptoms. Her past psychiatric history is vague and not clear if she has a primary mood or anxiety disorder, but it is important to further evaluate this after withdrawal symptoms have been managed and consider other diagnoses such as PTSD or a personality disorder. It is possible that she has both an independent psychiatric disorder as well as SIMD. Some may be tempted to consider her overdose attempt as “halfhearted” and “a call for help” and to dismiss SIDD as less significant than an MDD because the former resolves so quickly. However, women with multiple SUDs are more likely than men to have underlying co-occurring disorders, and risk for suicide attempts and completed suicide is high (51). Her suicide attempt

was very dangerous, and continuing her use of both heroin and benzodiazepines will likely result in further overdoses and eventual death—either accidental or deliberate. The risk of death from opioid overdose approximately doubles when benzodiazepines are added to the mix, and benzodiazepine use has been identified in 50%-80% of heroin deaths (52). Investigating unsafe sexual practices and needle sharing and screening for HIV disease and viral hepatitis is necessary for anyone using intravenous drugs, and it would be wise to obtain a toxicology screen to rule out other unreported substance use. Assessing for domestic violence and PTSD is also very important.

Treatment Issues Patient safety and suicidality are primary issues here. The clinician must assess the severity of the suicidal impulse and the social supports available before deciding whether a residential setting is appropriate. The clinician should assess what type of suicidal thoughts the person is having, whether he or she has formulated a plan to carry out the idea, whether he or she has the means to complete the plan, whether he or she has made prior attempts and, if so, how serious were the attempts. It is important to explore reasons to continue living and whether there are other alternatives to committing suicide. Assessing the degree of anxiety and agitation in the patient is also important. People with multiple SUDs and intravenous drug use are often demoralized because of treatment failures and severe psychosocial stressors, which contribute to a sense of hopelessness and shame. It is essential to engage Ms. A in a motivational manner and assure her that her pain and addiction as well as depression and anxiety can be managed through a combination of pharmacotherapy and psychotherapy, such as buprenorphine or methadone and adjunctive nonaddictive medications for residual psychiatric disorders. A trauma-informed substance treatment program for women would be ideal for Ms. A. Safety from benzodiazepine withdrawal is also an important issue that must be considered. She may be minimizing her benzodiazepine use and thus will need ongoing monitoring for withdrawal symptoms. Benzodiazepine withdrawal is best handled on an inpatient basis and can be assessed and treated along with her opiate dependence, psychiatric symptoms, and suicidality.

Treatment Considerations Assessing a patient’s reliability (likeliness to follow through) may be difficult if the patient is previously unknown to the clinician. A variety of factors enter into

this assessment, including motivation, denial, awareness, craving, relapse triggers, and availability of a supportive environment. Such an assessment is part of the safety management for this patient. Engagement in an addiction treatment program will depend on the patient’s denial, motivation, and awareness of the centrality of drugs and alcohol, as well as the pull of other social relationships such as children, significant others, and family members. Attention to these psychosocial issues may be the key to engagement. Focusing on a comprehensive assessment, including relapse triggers, can be the way to engage a difficult, ambivalent patient. Such intervention remains part of the art of medicine and hinges on the physician’s style of practice, local resources, and managed care practices. It is a complex challenge each time and must be individualized to each situation.

CONCLUSIONS The SIMDs are common illnesses that often are associated with (but are not limited to) SUDs. Although they frequently are short-lived, these disorders are by no means clinically insignificant. Serious self-injury is reported with SIDD, and safety is an important clinical issue. This situation can present a clinical dilemma in determining the proper level of care. Regardless of what is available in the practicing clinician’s local area, services that treat co-occurring psychiatric and addiction disorders in parallel rather than in series typically provide improved clinical and cost-effective outcomes. Confusion about the diagnosis can delay interventions; therefore, achieving clarification through a comprehensive evaluation is the first order of business after safety is addressed. Although abstinence is a critical factor in recovery from SIMD, it is not always the only factor. Regular psychosocial treatments for SUD are relevant so long as the patient is behaviorally manageable and not psychotic or delirious. When the patient’s behavior is unsafe or unmanageable, a psychiatric unit may be necessary until the patient’s behavior is less risky. If a specialized inpatient unit for co-existing disorders is available for such severe cases and can manage the patient’s behavior with seclusion, restraints, psychotropic medications, or a locked unit, it may be the best choice. Such patient–treatment matching should be done on an individual basis, depending on the patient’s needs, the resources available, and the skills and preferences of the clinicians involved.

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CHAPTER 93

Co-occurring Mood and Substance Use Disorders Edward V. Nunes and Roger D. Weiss

CHAPTER OUTLINE Overview and Diagnostic Criteria Prevalence and Prognostic Effects of Co-Occurring Mood and Substance Use Disorders Differential Diagnosis Management of Co-Occurring Mood and Substance Use Disorders Summary and Future Directions

OVERVIEW CRITERIA

AND

DIAGNOSTIC

Significance Depressive disorders, major depression and persistent depressive disorder (dysthymia), are among the most common psychiatric disorders in the general population. Estimates from community surveys show that over 10% of the general population has experienced a depressive disorder at some point in their lifetime, and the prevalence of substance use disorders (SUDs) is increased by a factor or 2 or more among individuals with major depression (1). Major depression is the most common co-occurring psychiatric disorder encountered among patients presenting for treatment for SUDs, with lifetime prevalence rates ranging from 15% to 50% across samples studied from various treatment settings (2). Among patients with SUDs, major depression has been associated with worse outcome, including worse substance use outcome, worse psychiatric symptoms, and increased suicide risk. Clinical trials suggest that treatment of depression among patients with co-occurring SUDs with medication or behavioral therapy can improve outcome. Thus, it is very important for clinicians working with such patients to be able to recognize and treat depression or make appropriate referrals for treatment. Bipolar disorder is more rare in the general population, with estimates of the lifetime prevalence of bipolar I disorder ranging from 1% to 3%, another 1% for bipolar II disorder, and 2% or more having subthreshold disorders in the bipolar spectrum, each of which is associated with moderate to severe functional impairment (3,4). Bipolar disorder is correspondingly less common than major

depression among samples of patients seeking treatment for SUDs in routine outpatient settings. However, the strength of association between bipolar disorders and SUDs is larger than for depressive disorders, with the presence of a bipolar disorder increasing the likelihood of an SUD by a factor of 4 or more. Hence, among patients with bipolar disorder, the prevalence of SUDs is 40% or more (5), and patients with both substance and bipolar disorders are especially likely to be encountered on inpatient settings or other clinical programs serving psychiatric or so-called dual diagnosis populations. As with unipolar depression, co-occurring bipolar and SUD is associated with worse prognosis, and while clinical trials are more limited, those that have been conducted suggest that proper treatment of bipolar disorder improves substance use outcome. Further, many patients with bipolar disorder (particularly those who have had bipolar disorder for a long time) will present with a depressive syndrome, but the treatment recommendations for bipolar depression are quite different from unipolar depression. For bipolar disorder, mood stabilizer medications (eg, lithium, valproate, carbamazepine, lamotrigine) are the mainstay of pharmacotherapy, rather than antidepressant medications. Thus, it is very important for clinicians working with patients with SUDs to be able to recognize bipolar disorder, distinguish unipolar depression from bipolar disorder, and either treat or make appropriate referrals for treatment. Substance-induced mood disorder (depressive or bipolar) is a persistent mood disturbance (eg, depressed mood or pervasive loss of interest in the case of depressive disorder) that impairs functioning and warrants clinical attention but which has occurred only in the context of active substance use. This category was introduced in DSM-IV to recognize that there exist mood syndromes that are more than just the usual intoxication or withdrawal effects of substances on the one hand but cannot be clearly diagnosed as independent depressive or bipolar disorders on the other. Research suggests that substance-induced depression has prognostic significance and may convert to independent depression over a subsequent follow-up period when the depression persists or emerges during abstinence from substances (6). Disruptive mood dysregulation disorder (DMDD) is a new diagnosis, added in DSM-5 under the category of depressive disorders, consisting of severe recurrent temper outbursts, accompanied by a persistent irritable or angry mood most of the time. Onset is in childhood, before the age of 10. This diagnosis was introduced in DSM-5 in part because of the recognition of a subgroup of children with severe irritability and temper outbursts, who were being misdiagnosed as childhood bipolar disorder despite an absence of sustained

episodes of hypomania or mania and major depression required for the bipolar diagnosis. The symptoms may persist into adolescence and adulthood, and while emergence of bipolar disorder is rare in adolescence and adulthood, depressive or anxiety disorders often develop. Co-occurrence and overlap with other mood, anxiety, and disruptive disorders (conduct disorder, oppositional defiant disorder, attention deficit hyperactivity disorder) are high. Treatment research is limited, though a range of options have been suggested, including antidepressants, anticonvulsant/mood stabilizers, stimulants, neuroleptics, and alpha-2 agonists (7). In adolescence, co-occurrence of a syndrome of irritability similar to DMDD with heavy cannabis use has been described, responding to the anticonvulsant Depakote (8). The diagnosis is new, and there is limited evidence to date on substance comorbidity. Therefore, DMDD will not be discussed in further detail in this chapter. The main take-home message regards the differential diagnosis of irritability among patients with SUDs. Irritability and aggression can be features of a number of intoxication or withdrawal syndromes and are also common in antisocial personality, which has high comorbidity with SUDs. However, it is important to examine the past history and developmental history for evidence of chronic problems with irritability or aggression that began in childhood and appear independent of substance use during adolescence and adulthood. This may represent a mood syndrome (DMDD) and prompt consideration of pharmacotherapy.

A Note on DSM-IV and DSM-5 The Diagnostic and Statistical Manual of Mental Disorders (DSM) provides the commonly accepted diagnostic criteria for mental disorders. The 4th edition (DSM-IV) (9) was published in 1994 and has been replaced by the 5th edition (DSM-5) (10) in 2013. Most of the research on the prevalence, prognostic, and treatment significance of co-occurring disorders derives from DSM-IV or earlier criteria sets. DSM-5 did not involve substantial changes to the criteria for mood disorders, other than the addition of the new category DMDD, as noted above. Importantly, the approach to co-occurring mood and SUDs, including the category of substance-induced mood disorders, is virtually unchanged between DSM-IV and DSM-5. Hence, this chapter will describe and employ the DSM-5 criteria, with the understanding that much of the evidence base on co-occurring mood and SUDs derives from the earlier but similar DSM-IV criteria.

DSM-5 Criteria for Depressive Disorders and

Bipolar Disorders A brief overview of DSM-5 mood disorders (10) is provided in Tables 93-1 (depressive disorders) and 93-2 (bipolar disorders). Readers who are less familiar with how to take a history to detect these disorders are encouraged to obtain some experience with one of the semistructured psychiatric diagnostic interviews such as the Structured Clinical Interview for DSM-IV or DSM-5 (SCID) (13), the Psychiatric Research Interview for Substance and Mental Disorders (PRISM) (12), or the Mini-International Neuropsychiatric Interview (MINI) (14). These interviews guide the clinician in how to ask about each of the symptoms and apply the DSM criteria, and practice using them constitutes an excellent training exercise.

TABLE 93-1 Synopsis of Diagnostic Criteria for DSM-5 Depressive Disorders and Important Issues to Consider in Diagnosing Depressive Disorders in Patients Who Are Using Drugs or Alcohol

Mood disorders, grouped into depressive disorders and bipolar disorders, consist of combinations of mood episodes (major depressive episode, manic episode, hypomanic episode, mixed episode). For detailed criteria, see the full DSM-5 criteria and accompanying discussion (10).

TABLE 93-2 Synopsis of Diagnostic Criteria for DSM-5

Bipolar Disorders and Important Issues to Consider in Diagnosing Bipolar Disorders in Patients Who Are Using Drugs or Alcohol

Bipolar disorders consist of combinations of mood episodes (major depressive episode, manic episode, hypomanic episode, mixed episode). For detailed criteria, see the full DSM criteria and accompanying discussion (10).

Depressive Disorders DSM-5 defines a major depressive episode (Table 93-1) as a period of persistent, relatively severe depression or pervasive loss of pleasure or interest in usual activities, with associated depressive symptoms (disturbances in weight, appetite, sleep, and energy, agitation or motor slowing, diminished concentration, feelings of worthlessness or guilt, thoughts of death or suicide), lasting at least 2 weeks, and that interferes with functioning. Persistent depressive disorder (dysthymia) is a period of milder but chronic depression lasting at least 2 years. Major depressive disorder is diagnosed when there have been one or more major depressive episodes. Major depression may occur as a single isolated episode, may run a chronic episodic course with multiple recurrences, or may be chronic and unremitting. Major depressive episodes may also be superimposed on a chronic dysthymic pattern. At its most severe case, there can be psychosis, often involving delusions of paranoia or guilt (eg, the patient begins to believe he or she has committed a terrible crime and will be punished). Risk factors for depressive disorders include a genetic component, as well as stress (eg, losses) and trauma. Thus, in taking a history, it is always important to ask about family history and about stressors and traumatic experiences. DSM-5 also requires that a depressive disorder is not caused by substance use (alcohol, drugs, or a medication) or a medical condition (eg, hypothyroidism or other systemic illnesses). Thus, a medical history and workup can be an important component of the diagnostic evaluation. Finally, when evaluating a patient presenting with a major depressive episode or a syndrome of dysthymia, it is important to review the history for past episodes of mania, hypomania, or mixed mood episodes (episodes containing both depressive and manic features simultaneously). The presence of one of these indicates that the patient has a bipolar disorder.

Bipolar Disorders Bipolar disorders consist of episodes of major depression or dysthymia, alternating with episodes of mania or hypomania, at some time during the lifetime course. Bipolar I disorder is diagnosed when there are one or more episodes of mania over the lifetime, although most such patients also have depressive episodes. Mania is a severe disturbance consisting of euphoric, expansive, or irritable mood, high energy, less need for sleep (eg, only a few hours per night), grandiose thinking (eg, believing one has special powers, religious revelations), and increased speech and activity level. Functioning is

severely impaired with disorganized, inappropriate behavior, and patients often become psychotic with hallucinations and delusions that may be grandiose (“I am the messiah”) or paranoid (“the CIA is after me”). Mixed states also occur, in which the patient meets criteria for both mania and major depression during the same episode. Bipolar II disorder describes patients with a history of hypomania and of major depressive episodes. Hypomania is a milder form of mania, without psychosis and with less functional impairment. In some cases, functioning may temporarily improve during hypomania, with high levels of productivity and creativity. In most cases of bipolar disorder, depressive episodes are predominant (particularly later in the course of the disorder), with less frequent mania or hypomania. Thus, patients with bipolar disorder often present with major depression, or dysthymia, and a careful lifetime history is needed to determine whether there have been past episodes of mania or hypomania. It is also useful to interview family members about this, since patients themselves often have little insight during mania or hypomania and may not experience these states as abnormal. As with depressive disorders, genetics, stress, and trauma are risk factors, so that family history and history of stress and trauma exposure are important. DSM-5 requires that drugs (particularly stimulants), medications, or medical illnesses that might mimic bipolar disorder symptoms (eg, hyperthyroidism) be ruled out.

Distinguishing Substance-Related Symptoms From Mood Disorders

Mood

The problem of distinguishing mood symptoms caused by substance intoxication or withdrawal or chronic exposure to substances, from independent mood disorders, is one of the pivotal challenges for clinicians working with substanceusing patients. Hence, it is a central focus of this chapter. Mood symptoms (eg, sadness, apathy, irritability, pessimism, hopelessness, fatigue, appetite changes, anxiety, insomnia or hypersomnia, euphoria, hyperactivity) are extremely common among patients with drug or alcohol use problems. Often, such symptoms are components of substance intoxication or withdrawal and will resolve with abstinence; in that case, the indicated treatment is aggressive treatment of the substance problem. At other times, the mood symptoms are components of an independent mood disorder that needs to be treated in addition to treating the substance problems. In between are the substance-induced mood disorders, where the mood symptoms exceed what would be expected from intoxication or withdrawal but cannot be established as independent.

Table 93-3 provides a summary of the overlap between symptoms of substance intoxication and withdrawal as listed in DSM-5 and symptoms of depressive and bipolar disorders. It is a worthwhile exercise to review the descriptions in DSM-5 (and the criteria) of the various substance intoxication and withdrawal syndromes. It is also important to consider the time courses of the intoxication and withdrawal syndromes. Intoxication syndromes typically resolve within hours of last substance exposure. Withdrawal syndromes typically resolve with a few days of last substance exposure, although there is greater variation across substances. Cannabis withdrawal, for example, may not begin until several days after cessation of cannabis and may last for 1 to 2 weeks.

TABLE 93-3 Similarities and Differences between DSM-5 Intoxication or Withdrawal Symptoms and Symptoms of DSM-5 Mood Disorders

Note: The table lists DSM-5 symptoms for intoxication or withdrawal from each of the main substance classes and shows where there is overlap with similar symptoms of DSM-5 depressive syndromes (major depression, dysthymia) in column 2 or bipolar syndromes (mania, hypomania) in column 3; column 4 lists intoxication and withdrawal symptoms that are not consistent with mood disorder symptoms and would be helpful to distinguish substance effects from mood disorders.

Abstinence or Initiation of Substance Treatment Improves Depression This point cannot be overemphasized. Studies among pre–DSM-5 defined

alcohol- (15–17), opioid- (18), and cocaine-dependent patients (19,20) have documented elevated scores on depression symptom scales that improve substantially after initiation of abstinence upon treatment entry, such as hospitalization for withdrawal management or initiation of methadone maintenance. Thus, initiation of treatment for the substance use problem and efforts to achieve abstinence should always be a first step in the treatment of a patient with co-occurring mood and SUDs.

Some Cases of Depression Will Persist Despite Abstinence or Substance Treatment This point deserves equal emphasis. Despite abstinence, or reductions in substance use, some cases of depression will persist. Evidence suggests that a careful clinical history can distinguish mood disorders that are independent of substance use and will persist in abstinence from those that will resolve with abstinence. For example, in a now classic series of studies, Brown and Schuckit (16,21) divided patients with DSM-defined alcohol dependence entering a 4week inpatient stay into those with no history of mood disorder, those with a “secondary” mood disorder (onset after the onset of alcohol use disorder), and those with a “primary” mood disorder (mood disorder onset prior to the onset of alcohol use disorder). All three groups had substantially elevated Hamilton Depression Scale (HDS) scores at the outset. After 1 to 2 weeks of abstinence, the groups with no mood disorder or a secondary mood disorder experienced reductions of over 50% in their HDS scores with scores dropping into the normal or mildly depressed range, no specific treatment for depression needed. However, in the group with primary mood disorder, there was no change in the depression scores over 3 weeks of abstinence, and two-thirds of those patients had HDS scores > 20 after 3 weeks of abstinence, consistent with severe depression. For these patients, aggressive treatment of the alcohol use disorder did not take care of the depression, and most clinicians and researchers would now agree that these patients with primary depression, identified with a careful lifetime psychiatric history, need to receive treatment for their depressive disorder, in addition to continued treatment for the alcohol use disorder.

PREVALENCE AND PROGNOSTIC EFFECTS OF CO-OCCURRING MOOD

AND SUBSTANCE USE DISORDERS Mood Disorders Among Patients Seeking Treatment for Substance Use Disorders Numerous studies have been published examining the prevalence of mood disorders among patients admitted to alcohol or drug treatment programs, mainly inpatient withdrawal management or rehabilitation units, outpatient programs, or opioid maintenance programs. Reviews of this literature (2) show lifetime prevalence rates of major depression ranging from 20% to 50%, with rates of current major depression in the 10% to 20% range, substantially exceeding rates found in the general population. These high rates of comorbidity may occur in part because depression may be a factor that motivates patients with SUDs to seek treatment. Bipolar disorder is less common in these samples, consistent with its low prevalence rate in the general population. Thus, clinicians seeing patients in these typical addiction treatment settings should expect to see high rates on co-occurring depression but should also remain alert for cases of bipolar disorder, mindful that bipolar disorder often presents as depression, and review of the past history is needed to identify past episodes of mania or hypomania.

Comorbidity of Mood and Substance Use Disorders in the General Population Table 93-4 summarizes the odds ratios of association between SUDs and mood and other psychiatric disorders, derived from three major community surveys— the Epidemiologic Catchment Area (ECA) Study (22), the National Comorbidity Survey (NCS) (23,24), and the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) (1,3). As can be seen in Table 93-4, odds ratios are at least 2.0 for most combinations of disorders, showing that the presence of an SUD at least doubles the odds of a mood disorder, or other disorders, being present. It is notable that the odds ratios for major depression and dysthymia (persistent depressive disorder) are similar. Thus, while dysthymia is often thought of as a mild version of depression, it should not be discounted in the clinical evaluation. The hallmark of dysthymia is its chronicity, and the presence of chronic depressive symptoms across the course of an SUD, even if the depressive symptoms are milder, should be taken seriously.

TABLE 93-4 Odds Ratiosa Reflecting the Strength of Association or Co-occurrence between Alcohol or Drug Dependence Disorders and Affective and Other Selected Disorders from Three Community Surveys

Note: Data taken from three community surveys: the Epidemiologic Catchment Area (ECA) Study, the National Comorbidity Survey (NCS), and the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC); odds ratio can be interpreted roughly as the multiple by which the prevalence of a disorder across the rows (major depression, dysthymia, etc.) is increased when alcohol or drug dependence is present, compared to individuals without alcohol or drug dependence. aECA and NCS report odds ratios on lifetime prevalences of co-occurring disorders; NESARC reports odds ratios on 12-month prevalences of co-occurring disorders. bFor these co-occurring disorders in NCS, odds ratios are reported for men and women combined. cFor NCS and NESARC, odds ratios are for bipolar I disorder with a history of full mania. dFor NESARC, odds ratios shown are for panic disorder with agoraphobia; odds ratios for panic disorder without agoraphobia were similar.

For bipolar disorder, the odds ratios are substantially larger than for major depression or dysthymia. When depressive symptoms are present, it is important to search the history carefully for past episodes of mania or hypomania, since bipolar illness has a particularly strong association with SUDs, and it has specific treatment implications that differ from those for unipolar depression.

Depression May Signal the Presence of ADHD, PTSD, or Other Disorders

As can be seen in Table 93-4, other common disorders, including attention deficit hyperactivity disorder (ADHD), posttraumatic stress disorder (PTSD), and other anxiety disorders, have odds ratios of association with SUDs that are as large as or larger than the associations for depressive disorders. These disorders are covered in detail in other chapters in this text. The point to make here is that these disorders often co-occur with depression, may be more easily distinguished from toxic and withdrawal effects of substances, and have distinct treatment implications. Thus, in patients with SUDs who present with depressive symptoms, it is important to look in the history for these other disorders. For common anxiety disorders (social phobia, panic disorder with or without agoraphobia, and PTSDs), which often co-occur with depression, the cardinal symptoms (fear of social interactions, spontaneous panic attacks and fear of public places, and re-experiencing symptoms triggered by reminders of traumatic events) are distinctive and not attributable to substance toxicity or withdrawal. Thus, the presence of one of these anxiety syndromes in a depressed person with an SUD strongly suggests the presence of an independent disorder, warranting specific treatment. Like depression, the anxiety disorders often respond to treatment with antidepressant medications, although they have distinct behavioral therapeutic indications. ADHD has strong associations with SUDs, with odds ratios of 2.8 and 7.9, respectively (25), as well as strong associations with major depression (odds ratio = 2.7), dysthymia (odds ratio = 7.5), and bipolar disorder (odds ratio = 7.4) (25). The symptoms of inattention and hyperactivity begin in early childhood and can often be recognized in the developmental history as problems with school performance in elementary school, well before the onset of drug or alcohol use. The symptoms, particularly poor attention and poor organization skills, often persist into adulthood and are responsible for substantial functional impairment and poor role performance during adulthood (eg, poor job performance, high divorce rate). This in turn lends itself to the development of depression. ADHD has distinct treatment implications, responding to stimulant medications, or guanfacine, as well as possibly to noradrenergic antidepressants. Antisocial personality is included in Table 93-4 to illustrate its strong association with SUDs. Patients with SUDs will often have antisocial features, but it is important to bear in mind that the presence of antisocial features, or disorder, does not rule out the presence of a mood or anxiety disorder, and in fact, they often co-occur.

Prognostic Effects A number of these studies have included a longitudinal follow-up, examining prognostic effects of co-occurring major depression on substance use outcome. A review of this literature (2) shows that studies examining a lifetime diagnosis of major depression (ie, major depression at any point during the lifetime) found little prognostic effect. In contrast, a current diagnosis of major depression has been consistently associated with worse outcome of substance use problems over follow-up periods ranging from 6 months to 5 years. This adverse prognostic effect holds for major depression diagnosed at an initial evaluation (26–29) and for major depression diagnosed during the follow-up period (30,31), among those with alcohol use disorder (28–32), methadone-maintained patients with opioid use disorders (26,27), and patients with cocaine use disorders (33). Another important pattern in the results from longitudinal studies is that depressive symptoms at the time of entry into treatment, as measured by an elevated score on a standard scale such as the Beck Depression Inventory (BDI) or HDS, have inconsistent prognostic effects (2). For example, in a study of inpatients with pre-DSM-5–defined alcohol dependence, Greenfield et al. (28) showed that an elevated HDS score at baseline was not associated with outcome across a 1-year follow-up, whereas a diagnosis of major depression at baseline did predict relapse to heavy drinking during follow-up. Dysthymia (ie, low-grade chronic depression) has received little study in terms of its prognostic effects on substance use outcome. However, there is some evidence that depressive symptoms have adverse prognostic effects when they persist during or after treatment of an SUD (34,35). This suggests that persistent depressive symptoms, even if not meeting criteria for major depression, should be taken seriously among patients with SUDs. Depressive symptoms among patients with cooccurring bipolar and alcohol use disorder have been associated with subsequent increased heavy drinking (36). Taken together, these data have clinical implications. Depression symptom scales such as the Beck or Hamilton can be useful as screening tools, but these need to be followed up with a careful clinical history, establishing the presence or absence of depressive disorder. A past history of a depressive disorder is an important component of a complete history, but it is current major depression that is most clearly associated with worse outcome among patients with SUDs and should be attended to in the treatment plan. Chronic low-grade depression (dysthymia) and depression that persists after initiation of treatment for the substance problem also warrant clinical attention.

Primary Care and Psychiatric Populations The majority of individuals with SUDs, depression, and other common mental disorders do not present at specialty treatment settings such as substance treatment programs. Instead, they often present at the offices of primary care physicians or other medical settings (37), where SUDs and depression are more likely to go undetected and may be associated with over- or underutilization of services and poor outcome (38). Patients may be unaware of these problems or may avoid discussing them with healthcare providers because of the considerable stigma attached to the idea of having a “psychiatric” problem. This presents an important challenge to addiction specialists, suggesting the need to reach out to these other settings with programs of screening and brief intervention (39). Among outpatients seeking treatment for depression in one large study (STAR*D), the prevalence of concurrent AUDs was 13% and drug use disorders 8% (40). Such rates are modest but exceed what would be expected in the general population. Among psychiatric inpatients, a more severely ill group, SUDs are common among both patients with major depression and bipolar disorder (41). Rates of current SUDs of 30% or higher have been observed among patients in treatment for bipolar disorder (5,41). The co-occurrence of mood and SUDs may be especially common among patients with serious cooccurring medical disorders such as HIV (42,43).

