THE AMERICAN PSYCHIATRIC ASSOCIATION
`
`PRACTICE GUIDELINE
`FOR THE
`Pharmacological Treatment of
`Patients With Alcohol Use Disorder
`
`THE AMERICAN PSYCHIATRIC ASSOCIATION PRACTICE GUIDELINE FOR THE PHARMACOLOGICAL TREATMENT OF PATIENTS WITH ALCOHOL USE DISORDER
`
`A lcohol use disorder (AUD) is a major public health problem in the United States.
`
`The estimated 12-month and lifetime prevalence values for AUD are 13.9% and
`29.1%, respectively, with approximately half of individuals with lifetime AUD
`having a severe disorder. AUD and its sequelae also account for significant excess
`mortality and cost the United States more than $200 billion annually. Despite its high
`prevalence and numerous negative consequences, AUD remains undertreated. In fact,
`fewer than 1 in 10 individuals in the United States with a 12-month diagnosis of AUD
`receive any treatment. Nevertheless, effective and evidence-based interventions are
`available, and treatment is associated with reductions in the risk of relapse and AUD-
`associated mortality.
`
`The American Psychiatric Association Practice Guideline for the Pharmacological
`Treatment of Patients With Alcohol Use Disorder seeks to reduce these substantial
`psychosocial and public health consequences of AUD for millions of affected individu-
`als. The guideline focuses specifically on evidence-based pharmacological treatments
`for AUD in outpatient settings and includes additional information on assessment and
`treatment planning, which are an integral part of using pharmacotherapy to treat AUD.
`In addition to reviewing the available evidence on the use of AUD pharmacotherapy, the
`guideline offers clear, concise, and actionable recommendation statements, each of
`which is given a rating that reflects the level of confidence that potential benefits of an
`intervention outweigh potential harms. The guideline provides guidance on implement-
`ing these recommendations into clinical practice, with the goal of improving quality of
`care and treatment outcomes of AUD.
`
`WWW.APPI.ORG
`
`ALKERMES EXHIBIT 2015
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
`
`Page 1 of 226
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`

`THE AMERICAN PSYCHIATRIC ASSOCIATION
`PRACTICE GUIDELINE FOR THE
`Pharmacological Treatment of
`Patients With Alcohol Use Disorder
`Guideline Writing Group
`Victor I. Reus, M.D., Chair
`Laura J. Fochtmann, M.D., M.B.I., Vice-Chair, Methodologist
`Oscar Bukstein, M.D., M.P.H.
`A. Evan Eyler, M.D., M.P.H.
`Donald M. Hilty, M.D.
`Marcela Horvitz-Lennon, M.D., M.P.H.
`Jane Mahoney, Ph.D., R.N., PMHCNS-BC
`Jagoda Pasic, M.D., Ph.D.
`Michael Weaver, M.D.
`Cheryl D. Wills, M.D.
`Jack McIntyre, M.D., Consultant
`Systematic Review Group
`Laura J. Fochtmann, M.D., M.B.I., Methodologist
`Joel Yager, M.D.
`Seung-Hee Hong
`Steering Committee on Practice Guidelines
`Michael J. Vergare, M.D., Chair
`Daniel J. Anzia, M.D., Vice-Chair
`Thomas J. Craig, M.D.
`Deborah Cowley, M.D.
`Laura J. Fochtmann, M.D., M.B.I., Consultant, Methodologist
`David A. Kahn, M.D.
`John M. Oldham, M.D.
`Carlos N. Pato, M.D., Ph.D.
`Joel Yager, M.D., Consultant
`APA Assembly Liaisons
`John P. D. Shemo, M.D., Chair of Area Liaisons
`John M. de Figueiredo, M.D.
`Marvin Koss, M.D.
`Annette L. Hanson, M.D.
`Bhasker Dave, M.D.
`Robert M. McCarron, D.O.
`Jason W. Hunziker, M.D.
`
`APA wishes to acknowledge the contributions of APA staff (Jennifer Medicus, Seung-Hee Hong, Samantha Shugarman,
`Michelle Dirst, Kristin Kroeger Ptakowski). APA and the Guideline Writing Group especially thank Laura J. Fochtmann,
`M.D., M.B.I.; Jeremy Kidd, M.D.; Seung-Hee Hong; and Jennifer Medicus for their outstanding work and effort in devel-
`oping this guideline. APA also thanks the APA Steering Committee on Practice Guidelines (Michael Vergare, M.D.,
`Chair), liaisons from the APA Assembly for their input and assistance, and APA Councils and others for providing feed-
`back during the comment period.
