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

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

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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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