DIFFERENTIAL DIAGNOSIS Etiological Relationships Between Mood and Substance Use Disorders Behind the problem of how to diagnose and treat mood symptoms among patients with SUDs lies the issue that there are multiple different potential etiological relationships between mood symptoms or syndromes and SUDs. A summary of these is presented in Table 93-5, along with possible underlying mechanisms and implications for diagnostic assessment and treatment. A complete review is beyond the scope of this chapter, but each of these relationships and mechanisms has some evidence to support it.

TABLE 93-5 Summary of Possible Etiological Relationships between Co-occurring Affective Symptoms/Syndromes and Substance Use Disorders

There are two important clinical implications here. The first is to appreciate the potential complexity and to avoid viewing patients in simplistic terms during diagnostic evaluation. All mood symptoms are not caused by toxic and withdrawal effects of substances nor is all substance use a result of underlying psychopathology (as in “self-medication”). The second point is to be cautious in formulating causal mechanisms between co-occurring disorders. For example, when depression resolves with treatment of an SUD and establishment of abstinence, this is consistent with the inference that depression was a toxic effect

of substance use. However, it is also possible that there was an independent mood disorder that responded to supportive elements of the behavioral therapy used to treat the SUD, with the potential to re-emerge at some future point.

DSM-5 Primary Versus Substance-Induced Mood Disorders Versus Expected Effects of Substances (Intoxication and Withdrawal) Prior to DSM-IV, there were several classifications for co-occurring disorders in the literature. These included “primary” versus “secondary,” referring to the order of first onset—a major depressive disorder would be considered primary if its age at onset preceded the age at onset of an SUD or secondary if the SUD came first. “Primary” was also used in a more loose sense to convey causality— the primary disorder is the main disorder, which drives any secondary disorders. In DSM-III, an “organic mood disorder” could be used to categorize a mood disorder caused by substance use. DSM-IV and DSM-5 advanced the field by synthesizing pre–DSM-IV approaches to define primary (or independent) mood disorders and creating the new category of substance-induced mood disorder, which is in turn distinct from and exceeds in severity and duration the usual intoxication and withdrawal effects of substances. The DSM-5 criteria, and our interpretation of them, are summarized in Table 93-6. Because the DSM-5 criteria, as stated, leave some details vague, a suggested operationalization is also included in Table 93-6, based on data from the diagnostic approach taken by the PRISM interview and its demonstrated prognostic significance (12,31).

TABLE 93-6 Summary of DSM-5 Scheme for Classifying Co-Occurring Mood and Substance Use Disordersa and Suggestions for Operationalization of Criteria Based on SCID-SAC or PRISM Interviewsb

aFor a complete statement of the criteria, see DSM-5 section on substance-induced depressive disorder (10). bStructured Clinical Interview for DSM-5, Substance Abuse Comorbidity Version (SCID-SAC) (11); Psychiatric Research Interview for Substance and Mental Disorders (PRISM) (12).

Primary (Independent) Mood Disorder DSM-5 defines a primary or independent mood disorder as one that precedes the onset of substance use or persists during significant periods of abstinence (1 month or more is suggested as a rule of thumb). We have found that the historical data needed to establish these criteria (ages at onset, presence of periods of abstinence, and mood syndromes occurring during abstinent periods) can be determined with good reliability from a clinical history (11) and have established good reliability for the categorical diagnosis with both a modified

SCID (11) and the PRISM diagnostic interviews (12).

Substance-Induced Mood Disorder The category of substance-induced mood disorder was established to recognize the phenomenon of co-occurring mood syndromes that cannot be established as chronologically independent of substance use (hence, meeting the definition of primary), yet the mood symptoms seem to exceed what would be expected from the usual intoxication or withdrawal effects of the substance(s) a patient is taking. A typical example would be a patient with a long-standing, chronic history of heavy substance use, who also has a syndrome consistent with major depression that has occurred only during substance use, yet the syndrome seems substantial enough to warrant clinical attention and perhaps specific antidepressant treatment.

Distinguishing Substance-Induced Mood Disorder From Expected Effects of Substances Expected intoxication or withdrawal effects of substances, and their overlap with symptoms of mood disorders, are summarized in Table 93-3. DSM-5 clearly specifies that the symptoms of either a primary (independent) or a substanceinduced mood disorder must exceed the expected effects of intoxication or withdrawal from the substances the patient is taking (see Tables 93-1 to 93-3). The term “substance induced” is somewhat confusing in that it implies cause and effect (substances causing mood symptoms). Thus, clinicians commonly use “substance induced” to describe intoxication or withdrawal effects, when DSM-5 in fact excludes these from a diagnosis of substance-induced mood disorder. For this reason, we have recommended a more neutral term, such as “substanceassociated,” that might be considered to replace “substance-induced” (44). A substance-induced mood disorder should, according to the criteria, resolve if abstinence is achieved. However, it has been shown that if rigorous criteria are set for making the diagnosis (see Diagnostic Methods, below), a substantial proportion of such cases diagnosed as substance-induced major depression at an index evaluation will persist during future abstinent periods, thus in effect converting to primary major depression (6,45). Thus, substance-induced depression may be viewed as a sort of in-between category, where a mood disorder syndrome is present, but whether it is temporally independent of substance use (and hence primary or independent) is uncertain at the time of evaluation. This highlights the importance of identifying and following

substance-induced depression, as it may convert to primary (independent) depression over time and as efforts are made to reduce or eliminate substance use.

Diagnostic Methods and Predictive Validity One of the problems with the DSM-IV/5 approach is that the criteria are left vague in certain respects. For example, the criteria for substance-induced depression require only a persistent depressed mood or loss of interest, without any mention of associated depressive symptoms (eg, appetite, sleep, energy, etc.) nor how many symptoms need to be present. Table 93-6 summarizes the DSM-5 criteria in the first column and suggests further operationalized criteria in the second column, based on the PRISM interview (12,31). To make a diagnosis of substance-induced mood disorder, PRISM requires full criteria for a mood disorder (eg, major depression or dysthymia) to be met and that each symptom contributing to the diagnosis (eg, insomnia, loss of appetite, low energy) exceeds the expected effects of the substances that the patients are taking; the interviewer is referred to the DSM-IV criteria sets for intoxication and withdrawal syndromes for the various substances (see Tables 93-1 and 93-2 for symptoms likely to overlap between mood and substance intoxication/withdrawal). The PRISM interview has been computerized (http://www.columbia.edu/~dsh2/prism) and may be used as a clinical diagnostic instrument and a way for clinicians to gain experience with the history taking needed to evaluate DSM-IV/5 mood disorders among patients with SUDs. Evidence for the predictive validity of the operationalization of the diagnostic criteria reflected in the PRISM comes from a longitudinal study of patients with SUDs (alcohol, cocaine, or opioids) interviewed with the PRISM at an index hospitalization on a co-occurring disorder inpatient unit and then followed for 1 year (6,31). About half of this sample had current major depression syndromes. About half of these major depression syndromes were diagnosed as independent (or primary) and half as substance induced. A PRISM diagnosis of substance-induced major depression was associated with failure of the SUD to remit, while a diagnosis of independent (or primary) major depression during a period of abstinence over the follow-up period was associated with a greater risk of relapse to SUD (31). Both disorders were associated with suicidal behavior or ideation (46). Further, of those cases diagnosed with a current substance-induced major depression, more than half converted into an independent major depression over the 1-year follow-up by

being shown to persist during at least a 1-month period of abstinence (6). Another study, using similar diagnostic methods, found a similar high rate of conversion to independent depression over a longitudinal follow-up (45). When predictors of the likelihood of depression occurring over the course of the 1-year follow-up were examined, a past history of independent major depression and the presence of concurrent anxiety disorders were both associated with increased likelihood of depression (6). This highlights the importance of a thorough clinical history on the lifetime course of depression, as well as inquiring about anxiety and other common co-occurring disorders. Ries et al. (47) tested a much simplified method of operationalizing the DSM-IV approach to co-occurring mood disorders. Specifically, they created a Likert-type scale that asks the evaluating clinician, after completing the clinical history, to rate the degree to which a mood disorder is independent or substance induced. This is reminiscent of the approach taken by the Structured Clinical Interview for DSM-IV (SCID) (13), which includes a module for substanceinduced depression that simply asks the interviewer to make judgment based on the criteria. Mood disorders rated toward the substance-induced end of the spectrum on Ries’ Likert scale were more likely to remit but were also associated with suicidal ideation and risk (48). This work suggests that the judgment of experienced clinicians may be relied upon to make valid distinctions between substance-induced and independent mood disorders. However, experience with psychiatric diagnosis supports erecting criteria that are as objective as possible in order to maximize reliability and validity.

Diagnosing Bipolar Disorder in the Setting of Substance Use Disorder Intoxication with cocaine or other stimulants may resemble hypomanic or even sometimes manic symptoms in regard to irritability, grandiosity, hyperactivity, talkativeness, impulsivity, insomnia, and paranoia. The impulsivity of alcohol or sedative intoxication may occasionally also resemble that of mania (see Table 93-3). However, full-blown mania (see Table 93-2) must last for at least a week, during which the symptoms should be persistent, whereas symptoms of intoxication are usually intermittent. For example, in mania, high energy and other symptoms can go on for days despite little or no sleep. In contrast, in cocaine intoxication, these symptoms usually last a matter of hours after cocaine use and are followed by a crash with increased sleep and low energy. Further, the marked impairment or psychosis required for mania is usually well in excess of

what would be produced by intoxication. For example, cocaine intoxication may produce paranoia that lasts for a few hours and resolves during the crash period, whereas the psychosis characteristic of mania, often either paranoid or grandiose, is persistent over days and weeks. The nature of paranoid symptoms due to cocaine intoxication as opposed to mania is often distinct as well. For example, cocaine-induced paranoia symptoms are often focused on drug-related issues (“someone is coming to steal my drugs; the police are after me”), whereas manic symptoms may focus on special powers or more bizarre paranoid ideas (eg, ideas of reference). Hence, in establishing a diagnosis of mania, nature of symptoms, persistence of symptoms over time, and severity of impairment are key markers, as well as occurrence of the symptoms during clear periods of abstinence. Frank mania is distinctive, despite ongoing substance use. Hypomania, which involves the same core symptoms as mania but may be briefer (at least 4 days) and with less impairment in functioning, may be more difficult to distinguish from substance intoxication or withdrawal effects. The same is true with cyclothymia, which may be difficult to distinguish from alternating periods of intoxication and withdrawal, mimicking hypomanic and depressive symptoms, respectively (see Table 93-2). Thus, it is particularly important to try to establish episodes of the mood disturbances during periods of abstinence or predating onset of significant substance use, according to the DSM-IV criteria for independent mood disorder. Rapid-cycling bipolar disorder is diagnosed when there have been at least four mood episodes over the past 12 months, punctuated either by periods of remission or by switches in polarity (from mania to depression, or vice versa). On the order of 20% of cases of bipolar disorder are rapid cycling, and the pattern is associated with greater impairment and poorer response to treatment (49,50). Some evidence suggests that the rapid-cycling subtype is associated with increased prevalence of SUDs (51). Thus, it is important to look for this pattern in the history. However, as for hypomania or cyclothymia, a pattern or multiple switches in mood states become more difficult to distinguish from the ups and downs of substance intoxication and withdrawal. It is important to establish in the history that hypomanic or manic syndromes have persisted over days or weeks before switching to depression, as well as seeking to establish occurrence of the symptoms during periods of abstinence. Substance intoxication is likely to exacerbate the disinhibition and poor judgment associated with mania and is associated with poor medication adherence (52), which promotes relapse. Thus, patients who present to emergency departments or other acute psychiatric settings with worsening mania

are likely to also have SUD in the clinical picture. For most patients with bipolar disorder, particularly those who have had the disorder for an extended period of time, the clinical course predominantly consists of depression, with occasional episodes of mania or hypomania. Thus, in a depressed patient with an SUD, it is important to carefully review the past history for episodes of mania or hypomania. In patients with chronic SUDs, in whom it is difficult to establish the presence of independent mood symptoms, clear-cut episodes of mania or hypomania, because they are distinctive from the usual effects of substances, are valuable in establishing that a primary (independent) mood disorder is indeed present and in need of treatment.

Summary of Recommendations for Diagnosis of Co-occurring Mood Disorders The accumulated evidence suggests a number of steps that the clinician can take during the clinical history to make this differential diagnosis between primary (independent) mood disorders, substance-induced mood disorders, and usual intoxication or withdrawal effects of substances (Table 93-7). These include:

TABLE 93-7 Summary of Diagnostic and Historical Features Useful in Making the Differential Diagnosis of DSM-5 Independent Mood Disorder (as Opposed to Substance-Induced Mood Disorder)

Establishing the presence of a full DSM-5 syndrome (eg, major depression, dysthymia, hypomania) (12) Establishing that each of the component criteria that make up the diagnosis exceeds the symptomatology that might be expected from the substances the patient is taking (eg, insomnia in a stimulant user) (12) Establishing the relative ages of onset and offset of mood disorder episodes in relation to periods of active substance use, to determine whether the mood syndrome (including past episodes) precedes the onset of substance use or has persisted during abstinent periods (12) Probing for a history of serious suicide attempts (53) Probing for a history of PTSD and other co-occurring anxiety disorders (54) Probing the developmental history for early-onset anxiety disorders or ADHD Probing the family history for mood, anxiety disorders, or other nonsubstance disorders (53,55) Documenting response to past treatment efforts, including psychosocial/behavioral or medication treatments for substance use and for depression, as these data may guide treatment planning going forward

MANAGEMENT OF CO-OCCURRING MOOD AND SUBSTANCE USE DISORDERS Depressive Disorders Antidepressant Medication Effect of Antidepressant Medication on Outcome of Depression Antidepressant medication has been the most thoroughly studied treatment modality for co-occurring mood and SUDs with numerous placebo-controlled trials in the literature. Two meta-analyses (56,57) reached similar conclusions that antidepressant medication is more effective than placebo in improving outcome among patients with co-occurring alcohol use disorder and depressive disorder, with the evidence less clear among patients with cocaine or opioid use disorder (the latter may be due to fewer high-quality studies, as some studies found positive results and others have not). Nunes and Levin (56) identified 14 placebo-controlled trials that selected patients with depressive disorders (major depression or dysthymia) co-occurring with alcohol, cocaine, or opioid use disorders and conducted an in-depth analysis of depression outcome, substance use outcome, and moderators of medication effects. The effect size (Cohen’s d: standardized difference between means of HDS score at outcome between medication and placebo groups) for the effect of medication on depression outcome was 0.38 (95% confidence interval 0.18 to 0.58), a small- to mediumsized effect that is in the same range and that observed in clinical trials of medications for treatment of routine outpatient depression (58). The magnitude of the effect size was strongly related to placebo response—the greater the placebo response, the smaller the effect of medication.

Effects of Antidepressant Medication on Substance Use Outcome In the Nunes and Levin meta-analysis (56), among studies that showed medium to large effect sizes of antidepressant medication in improving depression outcome (Cohen’s d > 0.5 standard deviations) (59–64), an effect size in the medium range was also observed on outcome measures of self-reported quantity

of substance use (56), whereas among studies with smaller effects on depression outcome, the effect size for self-reported substance use outcome was near zero (65–72). Categorical outcome measures reflecting criteria for remission or substantial improvement in substance use showed significant but smaller superiority of medication over placebo and overall modest rates of remission. This suggests the conclusion that treatment of a co-occurring depression with antidepressant medication may be helpful in reducing substance use when the depression improves. Torrens et al. (57) cast a wider net in their meta-analysis and analyzed placebo-controlled trials of antidepressant medications for SUDs, dividing studies into those which did or did not require co-occurring depression and focusing on substance use outcomes. They found a significant favorable effect of antidepressant medication on drinking outcome among patients with cooccurring alcohol use disorder and depressive disorders, with equivocal findings for patients with co-occurring cocaine or opioid use disorder and depression, although they conclude that further research in each of these populations is needed.

Results of Recent Trials Placebo-controlled trials of antidepressants are published since these metaanalyses have produced a similar pattern of results, as have more recent metaanalyses (73,74). Several negative trials have been published that had high placebo mood response (eg, [75–79]), while several studies with low to moderate placebo response showed some evidence of beneficial effects, at least on depression outcome (80–82).

Association Between Mood Outcome and Substance Use Outcome In addition to the finding that beneficial effects of medication on substance use outcome were observed in trials that demonstrated larger effects of medication on mood outcome (56), some trials also reported the correlation between mood improvement and substance use improvement within the trial data set. In these analyses, the relationship between improvement in mood and improvement in substance use outcome is consistently strong and positive (63,66,72,79,81). One study was able to show clearly that mood improvement mediates the effect of medication on substance use outcome (63), but most of such trials lack this type of mediational analysis. These data suggest that depression and substance use outcomes are, at least in part, causally related and support the idea of concurrently treating both disorders.

Moderators of Antidepressant Medication Effect Nunes and Levin (56) in their meta-analysis also studied moderators of medication effect—that is, features of the trials that predicted greater or lesser effect of medication compared to placebo on the outcome of depression. These bear detailed discussion, because they are useful in developing guidelines for management of patients with co-occurring depression and SUDs (see Summary in Table 93-8).

TABLE 93-8 Factors (Moderators) Associated with Efficacy of Antidepressant Medications in Clinical Trials Among Patients with Co-Occurring Depression and Substance Use Disorders and Implications for Clinical Practice

Placebo Response Low placebo response rate was the strongest moderator of medication effect, accounting for approximately 70% of the variance in effect sizes across studies (56). Placebo response was quantified as the percent improvement in the HDS score between baseline and end of study in the placebo group of each respective trial. Studies with low placebo response rates (in the 20% to 30% range) showed large medication versus placebo differences. In contrast, about half the studies had high placebo response rates in the 40% to 60% range; for this group of studies, the effect sizes hovered around zero, meaning no benefit of medication over and above placebo. High placebo response in these studies may represent

improvement due to the background treatment that all patients receive, which in these trials involved some form of psychosocial treatment for the SUD. This is part of what underlies our recommendation that treatment of the SUD is a first priority in the management of patients with co-occurring depression and substance problems. Treatment of the SUD may, in many cases, result in improvement in both substance use and depression.

Antidepressant Response in Patients With Alcohol Versus Drug Use Disorders Consistent with the findings of Torrens et al. (57), Nunes and Levin (56) found greater evidence for efficacy of antidepressant medications among depressed patients with alcohol use disorders than among those with drug use disorders. Across studies of patients with drug use disorders (cocaine or opioid use disorders), there is more heterogeneity, meaning some studies demonstrating benefits of antidepressants and others do not. The studies of patients with drug use disorders tended to have high placebo response, whereas more of the studies of patients with alcohol use disorders had methodological features associated with low placebo response and larger medication effects, namely, diagnosis of depression during a period of abstinence, treatment with a tricyclic or other noradrenergic medications (as opposed to a selective serotonin reuptake inhibitor [SSRI]), and absence of a manual-guided psychosocial intervention. Notably, a recent trial of venlafaxine among patients with major depression and cannabis use disorder showed high placebo response and no difference between medication and placebo on mood outcome over and above placebo. However, venlafaxine actually made cannabis use outcome worse compared to placebo (78). Another recent trial recruited from people who used intravenous opioids not engaged in any treatment and tested a combination of cognitive–behavioral therapy (CBT) plus the SSRI antidepressant citalopram (86). The combined treatment was superior to an assessment-only control condition in terms of proportion achieving remission from depression, and remission was associated with adherence. Most people engaged in unhealthy opioid use are not engaged in any treatment, and this trial (86) is of particular interest because it suggests the potential of targeting depression as a way of engaging more such patients in treatment. It also suggests the utility of a combined pharmacological–behavioral treatment approach, which may have the potential to benefit more patients than either treatment alone.

Diagnosis of Depression During a Period of Initial Abstinence Four placebo-controlled trials were conducted among patients with alcohol use disorder, who were diagnosed after at least 1 week of abstinence from alcohol (59,61,62,64). These studies yielded medium to large effects of antidepressant medication on both depression and drinking outcomes. Three of those studies (59,62,64) worked with hospitalized patients with alcohol use disorder with relatively severe depressive disorders that were shown to persist after withdrawal management and enforced abstinence on the inpatient unit. This finding suggests that, when possible, an effort should be made to help patients initiate abstinence and observe the response of the depression during early abstinence, prior to initiating antidepressant medication. Depression that persists during an initial period of abstinence would be consistent with what DSM-5 would call a primary or independent depression. Greater severity of depression is also known to be associated with stronger effects of antidepressant medication in clinical trials. With the advent of managed care and cost containment, hospitalization, particularly of several weeks’ duration, is less of an option than it was when these antidepressant trials were conducted. Further, many patients will resist hospitalization or be unable to set aside work or family responsibilities to go into a hospital. Many of the studies in which patients were diagnosed on an outpatient basis implemented efforts to obtain a systematic clinical history in order to establish that depression was independent of substance use on a lifetime basis. Some of these studies observed significant benefits of medication (60,61,63,80,81), although others that applied similarly careful historical criteria and methods failed to observe benefits of medication (eg, [67,68]). A recent large clinical trial among outpatient DSM-IV–defined alcohol dependence required both a brief period (1 week) of initial abstinence and a DSM-IV diagnosis of independent major depression using the PRISM interview (see Table 93-6), yet a substantial placebo response rate and no clear advantage of medication are still observed (76). One possible explanation is that even independent major depression among such patients may often respond to the milieu and background psychosocial treatment offered as part of medication trials, resulting in high placebo response and less of a role for medication.

Class of Antidepressant Medication Each of the meta-analyses that examined class of medication as a factor (56,57,74) reached a similar conclusion that the evidence of efficacy for SSRIs is less robust than the evidence for efficacy of tricyclics, mainly desipramine or

imipramine, and other medications with mixed modes of action. Many of the negative studies with SSRIs also had high placebo response rates, which do not suggest an inherent lack of efficacy of the medication. Further, several of the largest effects of medication (vs. placebo) were observed with SSRIs, fluoxetine (62) or sertraline (64), among hospitalized patients with co-occurring alcohol use disorder and severe depression. Among placebo-controlled trials with patients with alcohol use disorder not selected specifically for depression, there is evidence that SSRIs may produce worse drinking outcome compared to placebo among patients with type B alcohol use disorder (high-risk/high-severity subtype). Type B is characterized by severe alcohol problems, high levels of externalizing psychopathology, and early onset of alcohol problems. In contrast, patients with less severe/late-onset alcohol use disorder (type A) may benefit from SSRIs (83,84,87). An analogous finding was obtained among patients with PTSD; sertraline produced worse drinking outcome among patients with severe alcohol problems and later-onset PTSD, while sertraline was superior to placebo among patients with early-onset PTSD and less severe alcohol problems (88). Another trial among veterans with PTSD and alcohol use disorder found desipramine superior to the SSRI paroxetine on drinking outcomes (89). Similarly, venlafaxine, an SSRI with some noradrenergic reuptake inhibition (SNRI), made cannabis use worse compared to placebo among patients with cannabis use and major depression (78), and cannabis use disorder typically has adolescent onset. Thus, it may be that SSRIs are less effective, perhaps even counterproductive in depressed patients with SUDs who have externalizing symptoms and/or early onset of SUD. In terms of clinical recommendations, SSRIs have the advantage of being generally well tolerated, with less potential for sedation or other adverse effects. In contrast, tricyclic antidepressants (TCAs) generate a number of concerns including risks of sedation, overdose, QT prolongation, and seizures. Thus, we would continue to recommend SSRIs as the first-line treatment and move to a non-SSRI antidepressant, such as venlafaxine, duloxetine, mirtazapine (90), or bupropion, or a TCA if the SSRI trial fails. The exception might be a patient with early-onset substance use and prominent externalizing symptoms or antisocial personality features, for whom the data suggest caution in the use of SSRIs.

Concurrent Psychosocial Intervention One of the more intriguing findings to emerge from the meta-analysis (56) was

that placebo-controlled trials that offered a manual-guided psychosocial intervention as the background treatment (ie, received by all participating patients) tended to have high placebo response rates and lesser medication effects (eg, Refs. 69–71). These were interventions for SUD, including various cognitive–behavioral interventions or 12-step facilitation. Such interventions generally have components that focus on managing mood symptoms and thus may have inherent antidepressant effects. Also, these interventions may help reduce substance use, which in turn improves mood. The recent multisite sertraline trial, also a negative study with a high placebo response rate, offered all patients a medical management type of intervention, which was manual guided and emphasized abstinence and treatment adherence (76). In terms of clinical recommendations, these findings reinforce the importance of initiating treatment for the SUD as the first step with any patient with co-occurring SUD and depression. Treatment of the SUD may be enough to produce improvement in depression.

Behavioral Treatments for Co-occurring Depression and Substance Use Disorders A number of controlled studies have been conducted of psychosocial treatments for depression among patients with SUDs. These studies support the effectiveness of behavioral therapies for treatment of co-occurring depression and SUDs. A recent systematic review of studies of cognitive–behavioral treatments for concurrent depression and substance problems concluded this approach has promise, but more research is needed (91). A recent meta-analysis of controlled trials of combined CBT and motivational interviewing for patients with alcohol use disorder and major depression found small but significant effect sizes for improvement of both mood and alcohol outcome (92). Some of these are technology-based interventions, delivered over the Internet, not requiring an expert therapist, and thus have considerable potential for widespread dissemination (93). The community reinforcement approach (CRA) combined with voucher incentives is arguably the most effective behavioral treatment for SUDs. It is of interest in regard to treatment of depression because it emphasizes increasing a patient’s experience of reward and increasing pleasant activities (eg, family, friends, work, recreation). This has much in common with the behavioral activation component of CBT for depression (94). Several trials suggest the promise of CRA with voucher incentives for treatment of co-occurring SUDs

and depression (95–97). Behavioral activation itself has been tested in a small controlled trial among patients with co-occurring drug use disorders and depressive symptoms and found superior to a treatment as usual control on outcome of mood symptoms (98). Referral to self-help groups such as Alcoholics Anonymous is a standard practice in treatment of SUDs. A 12-step facilitation was among the background treatments associated with high placebo response in the antidepressant trials reviewed above (56). One observational study suggests that participation in Alcoholics Anonymous may reduce suicide risk (99). On the face of it, 12-step groups contain elements including social support that would seem likely to benefit both depression and substance problems among individuals who become engaged in the groups.

Medication Treatments for Substance Use Disorders Effective medications, such as disulfiram, naltrexone (100,101), buprenorphine, or methadone, should also be considered in the treatment of patients with cooccurring depression and SUDs. The importance of initiating effective treatment for the SUD among patients with co-occurring depression has already been emphasized, and these medications are highly effective in reducing substance use. For example, depressive symptoms decrease substantially during the first 1 to 2 weeks of methadone maintenance treatment for opioid use disorder (18), and about half of major depressive syndromes in patients presenting for methadone maintenance can be expected to resolve during those initial weeks of treatment (63). Naltrexone and disulfiram were both shown to be safe and effective among patients with co-occurring alcohol use disorder and psychiatric disorders, including major depression (100,101).