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`Contents
`
`Acronyms/Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix
`
`Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
`
`Overview of the Development Process . . . . . . . . . . . . . . . . . . . . . . . . . . 1
`Rating the Strength of Research Evidence and Recommendations . . . . 1
`Proper Use of Guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
`
`Rationale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
`
`Guideline Statement Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
`
`Guideline Statements and Implementation . . . . . . . . . . . . . . . . . . . . . . 7
`
`Assessment and Determination of Treatment Goals . . . . . . . . . . . . . . . . 7
`Statement 1: Assessment of Substance Use . . . . . . . . . . . . . . . . . . . . 7
`Implementation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
`Balancing of Potential Benefits and Harms
`in Rating the Strength of the Guideline Statement . . . . . . . . . . . . 8
`Quality Measurement Considerations . . . . . . . . . . . . . . . . . . . . . . . 9
`Statement 2: Use of Quantitative Behavioral Measures . . . . . . . . . . . 10
`Implementation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
`Balancing of Potential Benefits and Harms
`in Rating the Strength of the Guideline Statement . . . . . . . . . . . 11
`Quality Measurement Considerations . . . . . . . . . . . . . . . . . . . . . . 12
`Statement 3: Use of Physiological Biomarkers. . . . . . . . . . . . . . . . . . 12
`Implementation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
`Balancing of Potential Benefits and Harms
`in Rating the Strength of the Guideline Statement . . . . . . . . . . . 15
`Quality Measurement Considerations . . . . . . . . . . . . . . . . . . . . . . 16
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`Statement 4: Assessment of Co-occurring Conditions. . . . . . . . . . . . 16
`Implementation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
` Balancing of Potential Benefits and Harms
`in Rating the Strength of the Guideline Statement . . . . . . . . . . . 17
`Quality Measurement Considerations . . . . . . . . . . . . . . . . . . . . . . 17
`Statement 5: Determination of Initial Treatment Goals . . . . . . . . . . . . 18
`Implementation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
`Balancing of Potential Benefits and Harms
`in Rating the Strength of the Guideline Statement . . . . . . . . . . . 19
`Quality Measurement Considerations . . . . . . . . . . . . . . . . . . . . . . 19
`Statement 6: Discussion of Legal Obligations . . . . . . . . . . . . . . . . . . 19
`Implementation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
`Balancing of Potential Benefits and Harms
`in Rating the Strength of the Guideline Statement . . . . . . . . . . . 20
`Quality Measurement Considerations . . . . . . . . . . . . . . . . . . . . . . 20
`Statement 7: Review of Risks to Self and Others . . . . . . . . . . . . . . . . 21
`Implementation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
`Balancing of Potential Benefits and Harms
`in Rating the Strength of the Guideline Statement . . . . . . . . . . . 21
`Quality Measurement Considerations . . . . . . . . . . . . . . . . . . . . . . 22
`Statement 8: Evidence-Based Treatment Planning . . . . . . . . . . . . . . 22
`Implementation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
`Balancing of Potential Benefits and Harms
`in Rating the Strength of the Guideline Statement . . . . . . . . . . . 23
`Quality Measurement Considerations . . . . . . . . . . . . . . . . . . . . . . 24
`Selection of a Pharmacotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
`Statement 9: Naltrexone or Acamprosate. . . . . . . . . . . . . . . . . . . . . . 25
`Implementation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
`Balancing of Potential Benefits and Harms
`in Rating the Strength of the Guideline Statement . . . . . . . . . . . 27
`Quality Measurement Considerations . . . . . . . . . . . . . . . . . . . . . . 28
`
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`Statement 10: Disulfiram. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
`Implementation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
`Balancing of Potential Benefits and Harms
`in Rating the Strength of the Guideline Statement . . . . . . . . . . . 30
`Quality Measurement Considerations . . . . . . . . . . . . . . . . . . . . . . 31
`Statement 11: Topiramate or Gabapentin . . . . . . . . . . . . . . . . . . . . . 31
`Implementation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
`Balancing of Potential Benefits and Harms
`in Rating the Strength of the Guideline Statement . . . . . . . . . . . 33
`Quality Measurement Considerations . . . . . . . . . . . . . . . . . . . . . . 34
`Recommendations Against Use of Specific Medications . . . . . . . . . . . 34
`Statement 12: Antidepressants. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
`Implementation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
`Balancing of Potential Benefits and Harms
`in Rating the Strength of the Guideline Statement . . . . . . . . . . . 35
`Quality Measurement Considerations . . . . . . . . . . . . . . . . . . . . . . 35
`Statement 13: Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
`Implementation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
`Balancing of Potential Benefits and Harms
`in Rating the Strength of the Guideline Statement . . . . . . . . . . . 36
`Quality Measurement Considerations . . . . . . . . . . . . . . . . . . . . . . 37
`Statement 14: Pharmacotherapy in Pregnant or
`Breastfeeding Women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