Combining Medications for Depression and Substance Use Disorder A recent controlled trial among patients with co-occurring DSM-IV-TR–defined alcohol dependence and major depression found the combination of the antidepressant sertraline plus naltrexone superior to either medication alone or placebo on drinking outcomes (102). A small pilot trial found the addition of disulfiram to imipramine useful in patients with co-occurring depression and alcohol use disorder whose drinking did not respond to imipramine alone (103). These findings suggest the potential utility of combining medications for depression with medications for SUDs.

Adolescents and Treatment of Co-occurring Depression and Substance Use Disorder SUDs often have their onset in adolescence, as do mood disorders, and the combination is associated with expected risk factors such as physical or sexual abuse (104) and with worse clinical outcome (105). Effective intervention early in the course of these disorders has the potential to improve functioning during adolescence and prevents progression to chronic mood and substance use problems during adulthood. Treatment research on mood and SUDs in adolescents is limited. Controlled trials of antidepressant medication treatments among depressed adolescents (not selected for SUDs) have produced mixed results, often with high placebo response rates. An NIH-sponsored, multisite, randomized two by two trial of fluoxetine and CBT found fluoxetine superior to placebo on depression outcome, with the best outcome overall for the group receiving both fluoxetine and CBT (106,107). Several open-label trials support the effectiveness of fluoxetine for adolescents with combined depression and SUDs (105,108). In a placebocontrolled trial of fluoxetine among adolescents with depression and an alcohol use disorder (77), no difference in outcome between medication and placebo was observed. However, all patients in this trial received intensive CBT and motivational enhancement therapy (MET), and significant improvement from baseline in both depression and drinking was observed in the placebo group, as well as the group that received fluoxetine. In the other trial, adolescents with SUDs, major depression, and conduct disorder (CD) were randomized to fluoxetine or placebo while all received CBT; fluoxetine was superior to placebo on one of the two main depression outcome measures. The placebo response rate was high, with substantial overall improvements in depressive symptoms, conduct disorder symptoms, and self-reported substance use in both fluoxetine and placebo groups; fluoxetine was not superior to placebo on any of the substance use outcome measures, and in fact, urine toxicology outcome was slightly better on placebo than on fluoxetine (82). These two studies support the effectiveness of combined fluoxetine and CBT for treating adolescents with combined depression and SUDs. However, the high placebo response rates observed in both these trials echo the finding among trials in adults that included a manual-guided intervention as the platform treatment (56) and suggest manualguided psychosocial treatments like CBT alone may be effective for many depressed, substance-using adolescents. The lack of a favorable fluoxetine effect on substance use outcome, observed here, is also reminiscent of concerns,

deriving from trials in adults, about poor substance use outcome with SSRIs among those with type B alcohol use disorder (see discussion in section “Class of Antidepressant Medication”). Type B is characterized by early onset of alcohol problems and externalizing psychopathology; these adolescent samples had early onset (by definition) and in one trial also carried diagnoses of conduct disorder. The results are also consistent with the observation from the metaanalysis (56) that the effect of medication on depression may be more robust than the effect on substance use outcome.

Late Life and Treatment of Co-occurring Depression and Substance Use Disorders Although often thought of as a disease of the youth, SUDs occur in the elderly and may be an underrecognized problem in this population. The pattern of substances used may differ, with more alcohol and prescription drug problems among the elderly, often undiagnosed and untreated (109,110). In addition to depression among the elderly, problems with sleep and painful medical conditions, prompting prescriptions of tranquilizers or narcotic analgesics, may contribute. Sleep problems and pain need to be treated, but clinicians working with the elderly should take a careful history for risk factors (eg, past history and family history of substance use problems), proceed cautiously, warn patients of the risks and warning signs of addiction, and monitor patients for the development of warning signs, such as development of tolerance, escalating dose, and substance-related impairment. As patients with SUDs who are under treatment age, for example, among methadone-maintained patients, the diseases of aging, such as cardiac and pulmonary disease and arthritis, become more prevalent along with depression and other psychiatric disorders, complicating clinical management (111). Importantly, identification and effective treatment of depression (either with pharmacotherapy or behavioral therapy) may improve sleep, pain tolerance, and general functioning and in that instance could be expected to reduce the need for other prescription medications. Research on treatment of SUDs and co-occurring substance use and depression among the elderly is limited, but results to date are encouraging in suggesting that treatment methods developed for young and middle-aged adults can be cautiously extrapolated to the elderly. Findings include that alcohol intake at treatment outset does not interfere with the treatment of depression (112) and that depression and drinking outcome tend to be correlated (112,113). Since these elderly patients with co-occurring disorders are most likely to present in

primary medical or psychiatric care settings, a major challenge is to improve screening and intervention. One large trial showed that an integrated model of care (care for depression and SUDs within primary care) was superior to a referral-based model in promoting engagement in treatment of depression and alcohol problems (114).

Suicidal Behavior Depression/Substance Use

and

Co-occurring

Depression and substance use are both important risk factors for suicide, and thus, the potential for suicide needs to be carefully assessed in any patient presenting with this combination of disorders. Recent evidence suggests that both DSM-IV independent and substance-induced depression are associated with increase of suicidal thinking and behavior among patients with SUDs (46,48,53). Other common risk factors for suicide such as family history of suicide, history of trauma, history of irritability or violence, current support systems, and physical illness should also be evaluated (115,116). In recent years, considerable concern has been aroused by reports of antidepressants being associated with increased risk of suicide, particularly among adolescents and young adults, resulting in the addition of explicit warnings being added to the prescribing information of these medications. Certainly, suicide risk (thinking, intent, and behavior) needs to be followed carefully in any depressed patient with a SUD during a course of treatment, whether or not it was present at baseline. A general consensus, based on recent data (117,118), is that the benefits of antidepressant treatment (in terms of improved symptoms) outweigh the risks, although exacerbations of suicidal thinking or behavior may occur, and patients should be informed and closely monitored. Among patients with co-occurring depression and alcohol use disorder admitted to an inpatient unit, most of whom had substantial suicidal thinking at admission, treatment with fluoxetine improved depression and drinking outcome, and there were no suicide attempts (62).

Interventions at the Level of Service Delivery and Primary Care Most patients with depression, substance use problems, or both depression and substance use problems present to primary care physicians or to treatment providers in settings such as emergency rooms or primary care clinics (rather

than to specialty practitioners or treatment providers in specialty clinics). Given evidence from randomized controlled trials supporting the effectiveness of treating depression among patients with SUDs, an important challenge is how to translate this finding into a program of care that is effective and can be implemented in primary healthcare settings where the majority of such patients with mood depression and/or substance use problems are seen. Watkins et al. (119) conducted a group-level randomized trial in which over 20,000 patients participating in managed care organizations were screened, and those screening positive for depression were randomly assigned to usual care or to one of two quality improvement programs, one focusing on implementation of antidepressant medications and one focusing on implementing psychotherapy for depression. The primary care clinics at which these patients were treated were randomized to usual care or to implement one of the two quality improvement programs. For patients with both depression and substance use problems, both quality improvement programs were associated with increased likelihood of prescription of antidepressant medications and improved depression outcome compared to usual care. In the STAR*D study, where over 2,000 depressed patients in primary care psychiatric or medical settings were treated openly with citalopram, the rate of depression response was just as good among those patients with SUDs compared to patients without SUDs, although there was a somewhat lower rate of remission of depression (120). These studies suggest that efforts to increase treatment of combined depression and substance misuse in primary care settings would have favorable effects and should encourage more efforts to develop programs of screening and intervention in primary care settings. Another important question is whether patients with combinations of psychiatric and SUDs benefit when services for both problems are integrated into one treatment program, as opposed to a model in which psychiatric and substance problems are treated at separate programs. One large randomized trial found integrated services for patients with depression or problematic alcohol use resulted in superior outcome compared to a model in which patients were referred out to separate clinics for each problem (114). Whether services are best delivered with an integrated model or through referral out to specialty clinics depends on the availability of integrated services and the severity and complexity of each component problem. Referrals can also be effective, especially when efforts are made to enhance communication between treatment teams and different programs (121).

Depression and the Treatment of Nicotine/Tobacco Use Disorder The prevalence of nicotine use disorder (mainly smoking) is increased among patients with mood disorders and is very high among patients with SUDs. Yet, nicotine use disorder is often overlooked during the evaluation and treatment of both mood disorders and SUDs—perhaps because it does not cause immediate impairment in the same way as mood or drug and alcohol problems or perhaps staff are fearful of increased patient behavioral problems, including against medical advice discharges, should smoking be prohibited during treatment. Nonetheless, nicotine use disorder should be a focus of treatment planning, due to its substantial adverse long-term effects on health. Evidence on the cooccurrence of nicotine use disorder and depression also serves to illustrate the potential complexity of co-occurring psychiatric and SUDs. Interest in this comorbidity began, in part, with observations that a history of major depression was common among patients seeking treatment to quit cigarette smoking and that a history of depression was an adverse prognostic factor, predicting lower likelihood of successfully quitting smoking (122). Case histories, and a subsequent series, documented the emergence of severe depression after quitting smoking, which resolved only when smoking was resumed, suggesting that nicotine may function like an antidepressant medication for some patients (123). Studies suggest that treatment for nicotine use disorder is effective among patients with depression (124). However, few studies have evaluated the treatment of current depression among patients with nicotine use disorder, and in fact, current major depression has been an exclusion criterion from most clinical trials of treatments for nicotine use disorder. Clinical trials of treatments for nicotine use disorder have often examined the history of major depression as a moderator, also with surprising findings. These include the finding that noradrenergic antidepressant medications bupropion and the tricyclic nortriptyline are effective agents for treating nicotine use disorder, but their effect does not appear to depend upon a history of depression (85,125). For example, in a two by two trial, patients with nicotine use disorder were randomly assigned to nortriptyline or placebo and to either a cognitive–behavioral treatment or a control psychotherapy, and the patients were stratified into those with and without a history of major depression; a history of major depression was not associated with greater effectiveness of nortriptyline, although it was associated with a greater effectiveness of the cognitive therapy; further, analysis of mediators suggested that nortriptyline was having its

beneficial effect by reducing the initial dysphoria experienced by patients after they quit smoking (85). Thus, this would appear to be an example of an antidepressant medication having a beneficial effect on substance-induced mood symptoms. Several other studies have suggested addition of CBT for depression to nicotine use disorder treatment improved smoking outcome among patients with histories of major depression or greater severity of depression symptoms (126,127). Reminiscent of the questions raised above about the effectiveness of SSRI antidepressants among patients with SUDs, a recent meta-analysis suggests SSRIs are ineffective for nicotine use disorder (128). For example, fluoxetine has been found to be ineffective as treatment for nicotine use disorder (129) or perhaps even counterproductive (130). An exception is that one trial did find evidence of a beneficial effect of fluoxetine among smokers with more severe depressive symptoms at the outset of treatment (131).

Summary of Treatment Recommendations for Cooccurring Depression 1. Treat the substance use disorder. For any patient presenting with drug or alcohol problems, an important priority is to address the SUD. This can be easy to overlook when a clinician is called to consult about depression or when the patient is most bothered by the depressive symptoms. Substantial evidence, across substances, shows that treatment of SUDs, especially if abstinence is achieved, is associated with improvement of depressive symptoms. The full range of treatment options should be considered, including different levels of care, evidence-based behavioral interventions, as well as medications (eg, disulfiram, naltrexone, buprenorphine). 2. Evaluate the mood symptoms and look for other commonly co-occurring disorders (eg, PTSD, ADHD). Screening for depression can be accomplished during a review of systems in the initial clinical interview or with an instrument such as the BDI or the Patient Health Questionnaire (PHQ-9) (132). Patients who screen positive should be followed with a more in-depth psychiatric history, according to the DSM-5 (see Tables 93-6 and 93-7), to arrive at a diagnostic assessment of independent depressive disorder, substance-induced depressive disorder, or depressive symptoms as usual effects of substances. The history should be probed for evidence of bipolar disorder (history of mania or hypomania), since the treatment approach for bipolar disorder differs from that of depressive disorders, as

well as severity of depression and suicide risk, as these will influence the urgency with which treatment of depression is initiated. Other disorders that frequently co-occur with depression, including PTSD, other anxiety disorders, and ADHD, should also be explored in the history, as these also have distinct treatment implications. 3. Treat the depression and other co-occurring disorders. As the evidence reviewed above shows fairly clearly, primary or independent (as defined by DSM-5) major depression or dysthymia (persistent depressive disorder) among patients with SUDs should be treated. A guideline such as the Texas Medication Algorithm Project (TMAP) (133,134) can be applied to select antidepressant medications. Evidence-based behavioral therapies such as CBT or related approaches, as reviewed above (eg, behavioral activation, the community reinforcement approach), have also shown promise. Behavioral therapies avoid the potential for medication–substance interactions. Thus, it is worth considering as a first-line treatment for depression if personnel trained in the delivery of effective methods are available. To the extent that the depression is more severe with greater symptom levels, impairment, or suicide risk, medication should be preferred as the first-line treatment, perhaps in conjunction with behavioral treatment. The TMAP algorithm (133,134) recommends SSRI antidepressants as the first line of treatment due to their good tolerability and evidence of efficacy, unless the patient has a history of failure to respond to past adequate trials. However, as reviewed above, some evidence suggests SSRIs may be ineffective or even counterproductive for some patients with co-occurring substance and depressive disorders. TCAs have the most consistent evidence of efficacy from the clinical trials reviewed, although their side effect profile makes them less than ideal for patients with SUDs, including risk for overdose in the setting of opioid use disorders. Other medications with noradrenergic or mixed modes of action, such as venlafaxine, duloxetine, mirtazapine, or nefazodone, should be considered, mindful that fewer clinical trials have tested these agents for treatment of combined substance and depressive disorders. If other cooccurring disorders are present, such as bipolar disorder, anxiety disorders, or ADHD, these need to be considered in the treatment plan.

Bipolar Disorder Pharmacological Treatments

Overview of Medication Treatment for Bipolar Illness Pharmacological treatment is the mainstay of the treatment of bipolar disorder. More complete reviews of the pharmacological management of bipolar disorder can be found elsewhere (135,136), and the TMAP is a useful guideline (137). Briefly, this can be divided into the management of acute mania or hypomania, the management of bipolar depression, and maintenance medication to prevent relapse once acute episodes have resolved or improved. Management of mania or hypomania: Acute mania is typically treated with both a mood stabilizer (lithium, or an anticonvulsant) and an antipsychotic. Mood stabilizers that are FDA approved for treatment of mania include lithium and the anticonvulsant valproate, although carbamazepine and other anticonvulsants have evidence of efficacy as well. The combination is often preferable because mood stabilizers take longer time to work, while the antipsychotic medications work rapidly and are particularly useful in exerting rapid control over acute manic symptoms such as racing thoughts, agitation, and insomnia, as well as psychosis. Antipsychotic medications of both the first generation (eg, chlorpromazine, haloperidol, perphenazine) and second generation (such as risperidone, olanzapine, quetiapine) are effective. Frank mania is a medical/psychiatric emergency due to the potential for psychosis and/or severely impaired judgment, either of which can lead to dangerous and self-destructive behavior. Patients with mania often have little or no insight into their condition and may be uncooperative. Thus, these patients should be brought to an emergency room for acute pharmacological management and often need hospitalization to fully establish mood stabilization. Disordered substance use often accompanies acute mania or hypomania, and brief hospitalization can begin to bring this under control as well, establishing initial abstinence, and evaluating the relationship between manic symptoms and substance use. For maintenance treatment after an acute manic episode, mood stabilizers are the mainstay of treatment, with both lithium and valproate having solid evidence of efficacy in preventing relapse. Other anticonvulsants including carbamazepine and lamotrigine have evidence of efficacy as well. Valproate has been favored in recent years, perhaps because lithium has a narrow therapeutic window with serious toxicity and death if the levels become too high, thus requiring careful monitoring and a reliable patient with low risk of overdose. However, lithium is often uniquely effective and appears to reduce the risk of suicide; it should thus be considered in cooperative patients or in those with a significant other who can be involved to help monitor medication taking. Antipsychotics are less desirable

as maintenance treatments because of significant side effects that can develop with chronic use, including tardive dyskinesia, weight gain, and metabolic syndrome. However, an antipsychotic often proves necessary, in conjunction with mood stabilizers, to maintain stable mood. Antipsychotics, taken at bedtime, provide a nonaddictive alternative to benzodiazepines for sleep— insomnia is a typical symptom of mania or hypomania and is also often a chronic issue among patients with bipolar disorder. During chronic antipsychotic treatment, clinicians should monitor the motor examination and metabolic parameters, including body mass index and serum glucose and triglycerides. Three antipsychotics are available as long-acting depot injections: haloperidol (Haldol Decanoate), prolixin decanoate (Prolixin), and risperidone (Risperdal Consta). While rarely used as the sole treatment, the long-acting injections are especially useful, in combination with mood stabilizers or oral antipsychotics, for patients who struggle with medication adherence or in whom relapse is regularly preceded by discontinuing medication. The long-acting injection guarantees that at least some mood stabilizing medication is on board, even if the patient stops the other medications, and this can attenuate the severity of the mood relapse and facilitate intervention. Substance use disorder is more likely to occur in manic or hypomanic episodes than in depressive phases of bipolar illness (138), although it can certainly occur in conjunction with depression or during periods of euthymia (normal mood) as well. Hence, clinicians need to be prepared to medically manage acute intoxication or withdrawal. Management of Bipolar Depression: In most cases of bipolar disorder, depression is the predominant mood disturbance, with mania or hypomania occurring less frequently. Also, bipolar disorder patients are more likely to present for treatment of depression because depression is painful, whereas mania or hypomania can sometimes (but not always) be experienced as pleasurable, or the patient lacks insight into the adverse consequences of mania. Thus, as noted previously, it is very important to review the history of a depressed patient for evidence of past episodes of mania or hypomania or family history of bipolar illness. The management of bipolar depression differs significantly from the management of unipolar depression. Antidepressant medication, either given alone or in combination with antipsychotics or mood stabilizers, may be less effective than once thought (139) and may be detrimental, inducing/promoting mania, mixed mood states, or cycling of mood from mania to depression. Patients with bipolar depression often respond best to a mood stabilizer (lithium or anticonvulsant) and combination of a mood stabilizer with a low to moderate

dose of a second-generation antipsychotic—for example, risperidone (Risperdal), olanzapine (Zyprexa), quetiapine (Seroquel), ziprasidone (Geodon), aripiprazole (Abilify), or lurasidone (Latuda). Antidepressant medication may be considered if depression persists and mood stabilizer or neuroleptic treatment is established. Some research has established the efficacy of lamotrigine for bipolar depression (140). Lamotrigine may cause life-threatening skin reaction (StevensJohnson syndrome), and thus, the medication should be started at low dose (25 mg) and titrated slowly to the target dose range of 100 to 300 mg/d, with careful monitoring for dermatological reactions. However, once a maintenance dose is established without skin problems, lamotrigine is generally well tolerated and often quite effective in treating bipolar depression and preventing relapse. Omega-3 fatty acids, such as contained in fish oil, flaxseed, or some other vegetable oils, may be useful as adjunctive treatment to exert mood stabilizing effects and prevent relapse in bipolar illness (141). Hence, nutritional supplementation with fish or flaxseed oil may be considered as part of long-term management. A recent meta-analysis (142) showed that quetiapine and combined olanzapine and fluoxetine have been particularly successful in treating bipolar depression.

Medication Treatments for Co-occurring Bipolar and Substance Use Disorders Medications for Bipolar Disorder Compared to unipolar depression, there has been less research focused specifically on pharmacotherapy for co-occurring bipolar disorder and SUD, but some studies have been conducted and several detailed reviews are published (143,144). Only a handful of double-blind, placebo-controlled trials have been conducted of mood stabilizing anticonvulsant medications. Salloum et al. (145) showed in a double-blind trial among individuals with co-occurring bipolar and SUDs that valproate combined with lithium was superior to lithium plus placebo in reducing the number of heavy drinking days. In another well-designed, placebo-controlled trial among hospitalized adolescents with bipolar and SUDs, lithium improved both mood and substance use outcome (146). A third placebocontrolled trial examined carbamazepine among patients with cocaine use disorder with or without co-occurring mood disorders (147); the mood disorder group included both major depressive disorder and bipolar disorder, many of those being bipolar II; among the subgroup with mood disorders, carbamazepine improved depression outcome with a trend toward reduced cocaine use as well,

while the medication had no significant effects in the subgroup without mood disorders. Other open-label trials of anticonvulsant mood stabilizers among patients with SUDs and bipolar disorder have also shown evidence of good tolerability and efficacy, including lamotrigine (148,149), valproate (150,151), and gabapentin (152). Anticonvulsants have been studied as treatments for SUDs, based on hypotheses of beneficial effects on the pathophysiology of addiction (eg, augmentation of GABAergic inputs to the brain reward system). For example, substantial clinical trials suggest the efficacy of topiramate (153) and gabapentin (154) for alcohol use disorder, and a small trial suggests promise for topiramate (155) for cocaine use disorder. The evidence is unclear as to the efficacy of topiramate or gabapentin as treatment for bipolar disorder, but it does seem to be effective at reducing appetite and body weight among bipolar patients (156). Second-generation neuroleptic medications have also shown promise among patients with co-occurring substance use and bipolar disorders, including small open-label, uncontrolled trials on quetiapine (157) and aripiprazole (158). Quetiapine has been the subject of three randomized clinical trials. A doubleblind, placebo-controlled trial of quetiapine (up to 600 mg/d), added to other mood stabilizers in patients with bipolar disorder (mainly depressed) and SUDs (mainly alcohol), showed quetiapine superior to placebo on depression outcome; there was no main effect of quetiapine treatment on substance use outcome, but improvement in drinking outcome measures did correlate with improvement in depression scores (159). A second study (160) of quetiapine as an adjunct to either lithium or divalproex therapy for this population showed no benefit over placebo in drinking outcomes. Finally, a more recent study (161) compared quetiapine versus placebo in 90 patients with bipolar disorder and alcohol use disorder who were already taking a mood stabilizer. Quetiapine offered no advantage over placebo either in alcohol-related or mood outcomes. Taken together, the results of these trials resemble the larger literature on antidepressant medications among unipolar depressed patients (56) in suggesting that appropriate pharmacological treatment of a carefully diagnosed co-occurring DSM-IV/5 independent mood disorder improves mood symptoms, and in some studies, substance use improves as well. In each of the controlled trials, steps were taken in the diagnostic workup to establish the presence of an independent bipolar disorder (according to DSM-IV criteria), either through establishing persistence of mood symptoms during abstinence on an inpatient unit (146) or through a careful history (145,147). The same caveat applies that medication treatment of the mood disorder is generally not likely to adequately or fully treat

the SUD, so that specific attention in the treatment plan to behavioral or medication treatment for SUD also needs to be considered.

Medications for Substance Use Disorders There is little evidence regarding the use of medications for targeted treatment of SUDs among patients with bipolar illness. However, as a general principle, if a medication is indicated (eg, methadone or buprenorphine for opioid use disorder or naltrexone for alcohol use disorder), it should be initiated with careful monitoring. Cautions include the fact that disulfiram, arguably the most potent medication for preventing relapse to alcohol use disorder (when a significant other can be engaged to monitor the medication), has been associated in rare cases with episodes of psychosis, perhaps due to its action of inhibiting dopamine beta-hydroxylase, which increases brain dopamine levels (162). However, disulfiram and naltrexone have both been used safely and effectively in patients with co-occurring alcohol use disorder and other severe mental illness (including bipolar disorder) (100). An open-label trial suggested that naltrexone, an effective treatment for alcohol use disorder, was safe and associated with both improved mood and improved alcohol use among patients with co-occurring bipolar and alcohol use disorder (163); the majority of patients in that trial were depressed at the outset. A follow-up to this trial, a double-blind placebo-controlled trial with 50 patients, demonstrated a statistically nonsignificant trend favoring naltrexone on the outcome of drinking days (164). A cautionary note, however, has been sounded by a report of two cases in which treatment with naltrexone in patients with mania and concurrent alcohol use disorder was poorly tolerated, producing marked nausea (165). Similarly, in the open trial of naltrexone (163), more of the patients who dropped out had mania or hypomania. New-onset hypomania has been observed in a patient with opioid dependence after withdrawal management and induction onto naltrexone (166). This suggests that clinicians should carefully monitor patients with co-occurring bipolar and alcohol use disorders for side effects or clinical worsening when using naltrexone. Finally, one study has been conducted using acamprosate for 33 patients with co-occurring bipolar disorder and alcohol use disorder; this trial showed no benefit of acamprosate over placebo regarding drinking outcomes (167).

Other Medication Approaches An intriguing and potentially promising medication for the treatment of patients

with bipolar disorder and co-occurring SUDs is citicoline (cytidine-5′diphosphate choline [CDP-choline]), a mononucleotide consisting of choline, cytosine, pyrophosphate, and ribose. Citicoline increases incorporation of phospholipids into membranes, enhances synthesis of structural phospholipids, and has been studied as a treatment for ischemic stroke, Parkinson disease, traumatic brain injury, and glaucoma. Citicoline may increase production in cholinergic brain neurons of acetylcholine, a substance thought to be important in learning and memory. Similarly, in elderly patients with mild cognitive impairment, citicoline treatment produced greater improvements in verbal memory. Citicoline has been examined in three separate studies of patients with bipolar disorder and stimulant use disorders. A small, proof-of-concept study (N = 44) of those with bipolar disorder and cocaine use disorder found that patients receiving citicoline were significantly less likely than those receiving placebo to have a cocaine-positive urine test at the end of a 12-week study (168). In a larger subsequent study (N = 130), those receiving citicoline had better cocaine use outcomes, particularly early in treatment (169). A study of citicoline in depressed patients (including those with bipolar depression) with DSM-IV-TR methamphetamine dependence (N = 60) showed a beneficial effect of citicoline on depressive symptoms but not on methamphetamine use (170).

Behavioral Treatments While medications are essential for treating most cases of bipolar disorder, the behavioral approach to the patient is also important to successful management. The goals of behavioral and psychosocial treatment for bipolar disorder include (a) maintaining a treatment alliance and continuity of care, (b) securing adherence to medication treatment, and (c) coping with symptoms and addressing stressors or other circumstances that may lead to symptomatic exacerbations (171,172). An SUD may undermine each of these goals, and thus, an important related goal is to identify and address substance use problems. Bipolar disorder generally runs a chronic, if waxing and waning, course, and maintaining continuity of care is an essential challenge. Patients may become impulsive or lose insight into their illness, particularly during manic or hypomanic phases, or lose sight of the need for ongoing treatment during periods of remission or relative quiescence of symptoms. Poor adherence to medications is a frequent cause of relapse and poor outcome in bipolar disorder. Patients may be bothered by side effects of medications. Patients may miss certain aspects of their mood fluctuations that are blunted by mood stabilizing medications. While this is particularly true of manic or hypomanic phases that are often experienced

as pleasurable, some patients with bipolar disorder ironically resist the blunting of depressed mood as well, viewing their depression as a reflection of their “true” feelings. Finally, stressful life events, such as family conflict, and irregularity of daily routines and the sleep–wake cycle may contribute at a physiological level to the mood instability of bipolar disorder (171,172). These types of issues—medication adherence, insight into illness, and management of stress—should be addressed in the behavioral/psychosocial management of patients with bipolar and SUDs. Several specific behavioral/psychosocial treatments for bipolar disorder have been developed and have shown evidence of efficacy, including psychoeducation (173–175), CBT (176), Interpersonal Social Rhythm Therapy (177–179), and Family-Focused Therapy (180). Each to varying degrees addresses the common issues outlined above, including alliance, understanding the illness and its signs and symptoms, the importance of treatment adherence in general and medication adherence in particular, and the role of stressors and daily routines. Psychoeducation follows a medical model and emphasizes medication adherence, early recognition of symptoms, and social and occupational functioning. In addition to those basic goals, CBT seeks to understand and address connections between maladaptive thoughts or behaviors and mood disturbances. Interpersonal Social Rhythm Therapy, derived from interpersonal therapy for depression (177), addresses the impact of relationships on mood fluctuations and also emphasizes the importance of normalizing routines and the sleep–wake cycle and targets disturbances in these areas, particularly disturbances in sleep, as warning signs. Reduced sleep or insomnia is frequently harbingers of mania, and hypersomnia often signals impending depression. Family-Focused Therapy is based on evidence that a stressful family environment has been associated with worse outcome; this treatment approach seeks to reduce tension and improve family functioning and coping strategies. Readers working with patients with bipolar and SUDs are encouraged to become familiar with these approaches. Patients and their families and significant others need to understand bipolar disorder, recognize signs of relapse, and have strategies on how to intervene; each of these approaches affords a range of useful strategies.

Behavioral Approaches to Co-occurring Bipolar and Substance Use Disorders Integrated Group Therapy (IGT) (181,182) is the first group-based behavioral approach developed specifically for patients with both bipolar disorder and

SUDs and has been shown to be effective in reducing substance use in two randomized controlled trials (183,184). IGT is a manual-guided group treatment designed to serve as an adjunct to pharmacotherapy for bipolar disorder. It is assumed that the medications are managed during separate individual sessions with each patient’s physician. Founded on cognitive–behavioral principles and focused on relapse prevention, IGT incorporates aspects of the above reviewed behavioral treatments for bipolar disorder while addressing the unique interrelationships between bipolar and SUDs. The core principles of IGT include the idea that similar patterns of thought and behavior promote relapse to both mood episodes and substance use and patients are encouraged to approach their problems as a single disorder —“bipolar substance abuse”—rather than as a pair of disorders. This combats the tendency of patients to view one of the disorders as predominant and minimize the other. Each session is focused on a topic, such as “dealing with depression without abusing substances” and “recovery versus relapse thinking.” Each session begins with a “check-in” in which group members all report on their week in terms of substance use, mood symptoms, medication adherence, high-risk situations, and coping strategies employed. This is followed by a review of the topic of the previous week, followed by a presentation of the current topic and related coping skills to be learned; patients are given handouts and homework assignments to practice recovery skills during the coming week. The emphasis throughout is on similarities in the relapse and recovery process between the two disorders and the interrelationships between relapse to substance use and to mood episodes. There is also a strong emphasis on medication adherence, combating pessimism, and on maintaining daily routines and a regular sleep cycle. Since IGT is designed as an adjunctive treatment, it can be incorporated into a range of practice settings including either treatment programs for SUDs or psychiatric clinics serving bipolar patients or office-based practice. An individual cognitive–behavioral approach has also been developed for patients with combined substance and mood disorders (185). This approach includes medication monitoring plus 16 individual cognitive–behavioral sessions focused on an integrated approach to mood and substance use problems. In a randomized controlled trial among patients with bipolar disorder and SUDs, where the control group was medication monitoring alone, patients receiving this CBT had better medication adherence and fewer depressive symptoms compared to controls, but no difference in substance use outcome. Interestingly, the opposite pattern was observed in the initial trial of IGT, in which patients

assigned to IGT had superior substance use outcome, but mood symptoms were actually somewhat worse on IGT compared to the Group Drug Counseling control; the latter mood symptoms were in the mild range and could reflect greater awareness and hence greater reporting of mood symptoms on IGT. In the second trial of IGT, however, the number of patients who had a “good clinical outcome,” defined as being abstinent and having no mood episodes during the previous month, was more than twice as high for IGT patients than for patients receiving Group Drug Counseling (184). Taken together, the results of these trials suggest there may be a role for individual CBT approaches to patients with combined bipolar and SUDs. In addition to the integrated psychotherapeutic approaches described above, the entire treatment programs can offer an integrated approach, as developed by Farren et al. (186–188). This program, which consists of a combination of psychoeducation, individualized interpersonal therapy, relapse prevention group therapy, medications, and self-help groups, combines patients with bipolar and unipolar depression as well as SUDs. An important line of research has examined the effectiveness of integrated approaches to treatment of patients with severe mental illness and substance use problems, as opposed to the traditional approach of referring patients to different agencies for psychiatric and substance treatment, respectively. In addition to patients with schizophrenia, the severely mentally ill population includes patients with severe cases of bipolar disorder, major depression, or schizoaffective disorder. For example, Assertive Community Treatment (ACT) is carried out by treatment teams that seek to deliver all needed services (eg, treatment for psychiatric disorder, treatment for SUD, and social services) to patients without resort to outside referrals. ACT and other integrated treatment models have a strong empirical evidence base (189,190), including evidence of efficacy specifically among patients with bipolar and SUDs (191). As an alternative to integrated models, efforts to enhance cooperation between separate agencies focusing on diverse combinations of psychiatric and substance problems can also be successful (130).

Summary of Treatment Recommendations for Cooccurring Bipolar Disorder Initiation of effective treatment for the SUD is an important priority. However, the evidence on behavioral or service interventions suggests the importance of approaching the treatment of combined bipolar and SUDs simultaneously in an

integrated fashion. If the diagnostic assessment establishes a clear-cut diagnosis of bipolar I or II disorder, this is almost certainly independent of SUD, and medication treatment for bipolar disorder is generally indicated. Bipolar disorder often runs a severe and disabling course, and medications are usually essential to achieving a good outcome. Several specific behavioral approaches have also been developed, which are useful as adjuncts to medication treatment of bipolar disorder, emphasizing medication adherence; establishing a healthy, wellregulated lifestyle and sleep cycle; and combating cognitions that may promote mood swings or relapses. An acute episode of mania, hypomania, mixed mood episode, or bipolar depression often rises to the level of medical emergency, requiring emergency room management and hospitalization. Suicide is a significant risk with bipolar disorder, and patients should be monitored for signs and risk factors. The available evidence on the use of mood stabilizers and neuroleptic medications among patients with combined bipolar and SUDs suggests these medications are effective in improving both bipolar symptoms and substance use outcome. Guidelines for treatment for medication treatment of bipolar disorder can be followed, bearing in mind that a satisfactory outcome may depend upon combinations of medications. When the diagnostic assessment suggests a bipolar spectrum disorder (eg, cyclothymia or subthreshold bipolar disorder), the differential diagnosis between an independent bipolar disorder and a substance-induced mood disorder may be less clear. This differential is more difficult if the mood swings are less severe, of shorter duration, and consonant with intoxication or withdrawal symptoms of the substances the patient is abusing. In this instance, aggressive treatment of the SUD, combined with careful monitoring of the mood symptoms, may be warranted. Resolution of the mood symptoms with abstinence or improvement in the substance problems would add more credence to the substance-induced diagnosis, although mood swings may occur considerably later. Conversely, persistence of the mood symptoms despite improvement in substance use would suggest that specific treatments for bipolar disorder be considered. Available evidence suggests that the behavioral management of patients with combined bipolar and SUDs is important and should involve approaching both disorders in an integrated fashion, emphasizing common behavior patterns promoting recovery and relapse in both disorders and the importance of medication adherence and fostering a lifestyle conducive to recovery from both disorders. Manual-guided interventions (181,183) are available as well as integrated approaches at the programmatic level for patients with SUDs and mood disorders (183,185,186) or those who are severely ill and disabled

(188,189).

SUMMARY AND FUTURE DIRECTIONS This chapter has attempted to serve as a primer on the diagnosis and treatment of mood disorders and presents the evidence on diagnosis and treatment of mood disorders among patients with SUDs. Several common themes emerge from the literature on depressive disorders and bipolar disorders co-occurring with SUDs. Initiation and maintenance of treatment for the SUD are always a priority that should not be overlooked. Careful diagnostic assessment and a lifetime clinical history are important to making the differential diagnosis between independent mood disorders, requiring specific treatment, and substance-induced mood disorders that may resolve with abstinence or improvement in substance use. It is ideal to be able to observe the course of mood symptoms after reduction in substance use or abstinence, although abstinence will not always be achieved among outpatients and treatment will often need to be initiated without this information. To the extent that they have been tested in clinical trials, independent depressive or bipolar disorders seem to respond to the same medication or behavioral treatments that are effective for mood disorders in the absence of SUDs. Behavioral approaches may be effective as an alternative to antidepressant medication among substance-dependent patients with depression, while among bipolar patients, behavioral techniques have emphasized adherence to mood stabilizing medications and an integrated approach to substance and bipolar problems. The conclusions just summarized represent the product of an enormous research effort that has taken place over the last three decades, much of it publicly funded by the National Institutes of Health and its specific institutes including the National Institute on Drug Abuse (NIDA), National Institute on Alcohol Abuse and Alcoholism (NIAAA), and National Institute of Mental Health (NIMH). Progress achieved on the diagnosis and treatment of mood disorders, SUDs, and their co-occurrence is gratifying. Still, many questions remain unanswered or only partially answered and indicate further research. Work is needed on the DSM diagnostic criteria and associated clinical features, in order to improve the important differential diagnosis between independent and substance-induced mood disorders. More research is needed on medication and behavioral treatments. There is, to date, only limited research on the prognostic and treatment indications of substance-induced mood disorders. Finally, the cooccurrence of mood and SUDs invites a range of studies seeking to understand

the connection between these domains of disorders at a fundamental biological level. Examples may include studies on the effect of chronic exposure to specific substances (eg, cannabis, nicotine) on the development of mood disorders and vice versa, using genetics, brain imaging, and other biological probes. Such research promises to yield insights into the biology of each disorder as well as their combination and should help to place psychiatric diagnosis and treatment on a more pathophysiological footing, as is the ultimate goal beyond DSM-IV and DSM-5 (47).

ACKNOWLEDGMENTS Supported by grants P50 DA09236, U10 DA13035, K24 DA022412 (Dr. Nunes) and R01 DA15968, U10 DA15831, and K24 DA022288 (Dr. Weiss) from the National Institute on Drug Abuse.

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CHAPTER 94

Co-Occurring Substance Use and Anxiety Disorders Karen J. Hartwell, Dennis E. Orwat, and Kathleen T. Brady

CHAPTER OUTLINE Prevalence Screening and Differential Diagnosis General Treatment Considerations Alcohol and Anxiety Tobacco Products and Anxiety Disorders Opioids and Anxiety Disorders Cannabis and Anxiety Disorders Stimulants and Anxiety Disorders Conclusions Numerous studies suggest that anxiety disorders, symptoms of anxiety, and substance use disorders (SUDs) commonly co-occur. The interaction between these disorders and symptoms is bidirectional and variable. Anxiety disorders may be a risk factor for the development of SUDs. Anxiety disorders modify the presentation and outcome of treatment for SUDs, just as substance use and SUDs modify the presentation and outcome of treatment for anxiety disorders. Anxiety symptoms commonly emerge during the course of chronic intoxication and withdrawal. Individuals who are defined as having co-occurring anxiety and SUDs should meet criteria for the anxiety disorder independent of periods of acute intoxication and withdrawal. Table 94-1 provides brief descriptions of the major anxiety disorders. Obsessive–compulsive disorder (OCD) has historically been classified as an anxiety disorders and will be included in this chapter, although DSM-5 has now moved OCD and related disorders into their own category. In this chapter, the area of co-occurring SUDs and anxiety disorders is reviewed. Prevalence, diagnostic, and treatment issues are addressed.

TABLE 94-1 Brief Descriptions of Major Anxiety Disorders

From American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Association, 2013.

PREVALENCE General Population A number of epidemiologic studies conducted in the United States over the past several decades have concluded that anxiety disorders and SUDs co-occur more commonly than would be expected by chance alone (1–3). The National Epidemiological Survey(s) on Alcohol and Related Conditions (NESARC) are large, longitudinal cross-representative survey of U.S. adults focused on psychiatric and SUDs that has been conducted in three waves, wave I in 20012002, wave II in 2004-2005, and wave III in 2012-2013.The NESARC-III with a sample of more than 36 000 adults found significant association (OR 1.3) between any lifetime SUD and generalized anxiety disorder (GAD), panic disorder (PD), and social anxiety disorder (SAD) (4). Likewise, the association of alcohol use disorders (AUDs) co-occurring with GAD, PD, and specific phobia was significant with OR ranging from 1.2 to 1.4 (5). A large study examining the relationship between anxiety and DSM-IV substance dependence in young adults found that the onset of one or more anxiety disorders without

other comorbid psychiatric disorders such as depression preceded the onset of alcohol and/or other substance dependence 80% of the time (6). In a clinical sample of individuals diagnosed with OCD, 27% met criteria for a lifetime SUDs and 70% of individuals with a comorbid SUD reported that the OCD preceded the onset of the SUD by at least 1 year (7).

Addiction and Mental Health Treatment Populations Because the relationship between anxiety and SUDs is fraught with symptom overlap and diagnostic challenges, estimates of co-occurring disorders in treatment settings are variable and dependent on diagnostic techniques used and the specific disorder being assessed. In one large sample of substance use treatment clinics, 80% had at least one co-occurring anxiety disorder and comorbidity had a significant relationship to overall mental distress at the initial interview and 6 years later (8). Specific prevalence estimates are addressed in more detail in sections focused on individual anxiety disorders.

Primary Care Populations Anxiety disorders are common within primary care settings and associated with functional impairment, distress, and high utilization of medical care services (9). In a large random sample of consecutive primary clinic patients, ~20% had at least one anxiety disorder with GAD most common (8%), followed by PD (7%) and SAD (6%) (10). Within primary care, the identification of problems with anxiety is poor with only 23% of patients with anxiety recognized compared to 56% of depression (8). Substance use is also common among primary care populations with estimates of 26% past year use of illicit substances. Cannabis is the commonly used illicit substance (21%) followed by cocaine (7%) and prescription medications including opioids, sedatives, and stimulants (7%) (11). In a recent survey of about 13 000 primary care patients across multiple European countries, ~9% met criteria for DSM-IV alcohol dependence of whom only 22% had received treatment (12). Screening and brief intervention for unhealthy alcohol use is recommended by current practice guidelines (13,14); however, it has been challenging to incorporate in clinical practice. For example, in the 2011 Behavioral Risk Factor Surveillance System (BRFSS) survey, the prevalence of ever discussing alcohol use with a health professional was 15.7% among U.S. adults overall, 17.4% among current drinkers, and 25.4% among

binge drinkers (15). In a recent survey of physicians, nurse practitioners, and physician assistants, only 57% reported screening for substance use and less than half provided a brief intervention or referral to treatment (16).

SCREENING DIAGNOSIS

AND

DIFFERENTIAL

Based on prevalence data, individuals seeking treatment for anxiety should be assessed for the presence of an SUD, and conversely, individuals seeking SUD treatment should be assessed for comorbid psychiatric disorders, including anxiety disorders. However, differentiating co-occurring anxiety disorders and SUDs is a diagnostic conundrum. Substance use and withdrawal can mimic nearly every psychiatric disorder. These various substances have profound effects on neurotransmitter systems involved in the pathophysiology of anxiety disorders, and chronic substance use may unmask a vulnerability to anxiety or cause neurobiological changes that may manifest as an anxiety disorder. The best way to differentiate substance-induced, transient symptoms of anxiety from anxiety disorders that warrant treatment is through observation of symptoms during a period of abstinence. Transient substance-related states will typically improve with time. The duration of abstinence necessary for accurate diagnosis remains controversial and is likely to be based on both the diagnosis being assessed and the substance used. For example, long half-life drugs (eg, some benzodiazepines, methadone) may require several weeks of abstinence for withdrawal symptoms to subside, while shorter-acting substances (eg, alcohol, cocaine, short half-life benzodiazepines) require shorter periods of abstinence to make accurate diagnoses. A family history of anxiety disorders, the onset of anxiety symptoms before the onset of SUD, and sustained anxiety symptoms during lengthy periods of abstinence all suggest an independent anxiety disorder. Because of the high rate of co-occurrence of anxiety and SUDs, screening patients presenting at primary care, substance use, or mental health treatment settings is critical. This is especially important considering that early diagnosis and treatment can improve treatment outcomes. A number of screening tools are available and easily integrated into everyday practice. For example, the MiniInternational Neuropsychiatric Interview has a brief form that contains screening questions for PD, agoraphobia (AG), SAD, and OCD, among others (17). The screener contains one “yes or no” question for each anxiety disorder, and all are based on the DSM-5 criteria (Table 94-2). Numerous self-report questionnaires

have been developed to screen for anxiety disorders in the primary care settings. For example, the Four-Dimensional Symptom Questionnaire (4DSQ) is a 50item self-rating questionnaire developed to distinguish depression, anxiety, and somatization from general distress (18). The Hospital Anxiety and Depression Scale (HADS) is a 14-item self-rating questionnaire that measures both depression and anxiety (19). In a multisite trial, the 4DSQ and the HADS were administered to 295 patients on sick leave due to psychological problems excluding patients with known depressive or anxiety disorders (20). The 4DSQ demonstrated superiority compared to the HADS in detecting PD, agoraphobia, and social anxiety requiring treatment. These self-rating questionnaires and other screening tools can be administered by support staff in the office setting and can help to identify high-risk individuals. However, because of symptom overlap and diagnostic difficulties, a detailed interview may be necessary to fully differentiate substance-induced symptoms from primary mood/anxiety disorders.

TABLE 94-2 Screening Questions for Anxiety Disorders Adapted from the Mini-International Neuropsychiatric Interview

From Sheehan DV. M.I.N.I. International Neuropsychiatric Interview English Version 7.0.2 for DSM-5. 2016. http://harmresearch.org

GENERAL CONSIDERATIONS

TREATMENT

The integration of services and effective treatments from both psychiatric and

SUD fields is essential to the optimal treatment of individuals with co-occurring disorders. It is important to maximize the use of nonpharmacological treatments. Some research suggests that some traditional therapies, including group therapies and Alcoholics or Narcotics Anonymous, may be more challenging for individuals with anxiety disorders. A study of individuals entering communitybased intensive outpatient substance treatment found that clinically significant social anxiety interfered with recovery-related activities such as attending 12step recovery meetings, finding a sponsor, and speaking up in groups (21). Learning strategies to self-regulate anxiety can disrupt the cycle of substance use to combat intolerable subjective states and help individuals to acquire alternative coping strategies. Among psychosocial treatments, cognitive–behavioral therapies (CBTs) are among the most effective for both anxiety disorders and SUDs. The effectiveness of CBT for all of the anxiety disorders is well established in both clinical trials and naturalistic settings (22), and CBT has been utilized extensively in the treatment of SUDs (23). Research investigating pharmacotherapy for both substance use and anxiety disorders is progressing rapidly. The medical management of specific anxiety disorders will be discussed in detail later, but some general principles apply. Individuals in recovery often have complex, conflicting feelings and attitudes about medications and may see the need for pharmacotherapy as a sign of defectiveness or failure. For some patients, there is a struggle surrounding the use of medication and the belief that total abstinence from all psychoactive substances (including medications to treat addiction) is necessary for recovery (24). It is important to address the individual’s concerns about taking medication and to address the need for adherence in a proactive manner. In cases where the relationship of psychiatric symptoms and substance use is unclear, a careful assessment of the risks and benefits of using medications must be considered. Pharmacotherapies for anxiety disorders are well established and reviewed in detail in the literature (25–28). Pharmacotherapy decisions should generally follow routine clinical practice for treatment of the anxiety disorder with some exceptions. It is important to pay attention to potential toxic interactions between the prescription medications and illicit drugs and alcohol in case of relapse. It is also important to use the agent with the least addictive potential. A recent review of pharmacotherapies for the treatment of anxiety disorders indicated that selective serotonin retake inhibitors (SSRIs) as a class are generally considered as first-line medications due to overall effectiveness, tolerability, and safety (25). Serotonin–norepinephrine reuptake inhibitors (SNRIs) are typically seen as alternate first-line medications and utilized after

failure or inadequate response to an SSRI. Venlafaxine and duloxetine are efficacious in the treatment of GAD, and venlafaxine is also indicated for the treatment of GAD and SAD (25,26). Mirtazapine has shown promise in several open trials in PD and GAD with mixed results in SAD (29). Other antidepressants, such as the tricyclic antidepressants and monoamine oxidase inhibitors, are generally used as second- or third-line medications primarily due to problems with tolerability and lethality in overdose. Because of its limited effectiveness, buspirone is generally only utilized for the treatment of uncomplicated GAD (26). Anticonvulsants are receiving increasing attention for the treatment of a variety of psychiatric disorders. For the treatment of GAD, pregabalin has the greatest amount of support from multiple double-blind placebo-controlled randomized clinical trials (RCTs) (26). Gabapentin demonstrated promise in a double-blind RCT for SAD, in a subset of patients with more severe PD with agoraphobia, anxiety in breast cancer survivors, and in several studies of surgery-related anxiety (30). Hydroxyzine is also indicated for anxiety and likely attenuates anxiety by inhibiting the histamine H1 and serotonin 2a receptors (31). The serotonergic properties of the atypical antipsychotics are thought to augment the action of antidepressants in the treatment of depression, and as a result, these medications are also being investigated in the treatment of anxiety disorders. However, double-blind placebo-controlled RCTs of the atypical antipsychotics are still quite limited, and these agents should be reserved for use after failure of other interventions (26). The worrisome side effect burden of these medications including substantial weight gain and metabolic syndrome is a consideration in the clinical decision to prescribe these agents. Caution should also be exercised in the use of medications that lower seizure threshold in SUDs with the same potential. Benzodiazepines have demonstrated efficacy in the treatment of PD, GAD, and SAD (25,26). However, benzodiazepines adverse side effects include aberrant use and addiction potential, problematic sedation, cognitive impairment, and with prolonged use tolerance and withdrawal. Their use should be limited to patients who have not responded to at least three previous treatments such as an SSRI, an SNRI, and a psychotherapeutic intervention. As a rule, benzodiazepines should be avoided in patients with a current SUD and used with caution in those with a history of SUD. A short course of benzodiazepines may be considered as adjunctive medication during the early treatment phase when activation or latency of onset of the antidepressants is an issue. Additional recommendations include close monitoring for relapse, prescribing limited amounts of medication with restricted numbers of refills, and regular checking of

the state controlled substance databases. Finally, the use of agents targeting substance use specifically, such as naltrexone or disulfiram, as add-on treatment for individuals with comorbid SUDs and anxiety disorders is underexplored. In one study of 254 outpatients with DSM-IV alcohol dependence and a variety of comorbid psychiatric disorders, Petrakis et al. (32) investigated the efficacy of disulfiram and naltrexone or their combination in a 12-week randomized trial. Participants treated with naltrexone or disulfiram, as compared with placebo, had significantly more consecutive weeks of abstinence and fewer drinking days per week. In comparison to naltrexone-treated participants, disulfiram-treated participants reported less craving from pre- to posttreatment. The effects of the medications by specific comorbid psychiatric disorder were not discussed, but active medication was associated with greater symptom improvement (eg, less anxiety). No clear advantage of combining medications was observed. The use of adjunctive pharmacotherapy is likely to become more relevant as medication treatment options for SUDs increase. In the sections that follow, the prevalence rates, differential diagnosis, and treatment of GAD, SAD, OCD, and PD will be reviewed. Specific phobia will not be covered because most evidence suggests that this disorder has no special relationship with SUDs.

ALCOHOL AND ANXIETY Though the relationship between alcohol and anxiety disorders varies to some degree across specific disorders, drinking to self-medicate anxiety may make both occurrence and persistence of AUDs more likely (33–36). The relationship between anxiety and alcohol use may predispose young people to develop an AUD, with early-onset anxiety disorders associated with an earlier age of first alcohol use (37). The short-term relief of anxiety from alcohol use, in combination with longer-term anxiety induction from chronic drinking and withdrawal, may also initiate a feed-forward cycle of increasing anxiety symptoms and alcohol consumption (38). A recent Cochrane systematic review concluded that the evidence base of pharmacotherapy for comorbid alcohol and anxiety disorders was both of very poor quality and inconclusive (39). Previous research has indicated that alcohol use appears to attenuate the efficacy of anxiety disorder treatment (40,41). There is less robust meta-analysis level evidence that alcohol use treatment can be

integrated into the treatment of anxiety disorders generally, and vice versa, with improvements in outcomes for both alcohol and anxiety disorders (42). Psychosocial interventions have an established role in anxiety and SUDs and are often indicated even where they are not well studied in comorbid populations.

Generalized Anxiety Disorder In the recent NESARC-III survey study, using DSM-5 criteria for diagnoses, after correcting for other comorbid disorders, those with lifetime history of AUDs were found to have weakly increased odds of also having a lifetime history of GAD (OR 1.05-1.39).

Differential Diagnosis GAD symptoms have considerable overlap with withdrawal from alcohol. A DSM-5 diagnosis of GAD requires that symptomatology is not attributable to the physiological effects of a substance. Because of this, distinguishing substanceinduced anxiety symptoms from GAD can be challenging. As patients engage in recovery, ongoing assessment of anxiety symptoms will provide valuable information regarding diagnosis and need for continued treatment.

Treatment The most current guidelines for the pharmacological treatment of GAD are from the National Collaborating Centre for Mental Health (27). First-line medications are SSRIs with preference for sertraline, followed by an alternative SSRI or SNRI in the case of lack of efficacy. Pregabalin can be considered in the case of SSRI and SNRI intolerance. Benzodiazepines should only be used as a shortterm measure during crises, while antipsychotics should only be considered for refractory cases. Although effective for some individuals, controlled trials do not support the use of beta-blockers. Because GAD has a relapsing-remitting course and favorable number needed to treat for the prevention of relapse, long-term treatment of GAD is often indicated (43). There is little evidence-based research to direct treatment decisions for individuals with GAD and comorbid AUDs. Although SSRIs have not been well studied in individuals with co-occurring GAD and SUDs, they are efficacious in the treatment of uncomplicated GAD and relatively safe to use in individuals with SUDs. Pregabalin has demonstrated efficacy for GAD and alcohol withdrawal syndrome but has not been evaluated in comorbid AUD and GAD

(44).

Social Anxiety Disorder In the NESARC-III study, a 12-month history of AUD was associated with a mildly decreased odds of SAD (OR 0.63-0.98) and was not associated with a lifetime history of SAD (5). SAD maybe a risk factor for AUDs in some who use alcohol to selfmedicate, with SAD symptoms typically preceding onset of SUDs (45).