`Implementation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
`Balancing of Potential Benefits and Harms
`in Rating the Strength of the Guideline Statement . . . . . . . . . . . 38
`Quality Measurement Considerations . . . . . . . . . . . . . . . . . . . . . . 39
`Statement 15: Acamprosate in Severe Renal Impairment . . . . . . . . . 39
`Implementation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
`Balancing of Potential Benefits and Harms
`in Rating the Strength of the Guideline Statement . . . . . . . . . . . 39
`Quality Measurement Considerations . . . . . . . . . . . . . . . . . . . . . . 40
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`Statement 16: Acamprosate in Mild to Moderate
`Renal Impairment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
` Implementation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
`Balancing of Potential Benefits and Harms
`in Rating the Strength of the Guideline Statement . . . . . . . . . . . 40
`Quality Measurement Considerations . . . . . . . . . . . . . . . . . . . . . . 41
`Statement 17: Naltrexone in Acute Hepatitis or Hepatic Failure. . . . . 41
`Implementation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
`Balancing of Potential Benefits and Harms
`in Rating the Strength of the Guideline Statement . . . . . . . . . . . 42
`Quality Measurement Considerations . . . . . . . . . . . . . . . . . . . . . . 43
`Statement 18: Naltrexone With Concomitant Opioid Use. . . . . . . . . . 43
`Implementation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
`Balancing of Potential Benefits and Harms
`in Rating the Strength of the Guideline Statement . . . . . . . . . . . 43
`Quality Measurement Considerations . . . . . . . . . . . . . . . . . . . . . . 44
`Treatment of Alcohol Use Disorder
`and Co-occurring Opioid Use Disorder . . . . . . . . . . . . . . . . . . . 44
`Statement 19: Naltrexone for Co-occurring Opioid Use Disorder . . . 44
`Implementation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
`Balancing of Potential Benefits and Harms
`in Rating the Strength of the Guideline Statement . . . . . . . . . . . 45
`Quality Measurement Considerations . . . . . . . . . . . . . . . . . . . . . . 46
`
`Areas for Further Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
`
`Guideline Development Process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
`
`Management of Potential Conflicts of Interest . . . . . . . . . . . . . . . . . . . . 49
`Guideline Writing Group Composition . . . . . . . . . . . . . . . . . . . . . . . . . . 49
`Systematic Review Methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
`Rating the Strength of Supporting Research Evidence . . . . . . . . . . . . . 51
`Rating the Strength of Recommendations . . . . . . . . . . . . . . . . . . . . . . . 52
`
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`Use of Guidelines to Enhance Quality of Care. . . . . . . . . . . . . . . . . . . . 53
`External Review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
`Funding and Approval . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
`
`Glossary of Terms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
`
`References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
`
`Disclosures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
`
`Individuals and Organizations That Submitted Comments. . . . . . . . . 79
`
`Appendices: Review of Research Evidence . . . . . . . . . . . . . . . . . . . . 81
`
`Appendix A.
`Clinical Questions and Search Strategies . . . . . . . . . . . . . . . . . . . . . . 83
`
`Appendix B.
`Review of Research Evidence Supporting Guideline Statements. . . . 95
`
`Assessment and Determination of Treatment Goals . . . . . . . . . . . . . . . 95
`Statement 1: Assessment of Substance Use . . . . . . . . . . . . . . . . 95
`Statement 2: Use of Quantitative Behavioral Measures . . . . . . . . 95
`Statement 3: Use of Physiological Biomarkers . . . . . . . . . . . . . . . 96
`Statement 4: Assessment of Co-occurring Conditions . . . . . . . . . 96
`Statement 5: Determination of Initial Treatment Goals . . . . . . . . . 97
`Statement 6: Discussion of Legal Obligations. . . . . . . . . . . . . . . . 97
`Statement 7: Review of Risks to Self and Others . . . . . . . . . . . . . 98
`Statement 8: Evidence-Based Treatment Planning. . . . . . . . . . . . 98
`Selection of a Pharmacotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
`Statement 9: Naltrexone or Acamprosate . . . . . . . . . . . . . . . . . . . 99
`Statement 10: Disulfiram . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
`Statement 11: Topiramate or Gabapentin . . . . . . . . . . . . . . . . . . 172
`Recommendations Against Use of Specific Medications . . . . . . . . . . 190
`Statement 12: Antidepressants . . . . . . . . . . . . . . . . . . . . . . . . . . 190
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`Statement 13: Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . 205
`Statement 14: Pharmacotherapy in Pregnant or
`Breastfeeding Women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205
`Statement 15: Acamprosate in Severe Renal Impairment . . . . . . 205
`Statement 16: Acamprosate in Mild to Moderate
`Renal Impairment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206
`Statement 17: Naltrexone in Acute Hepatitis or Hepatic Failure . 206
`Statement 18: Naltrexone With Concomitant Opioid Use . . . . . . 206
`Treatment of Alcohol Use Disorder and
`Co-occurring Opioid Use Disorder . . . . . . . . . . . . . . . . . . . . . . 207
` Statement 19: Naltrexone for Co-occurring
`Opioid Use Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
`
`Appendix C.