Differential Diagnosis The key symptom of SAD, fear of performance or social situations, is specific to SAD and not generally associated with substance use or withdrawal, making diagnosis easier than it is for other co-occurring anxiety disorders.

Treatment Current initial pharmacological treatment recommendations for SAD include SSRIs, with preference for sertraline or escitalopram. For those with inadequate treatment response, second-line therapy includes alternative SSRIs with preference for fluvoxamine or paroxetine, or an SNRI (venlafaxine), with MAOIs being third-line (phenelzine) (28). There are a few studies examining treatment options in comorbid populations. Two small placebo-controlled studies of paroxetine in co-occurring AUD and SAD have demonstrated significant improvement in social anxiety with paroxetine treatment but no significant group differences in alcohol use in either study (46,47). A more recent controlled trial integrating a brief alcohol intervention into treatment failed to demonstrate decreased alcohol use or drinking behavior in at-risk drinkers with SAD (48). In an investigation of group therapy in 300 detoxified DSM-IV defined alcohol-dependent patients with and without SAD, no difference was found between groups in treatment adherence and outcomes. However, individuals with SAD chaired Alcoholics Anonymous meetings less often, were more ashamed of attendance, felt less integrated into the group, and were less likely to feel better after a meeting (49). Individual therapy may be better tolerated than group therapy, and a period of sobriety and skills training may be important before increasing exposure to social situations.

Obsessive–Compulsive Disorder The association of OCD and AUDs is less robust than for other anxiety disorders. In the National Comorbidity Survey Replication study, OCD was negatively correlated with AUD (50).

Differential Diagnosis Craving in SUDs can be intrusive and recurrent, comparable to the intrusive recurrent thoughts that drive behavior in OCD (51). DSM-5 diagnostic criteria specify that a diagnosis of OCD should not be made when symptoms are better explained by a substance-related or SUD. The thoughts and compulsions in individuals with AUDs are generally restricted to alcohol use and easily distinguished from OCD.

Treatment There are no controlled studies of pharmacological treatment of co-occurring OCD and SUDs. First-line medications for OCD are SSRIs, followed by switching to a different SSRI or mirtazapine, or augmenting with an antipsychotic. One recent study of intensive OCD-oriented residential treatment found lower past-year alcohol use predicted better treatment response (52).

Panic Disorder In the NESARC-III study, lifetime history of an AUD was associated with increased odds of PD (OR 1.12-1.44) (5). In one review of the literature, the risk of PD in the presence of AUDs was two to four times higher than in the absence of AUD (53).

Differential Diagnosis Individuals with panic attacks may use alcohol use to decrease panic symptoms and consequently develop an AUD (53). Because alcohol withdrawal may increase anxiety to the point of panic-like severity, a diagnosis of PD should only be made following several weeks of abstinence, if distinguishing temporal onset of PD and AUD cannot be readily done.

Treatment

The most current guidelines for pharmacological treatment of PD recommend against routine benzodiazepine, antihistamine and antipsychotic prescribing, in favor of SSRIs followed by imipramine or clomipramine in poor responders (28). Without treatment, the risk of relapse to alcohol use is increased (54). A few studies support the efficacy of CBT in the treatment of PD comorbid with AUD. In a study of an Internet-based CBT model for PD, problematic alcohol use attenuated, but did not eliminate, the benefits of the CBT intervention (40). One study compared hybrid CBT targeting both alcohol and panic versus treatment as usual in a 28-day chemical dependency program, demonstrating that CBT improved both drinking and PD outcomes (55).

TOBACCO PRODUCTS AND ANXIETY DISORDERS Between 2004 and 2011, smoking rates have declined significantly (p < 0.001) among individuals without mental illness (from 20% to 16%); however, comparable declines (p = 0.50) were not seen in individuals with mental illness (from 29% to 27%), including anxiety disorders (56). Data from the 2011 and 2014 wave of the Truth Initiative Young Adult Cohort, a national survey of young adults between the 18 and 34 years of age, found that 39% of current smokers preferred menthol brands, which was associated with greater odds of depression and anxiety (p = 0.03) suggesting that the menthol may be uniquely linked to affective vulnerability (57). The use of smokeless tobacco products is also increased among individuals with anxiety. For example, after controlling for cigarette smoking and demographics, the lifetime prevalence rate of exclusive chewing tobacco use was increased among individuals with PD (OR 1.5) (58). Despite the strong associations between smoking, tobacco use disorder, nicotine use, and anxiety disorders, there has been relatively little investigation of causal connections or treatment. Previous research has suggested that smoking and nicotine can alleviate anxiety, but other studies indicate that nicotine use and withdrawal can cause anxiety (59). The Netherlands Study of Depression and Anxiety, a longitudinal naturalistic cohort study, found that the onset of anxiety disorders was 5 years earlier for early-onset as compared to late-onset smokers, and this relationship remained after controlling for gender, education, and childhood trauma (60).

Differential Diagnosis

The anxiety and arousal associated with nicotine withdrawal can be distinguished from independent anxiety disorders by the time course. Prospective research suggests that nicotine withdrawal symptoms typically return to baseline within 10 days (61) and anxiety typically decreases within 4 weeks of quitting among smokers without comorbid psychiatric disorders (62). Anxiety symptoms that persist beyond the withdrawal period warrant further investigation. It is important to note that when individuals enter treatment programs, particularly inpatient treatment, their cigarette smoking is generally significantly curtailed. Anxiety related to nicotine withdrawal should be taken into consideration in any assessment of anxiety in individuals hospitalized for the treatment of either SUDs or psychiatric disorders.

Panic Disorder The relationship between PD and smoking is the best studied of all the anxiety disorders, and the majority of studies support a strong relationship between PD and smoking. In the NESARC wave I study, DSM-IV nicotine dependence was significantly associated with PD with agoraphobia (OR 4.6) and without (OR 3.9) (63). In a clinical sample of individuals with anxiety disorders, the PD group had the highest proportion of smokers, 40.4%, and was more likely to be heavy smokers compared to the SAD group, 20% (64). A history of panic attacks has been associated with daily, heavy smoking (20 or more cigarettes/day), nicotine dependence, and a history of failed quit attempts (65). Early smoking increases the risk for the development of PD (66), and the initiation of smoking may precede the onset of PD by many years (median, 12 years) (67). Breslau found that current but not past smoking was associated with the subsequent onset of PD and agoraphobia and the risk decreased with increasing time since quitting (68). The underlying neurobiological underpinnings of the association is not fully understood. Current explanations include a shared vulnerability to both disorders, the release of norepinephrine by nicotine producing panic-like symptoms, self-medication, and the result of respiratory abnormalities from smoking (69).

Social Anxiety Disorder Few studies have investigated the relationship between SAD and smoking. Although some studies have failed to demonstrate a relationship (70), one prospective longitudinal study of adolescents and young adults found that both

social fears and SAD were significantly associated with higher rates of DSM-IV nicotine dependence (71). Approximately 50% reported the onset of SAD before smoking. Among individuals with SAD, cigarette smoking may be used to attenuate social anxiety in anticipation of and during social situations. In a clinical laboratory study, young adult smokers with elevated social anxiety who smoked a cigarette had significantly reduced negative affect during a social stress task compared to those with average social anxiety scores (72).

Generalized Anxiety Disorder After adjusting for sociodemographic factors and additional comorbid psychiatric disorders, the 12-month prevalence of a DSM-IV–defined severe nicotine use disorder was significantly associated with an increased risk of GAD (OR 1.3) (73). In one prospective longitudinal study of adolescents and young adults, heavy smoking (≥20 cigarettes per day) was associated with an increased risk of GAD (21%, OR 5.5) during young adulthood (70). GAD is about twice as common in women than in men, and men are more likely to have nicotine addiction, use alcohol and nonprescribed medications to relieve symptoms, and less likely to seek treatment (74). A confounding issue is the high rate of cooccurrence of GAD between other anxiety and depressive disorders.

Obsessive–Compulsive Disorder The prevalence of smoking is significantly lower (p < 0.001) among adults with OCD (13.5%) and parents of youth with OCD compared to those with other psychiatric disorders and the general population, suggesting that the low prevalence of smoking may be familial and stimulating effect of nicotine may exacerbate OCD symptoms (75). OCD is a heterogeneous disorder, however, and smoking status differs based on distinct subcategories of OCD. In a clinical sample, the rate of smoking was highest among individuals with symmetry– counting–repeating–ordering symptoms compared to those with washing symptoms (p = 0.004) and taboo thoughts (p = 0.0007) (76). Nicotine administration decreases some forms of compulsive behavior in both nonsmoking human and animal studies (59). Further research is needed to examine the relationship of nicotine, obsessive–compulsive symptoms, and OCD.

Tobacco/Nicotine Treatment

Current guidelines for treating tobacco/nicotine use disorder recommend a combination of counseling and medication. Pharmacotherapy is recommended in all individuals attempting to quit unless there is a contraindication. Medications that reliably increase long-term smoking abstinence include bupropion sustained release (SR), all forms of nicotine replacement therapy (nicotine gum, nicotine inhaler, nicotine nasal spray, nicotine lozenge, and nicotine patch), and varenicline (77). In two large smoking cessation trials comparing nicotine patch, nicotine lozenge, patch + lozenge, and bupropion + lozenge, combination therapy was superior to monotherapy in all groups except those with low nicotine dependence living with a smoking spouse (78). In one of two comparative effectiveness smoking cessation trials, menthol smoking was associated with less success compared to nonmenthol smoking (OR 0.71) especially among African American women (79). Additional analysis also found that participants with a history of an anxiety disorder were less likely to be abstinent at 8 weeks’ or 6 months’ postquit, and neither monotherapies nor combination therapies were superior to placebo at 6 months (80). In contrast, no association was found between anxiety disorders and the cumulative probability of remission from DSM-IV nicotine dependence in an analysis of NESARC data from the 2000 to 2001 (81). Bupropion treatment can be associated with anxiety and agitation in some individuals, so should be used with caution in anxious patients. Buspirone (up to 60 mg/d) had a beneficial effect on abstinence in highly anxious smokers in one randomized controlled trial in high- and lowanxiety smokers. However, buspirone decreased abstinence in the low-anxiety group, and these effects reversed when the drug was withdrawn. No differential effects on abstinence were observed beyond the 3-month follow-up (82). Little information is available about the use of varenicline in smokers with anxiety disorders. In 2009, the FDA issued a black box warning for neuropsychiatric adverse effects, which was lifted in 2017. Meta-analysis of 17 placebo controlled RCT (n = 8027) including a subset of participants with psychiatric disorders found that varenicline did not increase the rates of depression, suicidal events, agitation, or aggression (83). Individuals with current or a past history of mental illness including anxiety had an increased risk of an adverse neuropsychiatric events in both the varenicline and control groups. One comparative study of standard nicotine patch (NRT), extended, flexible, combination NRT+ (patches with gum or inhaler), or varenicline in smokers, including individuals with comorbid medical and psychiatric problems, has been executed. Despite increasing abstinence in the early phase of treatment, neither varenicline nor NRT+ increased quit rates compared to standard NRT at the 1-year mark (84). Of note, no differences in psychiatric adverse events were detected between the

groups with and without psychiatric diagnoses of whom 21% had a lifetime history of an anxiety disorder, suggesting that smokers with anxiety disorders may safely be offered standard treatment, including varenicline. Supplemental analysis found individuals with a history of anxiety disorders were about twice as likely to endorse stress and almost four times as likely to endorse negative affect as a reason for relapse (85). Morisette (59,64) suggested that interoceptive exposure therapy may be helpful in reducing distress and anxiety during withdrawal by teaching individuals to tolerate internal cues such as negative affect, craving, and withdrawal symptoms. Cognitive therapy may also be helpful by addressing maladaptive thoughts associated with both anxiety and nicotine/tobacco use. Mindfulness and acceptance-based treatments also hold some promise. Given the high prevalence rates of anxiety disorders among tobacco users, and some research suggesting that first-line medications may be less effective, treatments aimed at the specific needs of this population need to be developed.

OPIOIDS AND ANXIETY DISORDERS The 12-month and lifetime prevalence rates of nonmedical use of prescription opioids increased from 0.9% to 4.1% and 2.1% to 11.3%, respectively, between the NESARC I and NESARC III (86). Likewise, the 12-month and lifetime rates prevalence of nonmedical prescription opioid use disorders increased from 0.4% to 0.8% and 1.4% to 2.9%, respectively, with only 18% ever treated. In NESARC II, the lifetime prevalence of anxiety disorders was double in individuals with OUDs (3.2%) compared to those without (1.42%) (87). Across studies, lifetime rates of SAD in individuals with OUDs have been reported between 3% and 39% (88). The lifetime prevalence of PD with AG, 5%, was lower compared with PD without AG, 14%, in individuals with OUDs. PDs without AG rates were higher in DSM-IV opioid dependence, 24%, than abuse, 10% (87). The lifetime prevalence rate of GAD among individuals with OUDs was 11% in the NESARC II study with 22% in opioid dependence compared with 7% in opioid abuse (87). In one outcomes study, the presence of a comorbid SUD decreased the likelihood of recovery from GAD by nearly fivefold and increased the risk of recurrence threefold (89).

Diagnosis Diagnosis of primary anxiety disorders in those with DSM-IV–defined opioid

dependence remains a challenge, as the relationship between anxiety and OUDs is complex (90). The release of endogenous opioids in response to stress has a modulating effect on anxiety, and blocking the opioid system with an antagonist produces anxiety symptoms in human volunteers and anxiety-linked behaviors in animal models (91). Anxiety is a key feature of opioid withdrawal (92). Stabilization in treatment including pharmacotherapy and psychosocial treatments can significantly reduce withdrawal-related symptoms in as little as 1 week.

Treatment While no clinical trials of treatments for co-occurring anxiety disorders have been conducted, general treatment principles apply. Patients presenting for treatment of opioid use disorders should be screened for anxiety, and the temporal relationship of anxiety symptoms to opioid use and addiction should be assessed (90). A comprehensive treatment plan is necessary to address the opioid use, anxiety, other comorbid SUDs, and chronic pain if present (88). Initial components should include medical withdrawal management and consideration of buprenorphine or methadone treatment. If anxiety persists after withdrawal management and stabilization, then specific treatments for anxiety should be considered. Physicians should choose anxiety medications with efficacy for the specific anxiety disorder being treated and with attention to special considerations described in this chapter. Symptoms of chronic pain such as poor sleep, anxiety, and loss of appetite may be misattributed to another psychiatric disorder. If chronic pain is an issue, consultation with a pain specialist may be helpful.

CANNABIS AND ANXIETY DISORDERS Findings from the 2012–2013 NESARC-III survey of adults indicated that the prevalence of past-year cannabis use and past-year cannabis use disorders were 9.5% and 2.9%, respectively, and markedly increased relative to 2001-2002 rates (4.1% and 1.5%, respectively) (93,94). In 2010, there were 17.4 million current American cannabis users over the age of 12, and cannabis was the most commonly used drug (76.8%) by current illicit drug users and was the only drug used by 60.1% of them (95). The relationship between cannabis and anxiety remains unclear. Meta-analysis, longitudinal, and epidemiologic evidence of an association between anxiety disorders and cannabis use disorders demonstrates

that the onset of anxiety seems to occur prior to cannabis use disorder onset for the majority of comorbid adults (96–98). A large, recent study of Scandinavian adults indicated that the positive association between cannabis use and anxiety incidence may be eliminated when confounders are well controlled (99,100). However, there is evidence that cannabis use results in acute anxiety symptoms during intoxication (101), and anxiety symptoms can develop as part of cannabis withdrawal (102). Zvolensky and colleagues (103) examined the relationship between cannabis use, panic attacks, and PD in a representative sample and found that after controlling for sociodemographic differences and lifetime SUD, lifetime cannabis use was significantly associated with an increased risk of lifetime panic attacks (OR 1.6) and current (OR 1.3) and lifetime diagnosis of PD (OR 1.6). Cannabis use as a strategy to cope with anxiety is also a focus of recent research. Studies suggest that the use of cannabis as a coping strategy may serve to enhance anxiety through an avoidance–anxiety cycle; cannabis users who report using cannabis to cope, may use cannabis more often (104), and have more cannabis-related problems and distress (105). Additionally, treatment for cannabis use disorder may be affected by comorbid anxiety, though this is understudied. In a large multisite trial investigating the effectiveness of two psychosocial treatments for cannabis use disorder, higher anxiety prior to treatment was associated with increased depression at baseline and increased cannabis-related problems at baseline and both follow-up time points (106). Of note, the results also suggested patients with cannabis use disorder may benefit from treatment focused on the development of skills to manage anxiety as anxiety reduction was associated with improved cannabis outcomes. A study comparing successful and unsuccessful quitters with a cannabis use disorder found that successful quitters were more likely to employ coping strategies such as alternative ways to relax and deal with unpleasant emotions than unsuccessful quitters (107). In sum, the relationship between cannabis and anxiety disorders is complex. Most research to date has found an association between anxiety and cannabis use and disorders, though causality and degree of mediation by confounders is not entirely determined. Additional research is necessary to further delineate the relationship between anxiety and cannabis use disorders.

STIMULANTS DISORDERS

AND

ANXIETY

There is relatively little research on co-occurring anxiety disorders and cocaine, methamphetamine, and amphetamine use. These agents stimulate noradrenergic systems, and acute intoxication is often associated with anxiety. Because of these anxiogenic effects, it has been postulated that individuals who are vulnerable to anxiety may be less likely to misuse or become addicted to this class of drugs (108,117). When anxiety symptoms are reported in individuals with stimulant use disorders, careful attention to the time course of anxiety symptoms relative to stimulant use is critical.

Prevalence In the NESARC I, the 12-month prevalence of cocaine use disorders was 0.27% and of amphetamine use disorders was 0.16%. Thirty-nine percent of individuals with amphetamine use disorders and 31% of those with cocaine use disorders reported lifetime anxiety disorders. Of individuals with anxiety disorders, 4.8% reported lifetime amphetamine use disorder and 5.4% reported lifetime cocaine use disorder (87). Studies of treatment-seeking individuals indicate that anxiety disorders are relatively less common in cocaine-using treatment-seeking patients as compared with patients with alcohol and other SUDs (109). One study (110) found lifetime prevalence of SAD in a population with DSM-defined cocaine dependence to be 13.9%, with SAD preceding the onset of cocaine dependence in nearly all cases. In a large sample from the Methamphetamine Treatment Project, participants completed self-report measures of anxiety (111). Women reported higher levels of anxiety than did men. Frequency of methamphetamine use was positively associated with severity of general anxiety and phobic anxiety. At 3-year follow-up, 26.2% of participants met criteria for current or past anxiety disorder, with GAD being most common. Among those with anxiety disorders, treatment adherence was poorer, and self-reported methamphetamine use was significantly higher during the follow-up period (112). In a review of two community surveys, lifetime noncocaine stimulant use was associated with lifetime diagnoses of nearly every anxiety disorder (113).

Diagnosis The compulsive foraging for misplaced cocaine that has been noted in patients with cocaine addiction (114) has commonalities with that of OCD. These symptoms generally occur only during acute intoxication and withdrawal and do not meet diagnostic criteria for OCD. The DSM-5, while instructing a diagnosis of excoriation disorder not be made when skin-picking behavior is attributable to

substance use, does suggest a diagnosis of substance/medication-induced obsessive–compulsive and related disorder should be considered when such substance-related behavior is clinically relevant (115). Cocaine has been reported to precipitate panic attacks in patients without previous PD (116), and caffeine can worsen panic and anxiety in those with PD (117). Methamphetamine and cocaine withdrawal symptoms include low levels of anxiety in the early days of abstinence (118,119). Therefore, a period of abstinence is warranted before diagnosing an anxiety disorder in individuals with stimulant use disorders.

Treatment There is a paucity of research focused on the treatment of co-occurring stimulant use and anxiety disorders. In one small case series, patients with cocaineinduced PD had substantial symptom improvement after treatment with either carbamazepine or clonazepam (120). Anticonvulsant agents, such as valproate and carbamazepine, have demonstrated efficacy in the treatment of PD. PD in patients with comorbid stimulant use may be linked to a sensitization mechanism and may respond particularly well to anticonvulsant medications. This hypothesis warrants further investigation. There are a number of psychosocial treatments with demonstrated efficacy in the treatment of stimulant dependence including contingency management and CBT (121). Clearly, individuals with cooccurring disorders should be engaged in evidence-based psychosocial treatment for their stimulant use.

CONCLUSIONS Because of the high co-occurrence of anxiety and SUDs and their prevalence in the population, primary care and mental health providers will encounter these conditions frequently in the course of their work. It is essential that providers address substance use patients’ anxiety symptoms as a routine part of treatment. This requires careful differential diagnosis that usually requires at least a brief period of sustained abstinence. Providers should also consider the mechanism of action of different medications and choose those with the lowest risk for abuse. Psychosocial treatments for anxiety and SUDs are excellent primary and adjunct treatments for these co-occurring disorders, and referrals should be made as necessary.

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CHAPTER 95

Co-Occurring Addiction and Psychotic Disorders Douglas Ziedonis, Xiaoduo Fan, Celine Larkin, Stephen A. Wyatt, and David Smelson

CHAPTER OUTLINE Introduction Definition of Psychotic Disorders Prevalence of Co-occurring Addiction and Psychotic Disorders Differential Diagnosis Management of Co-occurring Psychosis and Substance Use Longer-term Management Conclusion

INTRODUCTION The presence of substance use and psychotic symptoms poses special diagnostic and treatment challenges for clinicians in all treatment settings, including mental health, addiction, emergency room, and primary care settings. This chapter focuses on the tasks of assessment, diagnosis, and acute and long-term treatment considerations. The acute management of substance-induced psychosis is discussed in addition to the acute and long-term management of individuals with schizophrenia and addiction. There is a need for comprehensive assessment and integrated treatment that addresses the multiple diagnoses and problems associated with co-occurring addiction and psychotic disorders.

DEFINITION DISORDERS

OF

PSYCHOTIC

Psychosis is defined as a gross impairment in reality testing that is characterized by severe distortions of perception (as manifested by hallucinations) or thought (as manifested by delusions). According to the current edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) (1), key features that define the psychotic disorders include delusions, hallucinations, disorganized thinking (speech), grossly disorganized or abnormal motor behavior (including catatonia), and negative symptoms (Table 95-1). Hallucinations (eg, auditory, visual, tactile, olfactory) and delusions (paranoid, persecutory, grandiose, etc.) are labeled “positive” symptoms. “Negative” symptoms greatly impact interpersonal communication and include diminished emotional expression, lack of

motivation, anhedonia, decreased speech, and social withdrawal. Psychotic disorders include schizophrenia, schizoaffective disorder, delusional disorder, substance- or medication-induced psychotic disorder, psychotic disorder due to another medical condition, and others.

TABLE 95-1 Key Features That Define the Psychotic Disorders

PREVALENCE ADDICTION DISORDERS

OF CO-OCCURRING AND PSYCHOTIC

Addiction Treatment Populations Varying degrees of transient substance-induced psychotic symptoms are not uncommon among those who present while intoxicated; however, addiction treatment programs tend not to include individuals with more severe and persistent schizophrenia in longer-term rehabilitation treatment programs. In contrast, mental health treatment settings have recognized that their system must address co-occurring substance use in patients they serve, and they have developed “co-occurring disorders” (previously referred to as “dual diagnosis”) treatment programs at all levels of care. Psychotic symptoms can be induced by a variety of substances, such as alcohol, cocaine, cannabis (including synthetic), amphetamines, dissociatives, and hallucinogens, and often in combination. In the addiction treatment setting, the differential diagnosis most often is determined after a period of abstinence. In general, psychotic symptoms need to persist for at least month after cessation of substance use in order to make the diagnosis of a primary psychotic disorder comorbid with substance use (2,3). Although psychotic symptoms may persist even after cessation, only 1%-15% of individuals with a substance-induced psychosis still present symptoms beyond 1 month of abstinence (4). Delayed symptom clearance may be attributed to factors such as the type of substance, the duration of use, and preexisting psychiatric vulnerability. Duration of substance-induced psychosis can vary. For example, patients who develop methamphetamine psychosis may experience persistent psychotic symptoms and still require hospitalization, despite months of abstinence (5). Evidence suggests that chronic amphetamine use can result in long-term neurobiological changes, which may persist even after prolonged abstinence and present as a protracted psychosis that is phenomenologically similar to schizophrenia (6,7). A study of cocaine-induced psychosis by Selzer and Lieberman (8) suggested that a psychosis persisting for more than several days is likely suggestive of an underlying psychotic disorder.

Psychiatric Treatment Populations Several studies have examined rates of co-occurring addiction and schizophrenia and found that up to half of individuals with schizophrenia have a lifetime prevalence of substance use disorders (SUDs) excluding tobacco/nicotine use disorder (9,10). In the classic Epidemiologic Catchment Area community-based study, 34% of those with schizophrenia had an alcohol use disorder (AUD) and 28% had a drug use disorder (DUD), including 16% who used cocaine (9). More recently, the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) suggested that schizophrenia is associated with increased transition from abstinence to use, particularly for cannabis (11). The odds of those with schizophrenia also carrying a SUD diagnosis are 4.6 higher than those of the general population (3,12). Mental health treatment settings report rates of current nonnicotine SUDs in the population of individuals with schizophrenia in the range from 25% to 75%. However, these epidemiologic data represent a “best guess” of the true rates, given the challenges of diagnosing SUD in the presence of schizophrenia and the problems of diagnosing schizophrenia in the context of a SUD. Even an objective measure, such as routine urine drug screening in hospitals, may fail to detect or underestimate substance use (13). Of note, studies suggest that 70%-90% of patients with schizophrenia have tobacco/nicotine use disorder, and nicotine is not routinely included in reported rates of SUDs, making the actual numbers much higher. A Canadian study has shown that of 203 patients with first episode of psychosis, more than half (52%) presented with a comorbid SUD, most often alcohol or cannabis (14). A British survey of 123 patients with first episode of psychosis found that the frequency of substance use is twice that of general population and more common in men, with cannabis being the most frequently used drug other than nicotine (51%), followed by alcohol (43%). The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study was conducted across 57 U.S. clinical sites and included 1460 individuals with DSM-IV schizophrenia. At baseline, 60% individuals of the study sample were found to use at least one “substance of abuse” (illicit substances and alcohol), including 37% with evidence of an SUD (15). When compared with nonusers, those who use illicit substances and alcohol (with or without a diagnosed SUD) were more likely to be male, African American, less educated, and recently homeless. Furthermore, they were more likely to report childhood conduct problems, a history of major depression, and to have suffered a recent exacerbation of schizophrenia. Interestingly, substance use (with or without a

diagnosed SUD) was generally associated with higher or equivalent overall psychosocial functioning at baseline compared to abstinence from substance use (16). From the same study, a recent report examined the relationship between severity of illicit substance use at the time of study entry and 18-month longitudinal outcomes. It was found that those with moderate to heavy use of substances had significantly poorer outcomes in the domains of psychosis, depression, and quality of life compared with both those with mild use and abstainers (17). Some data suggest that the use of drugs or alcohol can lead to the earlier onset of schizophrenia in an already vulnerable individual (18). Cannabis is linked to an earlier onset of schizophrenia and more severe positive symptoms among individuals with schizophrenia (14,19,20). Substance use is also associated with an increased duration of untreated schizophrenia (21) and noncompliance with treatment (22). In first-episode patients, substance use is also associated with poorer functional response, more frequent relapses, and a greater symptom burden (23). The addition of illicit drug use often increases and exacerbates psychotic symptoms in psychiatric patients. In this population, ingestion of even relatively small amounts of drug over a short period can result in an exacerbation of psychiatric problems, increased risk of relapse and hospitalization, use of emergency department services, heightened risk of HIV or hepatitis B or C infections, suicidal behavior, loss of housing, or increased vulnerability to exploitation (sexual, physical, or other) (19), and poorer prognosis of medical conditions, such as diabetes, in patients with schizophrenia (24). In addition, medication nonadherence and substance use were found to negatively impact hospital readmission in a study of Australian patients with psychosis (20). Nicotine/tobacco use disorder is very common (70%-90%) and a major cause of increased morbidity and mortality in patients with psychotic disorders (25). A recent meta-analysis suggested that daily tobacco use is associated with an increased risk of psychosis and an earlier age at onset of psychotic illness; however, whether or not there is a causal link between tobacco use and psychosis remains unknown and merits further examination (26). Tobacco use by those with psychotic disorders is now receiving more clinical attention. Treatment guidelines and research are now available to guide clinical practice, including adding tobacco treatment to treatment plans (27,28). Effective strategies to address tobacco use in mental health and addiction treatment settings require broader system-level changes, supportive of and consistent with program missions, and patient recovery goals (29,30). Treatment of co-occurring

nicotine/tobacco use disorder among individuals with schizophrenia often requires a combination of medications and psychosocial treatment approaches, including continuity of care between primary care providers and community tobacco treatment resources (25). Organizational change strategies have been effective at decreasing tobacco use in addiction and mental health settings and at addressing barriers to integrated care (29,30). With adequate training, mental health clinicians can effectively help people with co-occurring nicotine/tobacco use disorder and schizophrenia improve their motivation and achieve tobacco abstinence (31). The Learning About Healthy Living (LAHL) treatment manual is available online and has been demonstrated to help individuals with lower motivation to learn more about the risks of ongoing tobacco use, increase motivation to change, increase orientation to wellness, and also decide to try to quit tobacco use (32).

Primary Care or Other Healthcare Settings Drug-induced exacerbation of psychotic disorders and transient substanceinduced psychotic symptoms are not uncommon in the emergency room setting; however, these cases are far less common in general primary care practices. Of the limited research for this category, most has occurred in the emergency room setting (33). For a patient who experiences psychotic symptoms and is actively using a substance at the same time, it is often challenging to determine whether the psychotic symptoms are due to a primary psychotic disorder or are substance induced, especially in the emergency room setting, where collateral information may not be available. Schanzer et al. reported that clinicians in psychiatric emergency rooms appear to have a tendency to attribute psychotic symptoms to a primary psychotic disorder rather than to co-occurring substance use (34). The incorrect diagnosis may have long-term negative implications including the associated stigma, unnecessary inpatient hospitalization, and inappropriate treatment with antipsychotic medications.

DIFFERENTIAL DIAGNOSIS A new patient presenting with both psychotic symptoms and active substance use can be a diagnostic dilemma, and the differential diagnosis must be broad. In addition to a primary psychotic disorder, clinicians must consider the possibility that these symptoms are caused by a general medical condition (Table 95-2) or

substance intoxication or withdrawal (Table 95-3). Psychotic symptoms can occur as the presenting symptom or may be part of a more complex syndrome of cognitive disorders, such as delirium or dementia. Psychotic symptoms can occur in the context of other categories of mental disorders, particularly affective disorders. For example, delusions or hallucinations may be a symptom of major depression or the mania phase of bipolar disorder, both disorders with strong association in the substance-disordered population.

TABLE 95-2 Psychosis Secondary to Medical Conditions

TABLE 95-3 Substances That Cause Psychotic Symptoms

The type and duration of psychotic symptoms are important in making a differential diagnosis. The following are general considerations; the DSM-5 should be consulted for more specific, definitive guidance. Psychotic symptoms

that have a sudden onset and that last more than 1 day but 7 mg, there are reports of more profound dissociative effects and “out of body” experiences (86–88). Excessive doses have resulted in respiratory depression, tachycardia, and hypertension (89). These doses may also result in false-positive urine immunoassay for phencyclidine (90). Management includes withdrawal management with activated charcoal and naloxone (although with limited efficacy) (91) though observation and symptomatic treatment are often sufficient.

MDMA (“Ecstasy”) and Psychosis 3,4-Methylenedioxymethamphetamine (MDMA or “ecstasy”) is a derivative of methamphetamine, which has a mixed spectrum of effects, including stimulant and hallucinogenic. MDMA increases the release and inhibits the reuptake of serotonin, dopamine, and norepinephrine from presynaptic neurons, as well as decreasing their degradation by inhibiting monoamine oxidase (92). Those who use MDMA report enhanced empathy, feelings of closeness to others, euphoria, mood elevation, greater tendency to socialize, increased selfesteem, and altered visual perceptions (37). Hallucinations associated with use

generally are mild but can be intense and severe. Deaths have occurred in cases that presented as a syndrome featuring severe hyperthermia, altered mental status, autonomic dysfunction, and dystonia (93). The mechanism is unclear, but, as with a serotonin syndrome, MDMA can have a direct effect on the thermoregulatory mechanisms that potentiate the context of the drug use. For example, MDMA often is used in the setting of dance parties where there is sustained physical activity, high temperatures, and inadequate fluid intake resulting in dehydration and an electrolyte imbalance. Concern about the long-term neurotoxicity of MDMA is growing. Long-term use can result in serotonin neural injury associated with psychiatric presentation of psychosis, panic attacks, anxiety, depression, flashbacks, and memory disturbances (94). Although older individuals with schizophrenia may be less likely to use MDMA, use of it and other designer drugs, prescription drugs, and substances must be considered and ruled out with new onset of psychosis.

Management of Schizophrenia Comorbid Substance Use Disorder

With

Pharmacological Treatment Antipsychotic medications are often an important component of the treatment of psychotic disorders in reducing long-term positive symptoms. Medications should be complemented by psychosocial therapy that engages patients, offers them practical training in interpersonal communication and crisis management, and develops their rehabilitation and recovery skills. The first step in medication management of co-occurring SUD and schizophrenia is to consider the best approach to treating the patient’s schizophrenia or chronic psychosis. This should be followed by consideration of the potential interactions between the substances used and the possible medication choices. In general, clinicians should avoid prescribing medications that cause sedation when treating patients who misuse sedating substances. In addition, clinicians generally should avoid prescribing medications with misuse liability. Patients who present with active substance use, psychotic symptoms, and noncompliance can be difficult to manage as outpatients. Improving medication compliance can be enhanced by reducing positive and negative symptoms, providing psychoeducation and social skills training in medication management,

using motivational enhancement techniques, establishing between-visit telephone contact, and switching the route of administration of the medication from oral dosing to a long-acting injected medication if patients are unable or refuse to take oral medications. Providing more intense monitoring and services via admission to a level of care higher than outpatient can be very helpful. Over the past decades, atypical antipsychotic medications have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of schizophrenia. Some of these drugs also have been studied for the treatment of SUDs (with and without coexisting schizophrenia) (12,19,95). This class of medication has the benefit of decreasing extrapyramidal side effects, when compared with conventional antipsychotics. In addition to acting on the dopamine system, atypical antipsychotics also bind to the serotonin system, which is thought to play an important role in maintaining addiction via craving. An accumulating body of literature has suggested that atypicals have some effectiveness in reducing use and craving for substances (96). Clinical judgment based on the individual patient’s situation should guide the choice of which antipsychotic medication is recommended. Some studies have found no difference between conventional and atypical antipsychotics used to treat patients with co-occurring disorders (97), while others have found that the atypical class may have some advantages (12,19,98–101). In some studies, clozapine appears to be more effective than risperidone (12,19,95,102) and olanzapine (101) in reducing alcohol and/or cannabis use and/or craving among patients with schizophrenia or schizoaffective disorder. A study by Brunette et al. (103) indicates that clozapine may also prevent relapses in patients with schizophrenia using alcohol, cannabis, or cocaine. Furthermore, risperidone and clozapine appear to reduce the likelihood of relapse for patients addicted to opioids (104). Akerele and Levin in a 14-week trial comparing olanzapine and risperidone in the treatment of patients with concurrent schizophrenia and cocaine/cannabis use showed a similar reduction in positive symptoms and improved adherence rates. There was a significant reduction in the use of cannabis in the risperidone group compared to those taking olanzapine; however, there was no significant difference in overall effect (105). Risperidone and ziprasidone increased patients’ retention in co-occurring treatment compared with olanzapine or conventional antipsychotics (106).

Interactions Between Substances and Antipsychotic Medications

Substances can interact with antipsychotic medications and, therefore, affect their efficacy and side effects in schizophrenia treatment. For example, in the CATIE study, illicit substance use was shown to attenuate the apparent superiority of olanzapine over the other antipsychotics based on the primary outcome measure of time to all-cause treatment discontinuation (107). The interactions are both pharmacokinetic and pharmacodynamic. By-products of tobacco smoking, particularly the polycyclic aromatic hydrocarbons, are metabolic inducers of the cytochrome P-450 1A2 isoenzyme (CYP1A2). Smoking is known to decrease blood levels of haloperidol, fluphenazine and thiothixene, olanzapine, and clozapine (101,108–110). Abstinence from smoking increases blood levels of antipsychotic medications. Smokers usually are prescribed approximately double the dose of conventional antipsychotic medications that is given to nonsmokers (111). There is a report of clozapine toxicity and seizure in the context of a quit attempt, presumably related to a sudden increase in serum levels of the drug (112). The effect on metabolism is important in making treatment decisions regarding inpatients whose smoking is curbed, as well as the patient who is attempting to quit smoking. The aggressive use of nicotine/tobacco use disorder treatments (including pharmacological) may not only reduce the high morbidity and mortality from this addiction but also enable the use of lower antipsychotic doses, thus reducing metabolic, neurological, and other serious side effects from these latter medications. Caffeine, a drug that is more than 90% dependent on CYP1A2 for its metabolism, is widely used in the general population as well as in patients with schizophrenia. Caffeine increases the levels of clozapine and olanzapine through competitive inhibition on CYP1A2 (113). One meta-analysis suggests that patients with co-occurring schizophrenia and SUD (especially cocaine related) are more likely to experience extrapyramidal adverse effects with antipsychotic medication (114). Substance use has been associated with earlier and more severe cases of tardive dyskinesia (115–117). However, other studies concluded that substance use had no effect on movement disorders when important covariates were considered (111,118,119).

Additional Medication Decisions After clinicians have chosen a primary medication treatment option that stabilizes the psychotic symptoms, they can consider the use of additional medication, as necessary, to manage comorbid depression, comorbid SUD, or

another psychiatric problem. For substance use, medications are chosen for specific purposes, including both withdrawal management and improvements on SUD-related outcomes (relapse rates, craving, etc.).

Psychosocial Treatment Individuals with both co-occurring mental health and SUD or those with substance-induced psychosis will benefit from both comprehensive psychosocial interventions and pharmacological treatments (120). This section will, however, focus on those individuals with a co-occurring mental health and SUDs as opposed to individuals with substance-induced psychosis. In both acute and long-term settings, research has demonstrated the importance of developing a positive therapeutic alliance as a cornerstone of psychosocial treatment. Moreover, research suggests that patients are more responsive and often willing to engage in treatment when the therapist consistently acts as a nurturing and nonjudgmental ally (121,122). Beyond the therapeutic alliance, there are a number of core treatment strategies that can improve the lives of such patients. Carey (123) has suggested a five-step “collaborative, motivational, harm reduction” approach: establish and develop a working alliance (124), help the patient evaluate the cost–benefit ratio of continued substance use (decisional balance in motivational enhancement therapy [MET]) (14), help the patient develop individual goals (125), help build a supportive environment (126) and a lifestyle that is conducive to abstinence, and helping learn to anticipate and cope with crises (20,123). Psychosocial treatment requires an awareness of the perceived “selfmedication” aspects of why individuals with schizophrenia believe they continue to use substances. Despite the negative consequences associated with a SUD, some individuals with schizophrenia report that using substances helps them cope with symptoms of their schizophrenia (27,127). While clinicians are likely to hear “self-medication” explanations from their patients, the skilled clinician will listen thoughtfully but understand that the research data supporting the concept are mixed (128). For example, individuals diagnosed with schizophrenia usually exhibit impaired sensory gating (operationalized in neurophysiological tests as a lack of P50 and P300 inhibition in the two-click paradigm), which can improve temporarily after nicotine use. On the other hand, quitting smoking leads to significant improvements in anxiety, depression, and stress in both psychiatric and nonpsychiatric populations (129). Providers need to understand these motivations of “self-medication” in order to help individuals develop

alternative ways to manage the symptoms they are self-treating with substances. Additionally, counseling can introduce other possible explanations for the individual’s ongoing use, such as treating withdrawal symptoms (not necessarily stress). Nonetheless, working with these patients requires that the therapist be direct in addressing inconsistencies. For example, if a patient has recent positive cocaine urine samples, yet denies any use during the preceding month, the clinician should be understanding of the initial stage of recovery, but point out the discrepancy. Abstinence may be a goal; however, the poorly motivated individuals may benefit from motivational interviewing to increase motivation to stop using substances and to maintain compliance with psychiatric treatment. Keeping patients engaged requires efforts to treat their schizophrenia and to provide encouragement and other “rewards” for small steps toward reducing substance use. It is important to evaluate outcomes other than total abstinence; for example, the clinician might assess the patient for reduced quantity or frequency of substance use, participation in treatment or other activities, compliance with medications and appointments, progress toward short-term goals, and involvement of family or significant others in treatment.

LONGER-TERM MANAGEMENT Ongoing treatment of psychosis and addiction requires integrated treatment that attempts to reduce the likelihood of relapse to substances and noncompliance with medications and promotes recovery and wellness. Clinical experience has shown that some psychiatric patients will continue to simultaneously display psychotic symptoms and actively use substances. If the diagnostic assessment was uncertain and the patient is able to achieve prolonged abstinence, the clinician then can consider withdrawing the medication and initiating a medication-free period. Symptoms that continue despite abstinence will require formal treatment. The optimal long-term management for schizophrenia is a combination of antipsychotic treatment, psychosocial treatment, and case management as needed. Long-term psychotherapy should consider a dual recovery therapy approach that integrates the best of mental health and addiction psychotherapy.

Management of Substance Use Disorders

With Co-occurring Psychotic Disorders Pharmacological Treatment of Substance Use Disorders For the treatment of alcohol use disorder, the U.S. FDA has approved the use of three adjunctive medications: disulfiram, acamprosate, and naltrexone. Disulfiram, a medication used to promote alcohol abstinence, shows some benefits in patients with schizophrenia and AUD (3,12,19,102). The clinical record of disulfiram is mixed, and a recent meta-analysis showed no difference between treatment and control groups in blinded studies (130). However, there was an effect in open-label studies. The possibility of an alcohol–disulfiram reaction requires that it be given only to patients who comprehend the consequences of alcohol consumption when taking disulfiram. According to some clinicians, administration of disulfiram at high doses (1000 mg) has produced psychotic symptoms in patients not diagnosed with psychotic disorders. Roncero et al. (96) caution against the use of disulfiram in patients with history of affective disorders, suicidality, cognitive deterioration, or poor impulse control. One should consider monitoring of hepatic function (12,19). Clinical studies of naltrexone, an opioid antagonist, in this population are supportive of their use in this population (131). Naltrexone is a relatively safe medication that can be used with patients who are at risk of relapse to alcohol; no alcohol/naltrexone reaction has been reported. Naltrexone’s most common side effects include headache and nausea. Naltrexone can precipitate opioid withdrawal, so clinicians should carefully assess patients’ use of prescription or illicit opioid prior to the administration of this medication. Liver function tests should be monitored when using either disulfiram or naltrexone. Naltrexone, an opioid receptor agonist, reduces drinking days, heavy drinking, craving, and overall use of alcohol in patients with co-occurring disorders (12,19). Although both acamprosate and long-acting injectable naltrexone have been shown to be safe and effective in treating AUD, there are no systematic studies of their use in patients with comorbid schizophrenia and AUD. Long-acting injectable naltrexone should be considered in the noncompliant patient. For cocaine addiction, there are no FDA-approved medications. For individuals with schizophrenia and cocaine addiction, there are numerous small studies that suggest some promise for a range of medications (desipramine, selegiline, mazindol, and amantadine); however, there is no strong evidence that any are effective. The best option is often to provide integrated psychosocial treatment and adjust the antipsychotic medication as needed (110,122,126).

Pharmacotherapy for tobacco addiction can include FDA-approved medications such as nicotine replacements (transdermal patch, gum, lozenge, spray, or inhaler), bupropion (Zyban), or varenicline (Chantix). FDA-approved pharmacotherapies combined with specialized tobacco treatment programs appear to benefit this population (109,124,126). Moreover, a recent large trial (132) compared varenicline and bupropion to nicotine patch or placebo in individuals with psychiatric disorders (including psychosis) and found no significant increase in subsequent risk of a diverse range of adverse effects. Despite modest evidence of an increased risk of psychosis due to bupropion (133), as an adjunct to antipsychotic medication, bupropion may help patients with co-occurring disorders who want to stop smoking (19,102), without adversely affecting their mental state (134). However, its potential to reduce the seizure threshold limits its use in the presence of an antipsychotic with similar effect, such as clozapine (96). There is some evidence that patients also prescribed atypical antipsychotics will have higher rates of abstinence, lower rates of attrition, and lower levels of expired carbon monoxide compared to those on typical antipsychotics (124). An important finding was that psychiatric symptoms were not exacerbated with abstinence (124,135).

Psychosocial Treatment Psychosocial treatment is considered an integral part of managing co-occurring disorders, according to a recent Cochrane review (136). Of note, all of the reviewed psychosocial interventions appear to be helpful, and there was not any relative advantage of any specific psychosocial intervention for those with SUD and severe mental illness (136). Co-occurring disorder treatment programs have used psychosocial interventions in strikingly different ways, but there are many core similarities. Some have favored an active outreach case management approach, whereas others have relied more heavily on MET in the clinical setting (122,137–140). Three specific psychosocial treatments that are commonly used across approaches and fundamental to co-occurring treatment are MET (141), relapse prevention (142), and 12-step facilitation (143). However, these three treatment approaches require modification from their original form due to the biological, cognitive, affective, and interpersonal issues often present among individuals with schizophrenia. These modifications of conventional SUD treatments should take into account the common features among individuals with schizophrenia, including lethargy as well as low motivation and self-efficacy, cognitive deficits, and maladaptive interpersonal skills. These psychosocial issues both highlight the need and sometimes difficulty for a strong treatment

alliance (117). The 12-step approach has been modified for people with cooccurring disorders, who often have reported some difficulty in engaging in 12step groups, given the perceived stigma toward individuals with serious mental illnesses and the cultural opposition to use of psychiatric medications. Dual Recovery Anonymous meetings, sometimes called Double Trouble, encourage recovery for both problems and emphasize the importance of taking appropriately prescribed medications. Spiritual health also is a focus of the meetings, including connecting with a higher power, developing a sense of community, and finding meaning and purpose in life. The research has shown that Double Trouble participation has both direct and indirect favorable effects on several important components of recovery, including abstinence from substances, medication adherence, self-efficacy for recovery, and improved quality of life (144). Several co-occurring treatment approaches with similar behavioral therapy models have been suggested. The Motivation-Based Dual Diagnosis Treatment model employs a stage-matching approach that combines mental health and addiction treatments, based on the patient’s motivational level, severity of illness, and dual diagnosis subtype. The Motivation-Based Dual Diagnosis Treatment approach acknowledges the distinctive features of the schizophrenia– addiction subtype (122). The model uses stages of change in assessing the patient and matches treatment strategies and goals (such as abstinence or harm reduction, medication compliance, session attendance) to the individual’s stage of readiness to change. MET is a primary psychosocial approach for the patient with poor motivation. However, when the traditional MET approach is used with co-occurring disorders, clinicians should recognize the need for adjustments, which include the following: The clinician should play a more active role in offering practical, useful solutions to the patient’s concerns about everyday survival. The clinician should not assume that such patients have the personal tools or social resources to solve problems effectively while actively engaged in addictionrelated behaviors. MET should be formulated as a continuing component of treatment rather than being limited to the four sessions that were envisioned for those with a diagnosis of SUD without schizophrenia The decision balance intervention, a cornerstone of MET, should be employed so that it fully accounts for the experience of substance use in relation to other and more systemic problems, such as schizophrenia and

medication compliance. The clinician should acknowledge that individuals with co-occurring disorders may not consistently accept the diagnosis of schizophrenia, may vary in their willingness to maintain medication for schizophrenia, and may have greater or lesser motivation to stop their substance use. Attending to the role of motivational stage is important to the success of the treatment plan. Clinicians must work to strengthen patients’ motivation while confronting the effects of schizophrenia and stressing the importance of medications in managing the condition. Interventions that address individual stages of change have an impact not only on rates of substance use but also on the severity of psychotic symptoms and on the need for antipsychotics (145). Certain conditions can work to accelerate a patient’s motivation to change through use of external motivators. Because external motivation often is lacking among patients with co-occurring disorders, the community reinforcement approach (146), including contingency management, explores a range of possible motivators—disability income, probation, family, and so forth—and uses those motivators to engage, support, and monitor patients in treatment. Treatment must address not only the effects of low motivation but also potential deficiencies in the cognitive skills. In individuals with schizophrenia, such levels often are lower than normal, so that the benefits of traditional relapse prevention treatment, which is built on a cognitive learning model, are sharply reduced (142). Thus, the treatment model must be modified and tailored to this patient population, switching the treatment emphasis from cognitive to behavioral approaches as needed. Traditionally, relapse prevention and 12-step facilitation have been used in addiction settings to help patients with a range of social, interpersonal, and problem-solving skills that lead to self-esteem and self-efficacy (147). Selfefficacy, in particular, is directly related to the change processes that influence maintenance and relapse (142,148). Relapse prevention and 12-step programs can help individuals increase their self-efficacy and self-esteem. However, relapse prevention therapy tends to be administered in a cognitive therapy manner, while clinical experience suggests using a more action-oriented behavioral approach, featuring role-playing, modeling, coaching, positive and negative feedback, and homework. Traditional psychiatric approaches of social skills training use this methodology in rehabilitation programs (149,150). The Lieberman modules include psychosis symptom management, medication management, leisure skills, conversation skills, and community reentry.

Traditional relapse prevention is easily adapted to work with individuals with schizophrenia with a focus on addressing difficulties in communication and problem solving. Dual Recovery Therapy integrates substance use relapse prevention, psychiatric social skills training, MET, and the “recovery language” of 12-step programs in linked group and individual treatment sessions (122). MET and recovery language were added to address patients’ often low levels of motivation for change and to take advantage of the common lexicon of the 12-step programs, with which many patients already were familiar. The resulting treatment is designed to enhance intrinsic motivation for change, bolster the patients’ sense of self-efficacy, improve their social skills, and give them tools for coping with high-risk situations. Training is grounded in cognitive– behavioral theory and targets the schizophrenic person’s cognitive difficulties (attention span, reading skills, and ability to abstract). The ability to communicate and solve problems is developed through role-plays that can be introduced in both group and individual therapy, whereas the understanding and management of their substance use problems are improved through an emphasis on coping strategies (eg, how to organize one’s time). The therapist gives ongoing consideration to both substance use and psychiatric problems, monitors their interaction, and adjusts the treatment emphasis accordingly. A patient’s motivation to address the symptoms of schizophrenia may not be the same as his or her motivation to address substance use, and treatment is best tailored to the individual’s motivation for each problem area. The first month of dual recovery therapy involves twice-weekly individual sessions. Motivation is assessed and enhanced in these early individual sessions, while the therapist works on building a strong therapeutic alliance. A plan for change is discussed, and basic skills that will be necessary for later group sessions are introduced. Subsequent individual sessions focus on reinforcing material discussed in group therapy. After the first month, once a therapeutic alliance has been established and the client has been prepared for group therapy, the structure shifts from two individual sessions per week to one individual and one group session. These sessions are linked, in that individual sessions are used to reinforce the material discussed during the group sessions. Group sessions follow a standard format, which begins with a relaxation exercise, followed by an update report from each client. Group structure is provided by focusing on a specific topic each week (eg, relapse prevention, mood management, symptom management, increasing pleasurable activities, communication skills, asking for help, and medication

compliance). Because skill building plays a central role in dual recovery therapy, behavioral rehearsal and role-playing are used regularly. Exemplary treatment programs for SUD with comorbid psychiatric disorders include the co-occurring disorders treatment program at the West Los Angeles Veterans Affairs Medical Center entitled Maintaining Independence and Sobriety through Systems Integration, Outreach, and Networking (MISSION), which is now listed in the Substance Abuse and Mental Health Services Registry of Evidence-Based Practices. Within MISSION, case managers and peers are trained to deliver dual recovery therapy but also use components of Critical Time Intervention case management and supported education, and most recently, the authors added trauma-informed care (151). Data from two nonrandomized studies (total N = 124) comparing MISSION participants to a comparison group who received VA treatment as usual (TAU) suggested that MISSION-Vet significantly improved treatment attendance, assisted with ongoing engagement in outpatient treatment, reduced the incidence of rehospitalization, and improved mental health and substance use outcomes (99,152). A RCT was also done involving 102 veterans comparing TAU in VA mental health specialty care plus MISSION-Vet (TAU) to a group that received TAU plus health education (health education served as an attention control condition). Those randomized to MISSION-Vet demonstrated significantly better treatment engagement and had fewer substance use days and fewer days of being “bothered” by symptoms compared to those in the attention control (153). In a large 5-year study, 406 homeless veterans received VA homeless specialty care (TAU) or VA homeless specialty care plus MISSION-Vet. Consistent with the previous findings, results suggested that individuals receiving MISSION-Vet were more likely to remain engaged in treatment, less likely to be hospitalized, less likely to use substances, and less likely to be bothered by mental health symptoms compared to those in TAU (154). For individuals with schizophrenia and SUD, the prognosis for long-term improvement and recovery depends on a treatment strategy that addresses both the addiction and schizophrenia, that responds to the unique vulnerabilities (cognitive, affective, social, and biological) of the individual, and that maintains an empathic and collaborative approach. Training programs should be designed to develop basic co-occurring disorders assessment and treatment competencies for all staff members. Clinicians should have skills and knowledge in integrating mental health and addiction treatment approaches, with special emphasis on MET, relapse prevention, and 12-step facilitation for addiction, as well as social skills training

and behavioral therapies for psychiatric disorders. Other helpful strategies include behavioral contracting, community reinforcement approaches, social skills training, money management, peer support/counseling, vocational/educational counseling, and family/network therapies.

Recovery Recovery is a journey of healing and transformation enabling a person with a mental health and/or SUD to live a meaningful life in the community of his or her choice while striving to achieve his or her full potential (155). The journey must include transformation of both mental health and substance use. It is often not a linear process and requires the consumer and provider to have patience and respect for the process. In fact, the journey often involves exacerbations and remissions that are all part of the process. Recovery can be reinforced on multiple levels, including the consumer or provider level as well as the system level. At the consumer or provider level, both parties must first view recovery as a process and have mutual respect for the journey. Both clients and providers must not be frustrated by disruptions or the nonlinearity, as it is the journey itself that is in fact the recovery. Substance Abuse and Mental Health Services Administration’s Center for Mental Health Services Resource Center provides practical assistance and a wealth of resources for designing and implementing antistigma activities and facilitating the process of recovery, including guidance on “Developing a Stigma Reduction Initiative”(155). The SAMHSA definition of recovery is “A process of change through which individuals improve their health and wellness, live a self-directed life, and strive to reach their full potential” (156). Within this broad definition, SAMHSA identified four major domains that support recovery: health, home, purpose, and community. In practical terms, mental health recovery focuses on minimizing the effect of illness on quality of life, rather than just simple symptom reduction, and on fostering patientcentered, autonomy-supporting care (157,158). SUD recovery also considers the importance of abstinence from substances. Recovery is a term being embraced by mental health and addiction treatment provider systems and consumers. In both systems, there is an increased focus by clinicians to engage in supporting recovery and for the systems to integrated peer specialists, consumer-run services, and consumer providers.

Engaging Family and Other Support

Networks Open Dialogue is a Finnish model of psychosocial intervention that was developed to address first break psychosis and has excellent outcomes for longterm recovery (159). This approach is recovery oriented with shared decisionmaking, empowering individuals, and engaging family and support networks. Treatment occurs in treatment meetings with multiple clinicians, the individual at the center of concern, and family/support network members. Meetings occur often in the home, community, and outpatient settings but can occur at any level of care. Open Dialogue has now been adapted and integrated into treatment programs in the United States and Europe. A recent study found good feasibility and acceptance of the approach in a U.S. clinic, as well as significant positive change in symptoms, functioning, and need for care in a small sample (160). Fidelity measures are available for treatment teams and at the organizational level (161).

CONCLUSION The co-occurrence of psychosis and substance use represents a unique challenge to clinicians and policymakers. To address these complex needs, there are numerous evidence-based interventions, which require commitment and innovation in order to be routine and sustainable. Such approaches represent an opportunity for significant improvement in clinical outcomes, morbidity, mortality, and quality of life among individuals with psychosis and substance use.

ACKNOWLEDGMENTS The authors would like to acknowledge Dr. Marc Steinberg, Makenzie Tonelli, Aurelia Bizamcer, and Adrienne Vaiana for their contributions in previous editions of this chapter.

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CHAPTER 96

Co-occurring Substance Use Disorder and Attention Deficit Hyperactivity Disorder Frances R. Levin and John J. Mariani

CHAPTER OUTLINE Introduction Etiology of ADHD and Implications for Substance Use Disorder Vulnerability Neuroanatomical Abnormalities Observed Among Individuals with ADHD Epidemiology of ADHD and Substance Use Disorders The Impact of Having ADHD Alone and with Substance Use Disorders Possible Reasons for Linkage of ADHD and Substance Use Disorders Diagnosis of ADHD Treatment of Co-occurring ADHD and SUD Summary

INTRODUCTION This chapter examines two common psychiatric problems: attention deficit hyperactivity disorder (ADHD), a disorder that manifests itself in childhood, and substance use disorders (SUDs), which often occur in adolescence or early adulthood. Over the past three decades, it has become increasingly clear that most individuals diagnosed with childhood ADHD continue to have impairing symptoms into adulthood (1). The coexistence of a SUD makes it more difficult to treat the ADHD symptoms (2). Similarly, untreated ADHD may make it less likely that standard treatments for SUD will be as effective (3–6). The overrepresentation of ADHD in persons with a SUDs, the reasons for this association, the diagnostic issues related to making the diagnosis of ADHD in adults with a SUD, and the implications for treatment are discussed.

ETIOLOGY OF ADHD AND IMPLICATIONS FOR SUBSTANCE USE DISORDER VULNERABILITY There are numerous etiologies that have been proposed to explain why ADHD occurs. These factors include genetic, environmental, neuroanatomical, neurochemical, and central nervous system (CNS) insults. Evidence of a genetic

basis for the pathophysiology of ADHD derives from family, twin, and adoption studies, as well as molecular genetics research. Numerous twin studies have yielded a heritability estimate of 0.8 (7,8), suggesting that the genetic component is strong, but environmental factors also play a role. Younger parental age (9) and perinatal factors (10) are associated with an increased risk for ADHD, suggesting complex interactions between genetic and environmental risk factors. Adoption studies have confirmed that familial clustering of ADHD is due to genetics rather than a shared environment (11). Molecular genetics studies support the theory that ADHD is a heterogeneous disorder, dependent on several interacting genes. Prominent among these are the genes for the dopamine transporter (DAT) and the D4 dopamine receptor (DRD4) (7,8,12–14). Notably, 9-repeat allele carriers of the DAT have been associated with enhanced neural responsivity to nicotine cues and may have a role in alcohol use disorder, whereas 10-repeat homozygosity of DAT1 may contribute susceptibility to ADHD (15–17), suggesting that certain genetic aberrations of the DAT genotype are associated with higher risk for ADHD and SUDs. In individuals with ADHD, the 10-repeat DAT1 allele is associated with decreased cortical thickness of the right prefrontal cortex (PFC) (18). Altered DRD4 expression results in reduced receptor effectiveness and increased gamma-aminobutyric acid transmission, thereby decreasing pyramidal cell firing (19). Various polymorphisms of the DRD4 alleles have been shown to be associated with heroin addiction, alcohol use disorder, and ADHD (20–23). Medications that inhibit the DAT, including methylphenidate and amphetamine, increase synaptic dopamine levels and ameliorate the symptoms of ADHD. Other candidate genes of interest that have been associated with ADHD include (a) SNAP-25, which is associated with neuronal release of DA (7,24); (b) serotonin 1B receptor (HTR1B) (25); (c) tryptophan hydroxylase 2 (TPH2), which catalyzes tryptophan to produce a precursor to serotonin (24–26); and (d) alpha-1A adrenergic receptors (ADRA1A) (8,25,27).

NEUROANATOMICAL ABNORMALITIES OBSERVED AMONG INDIVIDUALS WITH ADHD Neuroimaging studies of ADHD patients have demonstrated reduced volume of the PFC (28). The PFC is densely populated with DA receptors (especially D1)

and NE receptors, and balanced DA tone in the PFC is essential for normal working memory function and attention regulation (19,29). Dysfunction in these brain areas is also thought to be associated with the poor inhibitory control and addiction (30). Structural imaging studies of ADHD patients have revealed several common findings: smaller volumes in the dorsolateral PFC, cerebellum, and subcortical structures (31,32). Of note, Castellanos et al. (33) found a fixed brain volume abnormality in ADHD: smaller total cerebral brain volumes from childhood through adolescence (33). Another important functional neuroimaging finding has been that the dorsal anterior cingulated cortex shows hypofunction in ADHD on tasks of inhibitory control (34). The hypothesis that dysfunction in frontal–subcortical pathways occurs in ADHD is supported by brain imaging studies, implicating the caudate, putamen, and globus pallidus, all of which provide feedback to the cortex for regulation of motor control, inhibition of behavior, and modulation of reward pathways (31,35). Notably, positron emission tomography using a raclopride tracer (a D2 receptor ligand sensitive to competition from endogenous dopamine) found decreased dopamine transmission in the caudate and other limbic regions among individuals with ADHD (36). The authors suggest that these abnormalities may contribute to the vulnerability to SUDs among those with ADHD. Certain environmental risks have also been associated with both ADHD and SUD. These include maternal smoking during pregnancy, premature birth, and low birth weight. McCormick et al. (37) also demonstrated that in low birth weight children, hyperactivity symptom scores increase as birth weight decreases. Manzardo et al. (38) found that premature birth was associated with later alcohol use disorder in boys, although not in girls. Prenatal environmental tobacco smoke is also a strong risk factor for ADHD. In a large nationally representative sample of children aged 4-15 years, Braun et al. (39) found that the overall adjusted risk for ADHD was 2.5-fold higher for children exposed prenatally to tobacco smoke. Notably, maternal smoking has been associated with an increased risk for nicotine use disorder in adolescent girls (40). It may be that for some ADHD individuals with comorbid tobacco/substance use disorder, there are common underlying risk factors that may be modifiable.

EPIDEMIOLOGY OF ADHD SUBSTANCE USE DISORDERS

AND

ADHD is the most common behavioral disorder of childhood, affecting 8% to 18% of children and adolescents worldwide (41). Up to 60% of children with ADHD continue to have symptoms into late adolescence and adulthood (42–44). Thus, not unexpectantly, a replication study of the National Comorbidity Survey (NCS) found the rate of adult ADHD to be 4.4% (45). A subsequent metaanalysis of six carefully selected studies found a somewhat lower ADHD prevalence rate of 2.5% (46). The authors note that this rate may be somewhat low because it was based on the use of strict Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV), criteria as well as several methodological difficulties that occurred in assessing for adult ADHD symptoms. Clinical experience suggests that many patients do not meet full criteria in adulthood but do continue to have significant impairment as a result of persistent ADHD symptoms. Several studies have demonstrated that the onset of substance use occurs earlier among adolescents with ADHD, and particularly those with hyperactive– impulsive symptoms (47,48). Further, SUD is overrepresented among those with both ADHD symptoms and the full ADHD diagnosis (49,50). In the National Comorbidity Survey Replication study, 15.2% of those with ADHD, compared to 5.6% of those without ADHD, had a SUD (45), demonstrating that SUDs are overrepresented in the general population of ADHD adults. In a subsequent study using the National Comorbidity Survey Replication Adolescent Supplement sample, Kessler et al. (51) found that the onset of adolescent substance use was earlier for those with ADHD compared to those without ADHD, but those with conduct disorder had an even earlier onset of substance use. Using another large sample of adolescents (the National Health and Nutrition Examination Survey), Brinkman et al. (52) found that ADHD and conduct disorder were associated with earlier onset of tobacco and alcohol use than having neither disorder. ADHD alone was associated with increased tobacco but not alcohol use. In a recent analysis of the National Epidemiology Survey on Alcohol and Related Disorders (NESARC), over 33 000 respondents were queried about ADHD symptoms, substance use, and SUDs (53). Even after adjusting for conduct disorders, both substance use and SUDs were associated with having ADHD symptoms (not the full diagnosis of ADHD at 17 years or younger), ADHD-combined, ADHD-hyperactive/impulsive, and ADHD-inattentive subtypes. Notably, regardless of ADHD diagnostic subtype, the lifetime prevalence rates for alcohol, nicotine, or cannabis use disorders were 20% or greater, with the highest rates consistently in the combined group. Similar to

work of others (47,54), having ADHD-hyperactive/impulsive symptoms was more reliably associated with substance use or SUD compared to having inattentive ADHD symptoms (53). Taken together, these studies suggest that ADHD and substance use are not independent disorders and that their association is not the result of ascertainment bias. Individuals with ADHD also have a greater likelihood of nicotine use disorder. Adults with ADHD have higher rates of nicotine use disorder than the general population (40% vs. 26%). The odds of current smoking in adolescents with clinically significant inattentive ADHD symptoms were 2.8 times greater than for those without inattentive ADHD symptoms (55,56). Analysis of the Longitudinal Study of Adolescent Health, a large perspective epidemiological survey of adolescents, found that for each self-reported inattentive and hyperactive symptom, the risk of lifetime tobacco smoking increased. Further, for those reporting ever smoking, increase in symptoms was associated with earlier age of smoking and number of cigarettes smoked (57). In meta-analyses conducted by Charach et al. (58) and Lee et al. (49), ADHD was associated with nicotine use and nicotine use disorders, along with other SUD. In a prospective study, Lambert and Hartsough (59) noted that individuals with ADHD had early onset of regular smoking and adults with ADHD were more likely to smoke daily than were controls. Additionally, adults with ADHD who smoke cigarettes have been found to experience more severe withdrawal when they cease smoking compared to those without ADHD. Similar and perhaps more striking than community samples is the overrepresentation of ADHD in treatment populations. Following up on smaller prevalence studies (60,61), a recent large multisite sample prevalence study conducted in ten countries found that the mean rates of adult ADHD in adults seeking treatment for their SUDs were 14% using DSM-IV criteria and 17% using DSM-5 criteria. Moreover, a meta-analysis of 29 studies evaluating for ADHD in adolescents and adults with various SUDs obtained an overall rate of 23%, with a confidence interval of 19%-27% (62). Notably, rates of ADHD were higher among those with cocaine use disorders in the van de Glind study but lower than other substance using groups in the van Emmerik study. Taken together, ADHD is commonly found among those seeking treatment for their SUD and yet surprisingly goes unrecognized in psychiatric (63) as well as substance use treatment populations.

THE IMPACT OF HAVING ADHD ALONE

AND WITH DISORDERS

SUBSTANCE

USE

ADHD has substantial morbidity in and of itself. In an individual with ADHD, occupational and social deficits attributed to substance use may be due in small or large part to persistent ADHD symptoms. Mannuzza and Klein (64) noted that children with ADHD who were followed into adulthood were more likely to have completed less schooling, to hold occupations with less professional or social status, to suffer from poor self-esteem, to have social skill deficits, and to have antisocial personality disorder (ASPD). Murphy and Barkley (65) found that, as adults, individuals who were diagnosed with ADHD in childhood were more likely to have had their driver’s licenses suspended, to have incurred speeding violations, to have quit or been fired from a job, and to have been married multiple times. ADHD symptoms appear to place these individuals at great risk for ASPD, mood and anxiety disorders, and SUDs (47,64,66–68). Women with ADHD may be particularly vulnerable to eating disorders, such as bulimia (69). In a longitudinal study, women with ADHD had fewer romantic relationships and poorer self-esteem than those with ADHD (70). Moreover, persistent symptoms seem to place individuals at greatest risk for early substance use (48,71). Individuals with ADHD have higher rates of incarcerations (66), recidivism, and violent criminal behavior (72,73). When ADHD symptoms are co-occurring with those of a SUD, the severity of impairment of each disorder is likely to increase. Moreover, the individual’s response to addiction treatment is adversely affected by comorbid ADHD. Biederman et al. (74) found that following a period of SUD, adults with ADHD were more likely to transition from an alcohol use disorder to a drug use disorder and to continue to use substances than were similar patients without ADHD. Likewise, among individuals with a lifetime history of a SUD, those who also had ADHD evinced a longer duration of having a SUD and a slower remission rate (75). Carroll and Rounsaville (3) compared the clinical course of cocaine use among individuals with and without childhood histories of ADHD. Those with childhood ADHD had an earlier onset of regular cocaine use, more frequent and intense cocaine use, and greater lifetime treatment exposure. Similarly, Levin et al. (76) found that among individuals with DSM-IV cocaine dependence entering a therapeutic community, those with ADHD were less likely to graduate from the program, compared to those with depression (and no ADHD) or those without

ADHD or depression. Graduation is an important milestone associated with better long-term outcome. Based on these findings, it is increasingly evident that ADHD may exert a negative effect on the course of a SUD and that treatment needs to be targeted at both the psychiatric and substance use disorders.

POSSIBLE REASONS FOR LINKAGE OF ADHD AND SUBSTANCE USE DISORDERS There are many pathways leading from having ADHD to the development of a SUD. In a comprehensive review, Molina and Pelham (77) put forth some of the underlying variables associated with ADHD (eg, biological vulnerabilities, impulsive anger, neurocognitive deficits) as well as intervening variables (eg, social difficulties, academic difficulties, conduct problems) that may lead to substance use and SUD. Because it is beyond the scope of this chapter, we will only focus on a few of these important variables that may explain the observed link between ADHD and SUD. There is considerable evidence that individuals diagnosed with childhood ADHD who also have conduct disorder as children are more likely to develop problems related to substance use (75,78–80). Further, in some clinical samples of delinquent adolescents, the presence of ADHD is associated with more severe conduct disorder symptoms and greater number of substance dependencies (79). Of note, in a 2-year follow-up study of adolescents with co-occurring DSM-IV substance dependence and conduct disorder, severity of initial conduct disorder and age of onset, but not severity of ADHD or treatment duration, predicted worse substance dependence outcomes (81). While some prospective studies suggest that the increased risk for substance use among ADHD children is mediated by conduct disorder (82–84), other studies suggest that ADHD confers a risk for substance use, even in the absence of conduct disorder (85,86). Further, several investigators have found that a substantial proportion of individuals with adult ADHD have an ongoing SUD in the absence of ASPD (47,87,88). In one review of 10 longitudinal studies, Lee et al. (49) concluded that the risk of developing a SUD may be partially or fully accounted by disruptive disorders. A subsequent meta-analysis by Serra-Pinheiro (89) of 16 studies found that when conduct disorder was controlled for ADHD was no longer conferred a risk for either illicit substance use or SUDs but

acknowledged that they were unable to look at different ADHD subtypes because of power limitations. Moreover, the authors note that it may be the ADHD that results in school failure, deviant peer groups, and the likelihood of both conduct disorder and substance use. Molina and Pelham (77) conclude that trying to control for CD when trying to determine the risk for SUD may “miss the potential for the cascading pattern of vulnerability that starts with temperament, childhood escalation of disruptive behaviors such as rule breaking and defiance and culminates with expanded behaviors that include early/heavier/escalating problematic substance use.” Regardless of how critical it is to focus on ADHD with CD or ADHD alone, it remains an open question whether ADHD alone confers a risk for illicit substance use and SUD in adolescents. Perhaps more important is whether or not the ADHD symptoms persist into late adolescence and adulthood. Once regular substance use is established, the presence of ADHD symptoms may increase the likelihood of heavy and impairing use, even in the absence of a disruptive disorder. Impulsivity is another factor that may facilitate the initiation and persistence of drug use among individuals with ADHD. A growing preclinical and clinical literature suggests that impulsivity is associated with increased likelihood of developing or having a substance use problem (90–92). Impulsivity, a common feature of ADHD, is associated with the inability to inhibit responses. More broadly, individuals with ADHD are often thought to have problems in executive function including difficulties in impulse control, attention, planning, and goaldirected behavior. Increased impulsivity may facilitate risk-taking behavior, involvement with drug-using peers, and poor cognitive skills to weigh the negative consequences of drug experimentation and continued substance use (55,56). Consistent with this, some investigators have found that ADHD individuals with hyperactivity/impulsivity, but not inattentive symptoms, are more likely to have early-onset substance use or eventual substance use problems than those without any ADHD symptoms, even in the absence of conduct disorder behaviors (47,48). While impulsivity may lead to substance use problems, individuals with ADHD may choose to use and eventually use various substances to mitigate ADHD symptoms or associated dysphoria (93,94). Deregulation and overexpression of the DAT also have been implicated in the pathophysiology of ADHD (7). As mentioned previously, the 10-repeat allele of the DAT gene has been associated with ADHD (95,96). Moreover, Gold et al. (97) conclude that ADHD risk has been associated with “homozygotes for risk alleles of the DRD2, 5HTT and DAT1 genes.” Genes coding for dopamine beta-hydroxylase along with other genes

involved in serotonin and glutamine transmission have been associated with ADHD (7,97). Unlike disease caused by single genes, ADHD is a highly hereditable, polygenic disorder. However, the “primary candidate genes associated with ADHD are involved in dopamine functioning, lending support to studies implicating catecholamines in the pathophysiology of ADHD” (12,98). In a recent study, assessment of adolescents with varying number of ADHD symptoms and hemizygotes expressing low production of MAO-A had blunted reward sensitivity and impaired prefrontal inhibition (99), suggesting that certain subgroups of individuals with ADHD symptoms might have a reward deficiency syndrome (100) and be at a higher risk for developing a SUD (6). In a comprehensive review, Kalivas and Volkow (101) note that all substances with nonmedical use liability produce their euphorigenic effects through their direct or indirect release of dopamine in the “reward” system of the brain consisting of the ventral tegmental area of the brain and the nucleus accumbens. With chronic drug use, derangements in the dopaminergic system produce a relative hypodopaminergic state. Supporting this, Nutt et al. (102) reviewed numerous studies that used PET imaging and 11C-raclopride PET binding to assess stimulant–dopamine release in persons with a chronic alcohol and other substance use disorder and found that regardless of the substance used, synaptic ventral striatal dopamine levels were lower in the persons with a SUD compared to placebo. Interestingly, one study found that high-risk young adults who had not yet developed a SUD were more likely to have diminished dopamine signaling compared to controls (103), suggesting that there may be impaired dopamine transmission prior to the onset of a SUD. Further, Kalivas and Volkow (101) adduce evidence from functional imaging studies among heavy drug users, which reveal that basal prefrontal regulation of behavior is reduced, contributing to the diminished salience of nondrug motivational stimuli and reduced decision-making capacity. What remains unclear is whether adults with a SUD develop dopaminergic derangements as a result of heavy chronic substance use or had underlying deficits prior to the drug use. If the latter is true, for individuals with hypodopaminergic functioning, in the prefrontal regions of the brain, as documented among individuals with ADHD (104,105) or other psychiatric conditions, such as schizophrenia (106), substances with nonmedical risk liability may be more salient and thus more likely to lead to a SUD. This concept of a common vulnerability has some support by family–genetic studies that have found higher than expected rates of alcohol and other SUDs in non–ADHDaffected relatives of probands who have ADHD but no co-occurring SUD.

Further evidence for this link comes from a family-based study evaluating the influence of parental SUD and ADHD on the risk for ADHD in offspring. While there may be a common risk for SUD and ADHD (107–109), several studies suggest independent risk (110). A potentially concerning explanation for the observed association between ADHD and substance use is that exposure to stimulants—even that prescribed by treatment providers—increases the likelihood that an individual will develop a problem with stimulants. This heightened risk is thought to occur by (a) the process of behavioral sensitization or (b) patients’ belief that, because a stimulant medication has been prescribed, they can use cocaine or other drugs without difficulty. In a meta-analysis, Humphreys et al. (111) concluded that the aggregate data do not support that stimulant treatment increases the risk of nonmedical substance use or use disorder. However, the authors did not find that treatment reduced risk compared to an earlier meta-analysis (112). Subsequent to this meta-analysis, one longitudinal study found that stimulant treatment of ADHD in childhood, particularly when administered from an early age, was associated with a lower risk for a SUD (113). Further, another recent metaanalysis that looked at longitudinal studies that target cigarette smoking found that stimulant treatment reduced the likelihood of cigarette smoking while controlling for conduct disorder (114). Limitations of many of the earlier studies that have attempted to assess whether stimulant medications are protective or potentially harmful have been the lack of attention to age of onset of stimulant medication and duration of treatment. In a recent analysis of 10 cohorts of seniors from the Monitoring the Future study, among ADHD adolescents, those administered with ADHD medication from an earlier age or longer duration were less likely to be current smokers or have past year use of illicit drugs (115). Consistent with this, a large Swedish registration study, which assessed individuals between 1960 and 1968, found that longer duration and earlier initiation of ADHD stimulant medication were associated with significant reduction in having a SUD at follow-up in 2009 (54). Taken together, these new data support that early initiation of ADHD treatment and longer treatment are protective into adulthood. From a clinical perspective, an untreated child is more likely to function poorly in school, seek out other marginalized peers, and become involved with alcohol or drugs. Moreover, one might postulate that sustained improvement in ADHD symptoms would be more likely to enhance psychosocial functioning and reduce the likelihood of SUD. Clearly, more research is needed to elucidate the relationships among ADHD, its treatment, and the development of SUDs.

DIAGNOSIS OF ADHD ADHD is characterized by inattention, impulsivity, and hyperactivity. To meet DSM-5 criteria for ADHD, individuals must have either (a) six symptoms of inattention in childhood or five symptoms at age 17 years or older (inattentive presentation) or (b) six symptoms of impulsivity and hyperactivity in childhood or five symptoms at age 17 years of older (impulsive/hyperactive presentation) or (c) both (combined presentation). Individuals who met full criteria in childhood but currently have fewer than six symptoms of inattention or hyperactivity/impulsivity are described as having ADHD, in partial remission. Some ADHD symptoms need to occur prior to the age of 12. This represents a change from DSM-IV where the age criterion required impairing symptoms prior to the age of 7; it is expected that this change will raise the prevalence rates in general and treatment populations. Further, some impairments from these symptoms need to be present in two or more settings, and the symptoms must produce clear evidence of significant impairment. Moreover, the symptoms cannot be better accounted for by another mental disorder (DSM-5, American Psychiatric Association [APA]) (116). The ADHD criteria emphasize both the developmental aspect of the disorder and the fact that childhood behavior problems often are situation bound. The more settings in which deviant behavior occurs, the more justified one is in saying that the behavior interferes with the child’s functioning and therefore warrants a diagnosis. A child who appears distracted and inattentive in only one setting (such as at school), but can listen well and pay attention in other settings, may have a learning disability rather than ADHD (117) or may have a cooccurring learning disability (118). Faraone et al. (109) argue convincingly that the diagnosis of ADHD may be particularly sensitive to developmental changes because the symptoms are performance based rather than experiential. For example, an individual being evaluated for ADHD is asked about his or her behavior (such as how well he/she follows directions or completes tasks), whereas an individual with depression is asked about his or her internal states (such as feelings of sadness or hopelessness) as well as behavioral manifestations (such as changes in sleep pattern or appetite).

Utility of ADHD Screening Instruments in

Substance-Using Populations Although ADHD is common among those with nicotine, alcohol, and other SUDs, it is often not assessed (119). While it is not unreasonable to intensively evaluate all persons who use substances for ADHD, a quick and more costeffective approach, particularly in clinical settings, is to administer a reliable screening instrument followed by a standardized diagnostic interview for likely cases (120). Three commonly used instruments include the Wender Utah Rating Scale (WURS, 25 items) (120), which screens for childhood ADHD, the Conners’ Adult ADHD Rating Scale (CAARS, 18 items) (65), and Adult ADHD Self-Report Scale Version 1.1 (ASRS-VI.I, 6 items) (121). Each of these screens has been used in the general and treatment populations with good results (45,65,76,120,122–124). The utility of these instruments in active substance users has also been studied in individuals with SUD. In a small Spanish sample of individuals with substance use problems, the ASRS-V1.1 was found to have good sensitivity (87.5%) (125). Another ADHD screening instrument, the Attention-Deficit Scales for Adults (ADSA), has also been evaluated in persons with an active SUD. This questionnaire, somewhat longer than the other instruments, consisting of 54 items, was found to have reasonable sensitivity (0.71) and specificity (0.82). Recently, a study was conducted to assess the clinical utility of three of the short, commonly administered instruments (eg, the WURS, the CAARS [18item], and the ASRS-V1.1) in a population of individuals currently seeking treatment for cocaine use disorder (126). The validity of the instruments was tested by comparing the screening results to the Conners’ Adult ADHD Diagnostic Interview for the DSM-IV (CAADID) (127). All three instruments demonstrated adequate sensitivity, specificity, and positive/negative predictive values, with the CAARS outperforming the rest on predictive parameters and the WURS having the greatest sensitivity. While these findings suggest that standard ADHD screening instruments may be reasonably applied in persons with an active SUD, the study was relatively small and conducted with primary cocaine users. In a subsequent study, the validity of the ASRS-V1.1 was assessed in a large sample (n > 1000) of treatment seekers coming for treatment for various SUDs. The sensitivity was good (at 0.84). Although the positive predictive validity was relatively low (0.26), the negative predictive validity was high (0.97), suggesting that few cases of ADHD were missed (128). The ASRS-V1.1 may be uniquely practical in that it is much shorter (only six items) and has

reasonable sensitivity and specificity. Thus, the implementation of these instruments with populations with ongoing SUDs is reasonable but should not replace a careful diagnostic evaluation.

Use of Neuropsychological Testing to Confirm ADHD Diagnosis ADHD is a clinical diagnosis that is best made by carrying out a comprehensive assessment that includes developmental history, learning history, evaluation of other psychiatric comorbidities, and medical evaluation. Although various neuropsychological tests, electrophysiological data, and neuroimaging tests have found differences among adults with and without ADHD (129–131), no test has adequate specificity to “diagnose” an individual with ADHD (132,133). However, continuous performance tests are the most evidence based of currently available psychological tests, demonstrating reasonable sensitivity and specificity and promising positive predictive power (132). Computer testing shows areas of dysfunction that may or may not be consistent with ADHD. However, testing may be useful for treatment or educational planning (119,132,134) since learning disabilities and academic underachievement are common in individuals with ADHD (64,135). While the utility of these tests in active substance-using populations has not been established (119), observing how individuals behave while taking neurocognitive tests can provide useful clinical information. An individual who demonstrates short latency responses, uncritical and careless performance with frequent false starts, off-task behaviors, and concentration problems might indicate the presence of ADHD (136).

Difficulties in Diagnosing Adult ADHD in Substance-Using Populations Although the DSM-5 provides clear-cut criteria for making the diagnosis of adult ADHD, diagnostic ambiguity often arises when one attempts to apply these criteria to individuals who have hazardous use of alcohol and other drugs. When possible, it is best to assess individuals when they have been abstinent for 2-4 weeks to assure the acute effects of alcohol or drugs or withdrawal from alcohol and/or drugs are not complicating the diagnosis. However, this should not preclude making a diagnosis if the patient is unable to become abstinent,

particularly when the patient is being evaluated in an outpatient setting.

Potential Reasons for Underdiagnosis As mentioned earlier, recalling symptoms that began at an early age can be problematic. While this is somewhat mitigated by the raising of the age of onset from 30 mg total per day, particularly if it is a high dose, so that doses can be modified according to patient response. If a patient cannot take oral medications, methadone can be given parenterally at half the documented oral dose. Liquid methadone “microenemas” have also been given via tuberculin syringe (no needle) in cancer pain with good results.

Patients Receiving Buprenorphine for Pain or Opioid Use Disorder Strategies for managing acute pain in individuals taking buprenorphine are emerging as experience accumulates. Buprenorphine binds avidly to opioid receptors and thus tends to block the action of other opioids; thus, it is sometimes challenging to obtain analgesia by adding another opioid (243). If acute pain occurs due to trauma or illness in a patient on buprenorphine, mu opioids can usually be titrated to higher doses to overcome the buprenorphine blockade. Use of an opioid such as IV fentanyl or IV or oral hydromorphone, which bind with relatively high affinity to mu opioid receptors, is often recommended, though morphine and others have been used effectively (244). Opioid titration in this setting should be done by an experienced clinician with close monitoring of the patient with naloxone available. When acute pain can be predicted in persons on buprenorphine, such as after elective surgery, some experts discontinue buprenorphine a few days before surgery (245–247). Carefully dosed methadone can be added if needed if withdrawal symptoms or craving emerge after stopping buprenorphine while waiting for surgery. However, other experts note the challenges of reinducing patients on buprenorphine once acute pain is resolved and report good results with continuation of buprenorphine and titration of an alternative opioid to achieve analgesia in the same manner as for unanticipated acute pain (248).

Alternatively, a patient on a low-dose buprenorphine (2-8 mg/d) may receive acceptable analgesia from a temporarily increased daily dose that is often administrated BID to achieve around-the-clock analgesia. Buprenorphine has been demonstrated effective in patients not currently using opioids in controlling acute pain (235,236). Because of its partial agonist properties and its near full receptor occupancy at relatively low doses, buprenorphine has traditionally been thought to have a ceiling effect for analgesia; however, this view has been challenged by recent studies and observations (249,250).

Document the Pain Treatment Plan It is important to be clear in communicating the pain treatment plan to all staff involved in caring for a patient with SUD. Stigma and misunderstanding are widespread among healthcare personnel, and these may lead to inadequate pain management when the primary treating clinician is not available and the plan is not clearly documented. In the absence of a clear and consistent structure, the patient’s behaviors may foster confusion of pain and addiction issues. Written documentation of the plan, displayed in a prominent and accessible location, may be necessary.

When Pain Persists Beyond Apparent Healing Many factors may lead a patient to report pain and to evidence a need for pain medications despite expected and apparent healing from surgery, trauma, illness, or other pain-provoking pathology. Continuing reports may elicit concerns that the patient’s behaviors reflect SUD rather than pain. However, it is important to methodically consider other possible explanations before concluding that this is the case. First, the patient may have an undetected physical problem, related either to the original painful problem or to a separate process. A thorough search for such a cause should be undertaken. The search should include a review of nociceptive causes of pain, such as an abscess or undetected fracture, as well as less common and often overlooked neurogenic causes of pain such as a neuritis, deafferentation pain, central sensitization, or evolving sympathetically maintained pain. A surprising number of common surgical procedures have protracted pain as a frequent complication, probably due to such factors as central sensitization and nerve trauma, referred to as pain chronification (251–253). Thoracotomies, herniorrhaphies, and hip/knee replacements, for example, may have a 40%-60% rate of protracted pain complications.

Second, the patient may be physically dependent on opioids and may be experiencing pain related to withdrawal as the medication is discontinued. As noted, withdrawal may mediate pain through a variety of mechanisms, including alterations in sympathetic arousal, changes in muscle tone, and alterations in opiate and other receptor function. Tapering of opioids slowly to avoid withdrawal is described earlier, and if medically feasible, is generally preferable to faster tapers that are associated with physical withdrawal. If increased discomfort occurs during the course of an appropriately crafted medication taper, the patient should be reexamined for an undetected physical origin of the pain. If none is found, nonopioid therapy should be optimized (such as TENS, NSAIDs, acetaminophen, antidepressants including duloxetine or TCAs, nerve block therapy, or physical and behavioral pain treatment modalities) and reduction of the opioid dosage may be continued with consideration for slowing the rate of taper. In most cases, the increased discomfort will be transient if withdrawal was the cause. If pain persists and no physical cause can be identified, treatment should be as for chronic pain. The third reason that a patient may seek to continue opioids when the underlying pain condition has resolved is that the medications may be ameliorating nonpain symptoms, such as sleep disturbance, intrusive memories, anxiety, or depression. Directed treatments usually are indicated and may allow tapering of pain medications in patients whose physiological pain driver has resolved. If a physical cause of pain, withdrawal-associated discomfort, or selfmedication is not present, SUD reassessment is needed. In a general hospital population, the latter reason is probably less common than the first three possibilities; however, it is likely relatively more common in the population treated by addiction medicine specialists. If SUD is suspected, the patient should be observed for behaviors suggestive of the diagnosis, including loss of control, continued use despite harm, and preoccupation with opioid use, with the understanding that any of these may be seen in patients with significant pain that is not effectively treated. The patient’s substance use history (including alcohol, tobacco/nicotine, and other drugs), as well as his or her family history of addiction, may add further useful information. If the patient has previously been in recovery, reengagement in recovery activities is imperative. Any active, untreated SUD is an indication for evaluation by an addiction specialist if available. If present, the patient’s opioids

can be tapered and alternative pain treatments implemented while SUD treatment is provided. Unless an underlying physical cause is identified, pain may resolve or improve after discontinuation of medications and treatment of addiction. If opioid taper is impeded by persistent craving or unsanctioned use, OUD pharmacotherapy, with either buprenorphine/naloxone or methadone, should be considered. If a taper is not possible because of recrudescence of pain despite alternative therapies, temporary continuation of opioid therapy, coupled with the necessary structure and support, may be selected as a component of chronic pain treatment and under close observation. If both persistent pain and OUD are present, combined opioid agonist therapy for addiction and nonopioid therapies for pain with collaborative care between SUD treatment providers and pain providers is indicated. Buprenorphine may be administrated BID to provide analgesic effect around the clock in patients with pain and OUD (see section in this chapter on Management of Chronic Nonmalignant Pain). A final consideration in the differential diagnosis of reports of persistent pain despite apparent healing is that the pain may be malingered. Occasionally, persons may feign pain in order to divert medications for sale, for personal use, or to share with others. Opioids must be discontinued if an individual is found to be diverting them, as use in this manner is both illegal and presents significant risk to the public health. In addition, a prescriber who knowingly provides opioids to a person who is diverting them may be liable to charges of drug trafficking. If the cause of reported persistent pain cannot be identified and there is no evidence that the patient is seeking drugs for nonanalgesic purposes, the clinical care team may consider to temporarily continue the opioid therapy while maximizing nonopioid therapy and with close monitoring of the patient’s pain, side effects, and function. If the patient’s quality of life is preserved or advanced without negative consequences, it may be that an undetected basis for the pain is present. The second choice is to taper opioids while maximizing the nonopioid pain treatment modalities. Which choice is appropriate for a particular patient is a decision best made by the clinical care team, with the patient’s informed participation.

Progressive Cancer-Related or Terminal Pain It has been estimated that pain is present in 24%-60% of persons undergoing cancer treatment, 58%-69% of persons with advanced cancer, and about 33% of

cancer survivors (254). As cancer survival has markedly increased, this creates a new population of persons with cancer or cancer treatment–related pain that is not necessarily related to a terminal illness and may persist in some patients despite cancer remission. Early studies reported low rates (5%) of SUD in oncology patients (255–257), whereas more recent examination of Medicare data found that the prevalence of SUD in men with advanced prostate cancer to be 10.6% (258) and another review found an OUD prevalence rate of 7.7% in patients with cancer pain of all types (259). Increased rates of oncological disease in patients with alcohol use disorder are suspected due to the known injurious effects of alcohol on cells and body tissues. Inflammatory or other repair responses to cellular injury can result in DNA mutations that play a role in inducing neoplastic changes. A chart review of 598 patients with advanced cancers found that 17% were positive for DSM-IV-TR–defined alcohol dependence on the CAGE screening tool, and only 13% were identified as with the same diagnosis before their palliative care consultation (260). They were also more likely to be taking potent opioids at the time of referral than patients who screened negative for SUD. Although not diagnostic of OUD, 39%-43% of patients with cancer on opioids screened with a score at medium to high risk for DSM-IV defined opioid abuse on standard screening tools. Treatment of advanced cancer-related pain in the patient with the disease of addiction is usually similar to that in the person without addiction; the comfort of the patient should be the primary goal. Opioids generally should not be withheld in patients with terminal illness when they are needed and effective because of concerns regarding addiction. However, if SUD-related problems are diminishing the patient’s quality of life, it can be necessary to maximize external controls (eg, having medications dispensed daily by others) and to insist on concomitant SUD recovery work or to rely on nonopioid treatments (261,262). The “therapeutic ladder” developed by the WHO is an accepted model for the treatment of cancer pain (Fig. 104-3) (263). Stage 1 of the ladder is for the management of mild pain and involves the use of nonopioid analgesics such as acetaminophen, aspirin, or NSAID as well as adjuvant medications such as tricyclics, anticonvulsants, and topical agents for pain and such associated symptoms such as insomnia, depression, and anxiety. Stage 2 of the WHO ladder addresses moderate pain. It involves use of a weak opioid preparation that combines opioids with acetaminophen or NSAID. Adjuvant medications for neuropathic pain and other symptoms should be used as indicated. For patients with continuous moderate pain, it is also reasonable to use a low dose of a long-

acting opioid. This may avoid the intermittent peak effects of short-acting opioids that some experience as rewarding and which may be disconcerting to some patients in recovery. If these are selected in place of combination medications, additional acetaminophen or NSAIDs usually should be added for their complementary analgesic effect.

Figure 104-3 The WHO step ladder for cancer pain treatment. Nonpharmacological pain treatment modalities should be used first line as appropriate for the pain condition and should be included for pain treatment at all levels of pain severity. Stage 3 of the WHO ladder, for management of severe pain, involves use of a titratable, potent opioid plus nonopioid analgesics and adjuvants as indicated. It is important to note that NSAIDs are particularly effective for bone pain related to metastases, so their continuation often is important even in the presence of high-dose opioids. Treatment should start as far along the ladder as necessary to achieve pain control. Aggressive titration of opioids is appropriate to control progressive cancer-related pain, which usually can be managed with oral or transdermal opioids. If these are not feasible because of absorption problems, vomiting, or technical problems with transdermal patches, parenteral treatment may be required, including continuous or PCA IV or subcutaneous administration or even intrathecal analgesia.

When opioids are not sufficient to control pain or have unacceptable side effects, more invasive approaches may be considered (264). Intraspinal infusions and nerve or plexus blocks may provide effective relief for many types of cancer pain (265). Neuroablative procedures such as celiac plexus block for pancreatic cancer pain and nerve root blocks for pain localized to one or two specific dermatomes (particularly if they serve sensory rather than motor functions, as in single-rib metastases) may provide definitive relief in difficult cancer pain situations (266). Spinal cord or peripheral nerve stimulation is helpful in some patients (267). Cancer may be accompanied by significant distress arising from fear, grief over impending losses, depression, anger, and spiritual conflict, which patients may try to self-medicate with opioids. However, in the case of the patient with SUD, such use causes further declines in function and quality of life. Directed, evidence-based nonpharmacological and pharmacological means of addressing such stressors should be employed. For many individuals in SUD recovery, appropriate resources may provide meaningful support. Therefore, it is helpful for the clinician to assess the patient’s experience with recovery and to help sustain participation in or reengaging with recovery groups, sponsors, and programs if these have been meaningful to the individual in the past.

Chronic Nonmalignant Pain Etiology and Phenomenology of Chronic Pain Chronic pain may occur for a variety of reasons. Tissue pathology may be ongoing or flare intermittently, stimulating nociceptive pain, such as in degenerative arthritis, relapsing pancreatitis, or sickle cell disease. Neuropathic pain such as a neuritis, neuropathy, phantom (deafferentation) pain, central sensitization (windup) pain, or sympathetically maintained pain continues after healing from an acute painful injury or from successful treatment of cancer. Or the experience of pain may have become intractable owing to entrenched psychosocial and behavioral patterns that have emerged over the course of experiencing persistent nociceptive or neuropathic pain and now reinforce or predominate the experience. Whatever the contributors to pain, chronic pain can engender secondary sequelae, such as sleep disturbance, mood disturbance, functional disabilities, increased stress, and/or self-medication with alcohol or other drugs that may

serve to perpetuate the experience of pain, creating an entrenched and intensified chronic pain syndrome. Active SUDs often have similar sequelae to those of chronic pain with respect to poor functionality and diminished quality of life. Therefore, when chronic pain and SUD co-occur, they may reinforce one another (Fig. 104-4), and it is important to address each of these conditions.

Figure 104-4 Synergy of pain and addiction. In the treatment of chronic pain, nonpharmacological strategies and nonopioid pharmacological strategies are preferable to opioid therapy, as outlined in most pain treatment guidelines put forth over the last several decades and as strongly articulated in the 2016 CDC guidelines (48) and the 2017 VA/DoD guidelines for opioid therapy in patients with chronic pain (49) and for low back pain (50). Effective treatment often demands a multidimensional approach and an active role on the part of the patient in both understanding and managing the pain. A foundation of self-care provides a context in which more specific therapies may be successful. Components of effective treatment often include physical rehabilitation, physical therapy modalities, cognitive–behavioral techniques,

meditation/relaxation, regional anesthesia, CIH modalities such as acupuncture and chiropractic manipulation, and nonopioid medications. These approaches are discussed in more detail in Chapters 101, 102, and 103. Opioids may temporarily provide additional benefit in selected patients with chronic nonmalignant pain as part of a multimodal pain treatment program and may be considered when other appropriate interventions fail to provide adequate relief or when other options pose greater risk. Any opioid therapy, however, and in particular long-term opioid therapy of chronic pain pose a spectrum of risks, for the individual patient and for the public health, as discussed elsewhere. In long-term opioid therapy, tolerance or hyperalgesia may lead to diminishing benefits for most patients, and unhealthy use may occur in vulnerable individuals. These clinical complications, along with the social harms of rising diversion and unhealthy use of opioids, coupled with the lack of clear evidence of long-term efficacy across the general population indicate great caution when using opioid therapy in chronic pain (48,49). The risks related to long-term opioid therapy likely outweigh the potential benefit in most patients, and the 2017 VA/DoD guidelines include a strong recommendation against initiation of long-term opioid therapy altogether (49) and in particular recommend against long-term opioid therapy in patients with untreated SUD and for patients < 30 years of age (49). In persons with SUDs, the risks are even greater than for the general population, making opioid therapy especially challenging, and new starts of long-term opioid therapy in patients with history of OUD should be avoided. Any new initiation of opioid therapy requires a careful balancing of potential risks and benefits, tailored to the individual, in order to make the best decision for and with the patient. The patient must be fully informed about the risks of opioids, the clinical justification for their use, and the risk mitigation strategies that will be implemented. All these discussions must be documented in the health record (48,49,268,269).

Universal Precautions in Opioid Therapy for Chronic Pain Because the risk of unhealthy opioid use for a given patient cannot be reliably determined, it is prudent to view all patients as having some level of risk and to employ a set of universal precautions in managing all patients (48,49,270–272). Just as the adoption of universal precautions has reduced transmission of infectious diseases, treating all patient as at risk for aberrant substance-related behaviors reduces the chances of adverse outcomes for both patient and provider.

The application of precautions only to selected patients believed to be at higher risk can result in stigmatizing those patients and missing other, less obvious, persons at risk. Commonly discussed universal precautions for opioid therapy include the following: Comprehensive pain assessment Assessment of risk for unhealthy opioid use Formulation of a differential diagnosis of contributing factors to pain Informed consent for treatment following risk–benefit discussion Documentation of a clear plan of treatment Initiation of opioid therapy as a trial with clear goals Reassessment of pain, level function, quality of life, and adherence to plan of care Urine drug testing (UDT) prior to opioid prescribing and routinely during opioid therapy at random intervals Querying state prescription drug monitoring programs (PDMP) prior to opioid prescribing and routinely during opioid therapy in concordance with state and federal guidelines Documentation of decision-making and care Opioid overdose education and prescribing of naloxone rescue medication Several of these elements of universal precautions bear further discussion. In addition, it is important to appreciate emerging evidence regarding opioid dosing for chronic pain.

Unhealthy Opioid Use Risk Assessment All patients with chronic pain are at risk of unhealthy opioid use and development of OUD when opioid medications are prescribed, even within the context of a comprehensive pain treatment plan and close monitoring. The most consistently described risk factors are prior SUD or mental health disorders. Other risk factors include younger age, male gender, history of incarceration, current cigarette smoking, early onset of substance use/unhealthy use, and history of childhood trauma. Though risk cannot always be accurately assessed, there is agreement among most clinical experts and regulatory boards that it is imperative to screen patients for risk of unhealthy opioid use before initiating opioid therapy for pain. Standard assessment of substance use history, when performed in medical settings, most often includes inquiry about past and present alcohol, tobacco, and illicit drug use (including treatment) and screening with CAGE (cutting down, annoyance by criticism, guilty feeling, and eye-

openers), DAST (Drug Abuse Screening Test), ASSIST (Alcohol, Smoking and Substance Involvement Screening Test), or other common instruments (273–275). A number of screening tools specifically designed to assess for risk of unhealthy medication use in the pain treatment setting are available in the literature; however, recent meta-analyses found insufficient evidence for their effectiveness in reducing unhealthy medication use or the development of SUD. For example, the Opioid Risk Tool (ORT), a five-question screening tool that is based on the patient’s personal and family history, has shown reasonable ability to discriminate between high- and low-risk patients (276), and Screener and Opioid Assessment for Patients in Pain—Revised (SOAPP-R), a 24-item selfreport screening tool, reports good predictive ability (277). Validity data have also been reported for a more recent screener, the Brief Risk Interview (BRI), composed of 12 items and designed to be administered by a clinician. However, studies comparing the predictive accuracy of the ORT, the SOAPP-R, and the BRI found highly variable and inconsistent rates of sensitivity and specificity; similarly, likelihood ratios for both the ORT and SOAPP-R were evaluated as essentially noninformative. It is important to be aware that none of these tools has been specifically validated for use in populations with identified SUDs. Though not a screen for risk per se, the Addiction Behaviors Checklist (ABC) (278) or Prescription Drug Use Questionnaire (PDUQ) (128) can be used to track behaviors of concern between clinic visits. Another promising tool to detect opioid misuse (a form of unhealthy opioid use) is the Current Opioid Misuse Measure (COMM), which has demonstrated 77% specificity and 77% sensitivity in identifying current prescription opioid misuse disorder in a primary care setting (279). Due to the limitations associated with the predictive and concurrent validity associated with these screeners, composite indices have also been described combining scores from tools with urine toxicology results. For example, Jamison et al. (280) created the Aberrant Drug Behavior Index (ABDI) and the Drug Misuse Index (DMI), which combines PDUQ or ABC scores with urine toxicology to predict relative risk.

Opioid Treatment Agreements A written opioid treatment agreement (OTA) is a valuable tool that can help ensure that the patient understands the potential risks and benefits of treatment. It may also help to mitigate the risks of treatment, though there is limited evidence of improvement in treatment outcomes (48,49,281–283). Most often,

the treatment agreement is between patient and clinical treatment providers, though engagement of the pharmacist and family in the treatment plan is likely to improve care (284). Usually, there are two components of an OTA: informed consent and a written plan of care that assures mutual understanding of the treatment plan (285). As described above, the risks of opioid therapy vary from individual to individual, and the degree of risk is not always possible to know when treatment is begun. Therefore, to avoid harm, it is important to treat all patients as having some level of risk and to use an OTA as a basis to inform treatment. The informed consent process should include consideration of the targeted benefits of treatment as well as general and patient-specific risks. Targeted benefits typically include Reduced pain Improved function Enhanced quality of life It is often helpful to establish individual functional goals, as these, along with reported pain, can provide a basis on which to evaluate the efficacy of opioid therapy as well as reflect outcomes that are meaningful to the patient. Functional goals might include, for example, measurable improvement in valued activities such as taking a daily walk of a certain duration, concentrating on reading for a specific period of time, or sitting through a church service or a movie. Discussion of risks should be individualized based on the patient’s history and comorbidities. Among potential risks commonly considered and cited in the informed consent portion of the OTA are Physical side effects (eg, nausea, itching, constipation, sweating) CNS side effects (eg, sedation, cognitive clouding, euphoria) Respiratory effects (eg, shallow breathing, decreased breathing rate, overdose and death) Endocrine effects (eg, low testosterone, amenorrhea, osteopenia) Physiological dependence and tolerance Hyperalgesia, increased pain Morbidity/mortality possible with unhealthy opioid use (including children and adolescents in the home) Substance use disorder

Risk of victimization (manipulation, theft, assault to obtain opioids) In addition, the recent CDC and VA/DoD guidelines suggest that discussion of naloxone use for overdose reversal be included in the informed consent component of the agreement (48,49), although no studies are available of outcomes related to naloxone prescribing to persons using opioids for analgesia. A small survey study of veterans on long-term opioids for pain indicated that they underestimated their risk for opioid overdose (286). Importantly, 21% reported having previously experienced an opioid overdose, and most desired a naloxone rescue kit to enhance their safety (287). Documentation of the plan of care is critical because opioids are subject to unhealthy use and diversion, with the potential for harm to the patient and the public (288). Typically, the plan of care includes such details as the following: Management of medications, such as Use of a single provider (or practice) in charge of prescriptions Which pharmacy will fill Process for dose/frequency changes; avoidance of self-initiated changes Keeping medications secure without sharing Frequency of appointments and urine toxicology testing for use of illicit substances and to confirm presence of prescribed substances Expected other pain treatment activities, for example: Attending cognitive–behavioral groups Physical therapy Exercising independently Meditation/deep relaxation Expected participation in treatment for substance use disorders, for example: AA or NA meetings Counseling Psychiatric care Avoidance of illicit or nonprescribed substances, alcohol, and prescribed CNS depressants in particular benzodiazepines Conditions under which opioids will be continued Improvement in pain Increased function Ability to adhere generally to the plan of care Condition under which opioids will be discontinued

Lack of progress toward goals of treatment Unsafe use of medications or harmful side effects

Urine Drug Monitoring Urine drug testing (UDT) includes UDS and confirmatory testing for unexpected or irregular results on UDS. Toxicology testing is nowadays considered routine prior to initiating opioid therapy and as part of long-term opioid treatment in order to document use of the prescribed medication and to identify use of illicit or nonprescribed substances. UDT can provide objective information, especially important in patients with SUDs who may be unable or unwilling to share accurate information and have difficulty controlling their medication use (289). An analysis within the VHA showed that veterans on long-term opioid therapy receiving care at facilities with more frequent ordering of urine drug screens had lower risk of suicide attempts (290). It is critical that clinicians take care in interpreting the results of the screen and using them to advance the care of patients. Most screening tests are immunoassays that can have false positives due to cross-reaction with other drugs and false negatives due to lack of reactivity to some opioids and sensitivities that are too low to detect low blood levels. Some panels do not test for a wide enough range of opioids, especially synthetics and semisynthetics; thus, certain opioids of concern to the provider will need to be separately added for testing. Drug screening panels differ in the drugs that are detected. Therefore, unexpected findings on a screening test should prompt confirmation usually by liquid or gas chromatography coupled with mass spectroscopy (291,292). Toxicology screens should be approached in a patient-centered way and can provide support for recovery in persons with addiction. Unexpected finding should trigger a discussion with the patient and lead to enhanced treatment of the individual depending on the reason for the finding (292). Care may need to be revised or changed, but toxicology results should be understood as a single point of information among many in the rich array of information the clinician has regarding the patient. In persons with no appreciated special risks for unhealthy medication use and no aberrant behaviors, toxicology testing is done randomly at a minimum of annual basis by many experts, though a recent expert consensus panel funded by a urine toxicology testing company recommended more frequent routine screening (293). For persons at higher risk, testing should be done more often, such as monthly or even more than weekly, especially during periods of high stress (49).

Opioid Dosing Long-term therapy with high-dosage opioids has been associated with increased risk of opioid-related harms including motor vehicle accidents (56), overdose deaths, and OUD (48,49). Thus, there is an increasing consensus that escalating opioid dosages in persons with stable pain disorders should be avoided, and increasing dosage requirements signal the need for reevaluation of therapy and consideration of a change in plan (48,49). Extant data provide good evidence that opioid-related overdose risk is dose dependent. In comparison to patients with chronic pain on low-dose opioids (defined as