`Additional Study Characteristics Relevant to
` Risk of Bias Determinations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209
`
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`Acronyms/Abbreviations
`
`AA Alcoholics Anonymous
`ACCME Accreditation Council for Continuing
`Medical Education
`AHRQ Agency for Healthcare Research and Qual-
`ity
`ALT Alanine aminotransferase
`APA American Psychiatric Association
`ASAM American Society of Addiction Medicine
`AST Aspartate aminotransferase
`AUD Alcohol use disorder
`AUDIT Alcohol Use Disorders Identification Test
`AUDIT-C Alcohol Use Disorders Identification
`Test–Concise
`CAGE Cut down, Annoyed, Guilty, Eye-opener
`CBI Combined behavioral intervention
`CBT Cognitive-behavioral therapy
`CDT Carbohydrate-deficient transferrin
`CI Confidence interval
`COMBINE Combined Pharmacotherapies and Be-
`havioral Interventions for Alcohol Dependence
`CRAFFT Car, Relax, Alone, Forget, Friends, Trouble
`CrCl Creatinine clearance
`DSM-III-R Diagnostic and Statistical Manual of Men-
`tal Disorders, 3rd Edition, Revised
`DSM-IV Diagnostic and Statistical Manual of Mental
`Disorders, 4th Edition
`DSM-IV-TR Diagnostic and Statistical Manual of
`Mental Disorders, 4th Edition, Text Revision
`DSM-5 Diagnostic and Statistical Manual of Mental
`Disorders, 5th Edition
`eGF Estimated glomerular filtration rate
`FDA U.S. Food and Drug Administration
`GGT Gamma-glutamyl transferase
`GRADE Grading of Recommendations Assess-
`ment, Development and Evaluation
`
`GWG Guideline Writing Group
`HIV Human immunodeficiency virus
`International Classification of Diseases, 10th
`ICD-10
`Revision
`IM Intramuscular
`IRR Incidence rate ratio
`MBSCT Modified behavioral self-control therapy
`MCV Mean corpuscular volume
`MDD Major depressive disorder
`MET Motivational enhancement therapy
`MI Motivational interviewing
`MM Medical management
`NIAAA National Institute on Alcohol Abuse and
`Alcoholism
`NIMH National Institute of Mental Health
`NNT Number needed to treat
`NQF National Quality Forum
`OPRM1 Genotype Opioid receptor μ 1 genotype
`OR Odds ratio
`OTC Over-The-Counter
`PCM Primary Care Management
`PEth Phosphatidylethanol
`Project MATCH Matching Alcoholism Treatments
`to Client Heterogeneity
`PTSD Posttraumatic stress disorder
`QTc Corrected QT interval
`RCT Randomized controlled trial
`RD Risk difference
`SNP Single nucleotide polymorphism
`SRG Systematic Review Group
`TSF Twelve-step facilitation
`USPSTF U.S. Preventive Services Task Force
`WMD Weighted mean difference
`
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`Introduction
`Overview of the Development Process
`
`Since the publication of the Institute of Medicine (now known as National Academy of Medicine) re-
`port, Clinical Practice Guidelines We Can Trust (Institute of Medicine, Committee on Quality of Health
`Care in America 2001), there has been an increasing focus on using clearly defined, transparent pro-
`cesses for rating the quality of evidence and the strength of the overall body of evidence in system-
`atic reviews of the scientific literature. This guideline was developed using a process intended to
`be consistent with the recommendations of the Institute of Medicine (Institute of Medicine, Com-
`mittee on Quality of Health Care in America 2001), the Principles for the Development of Specialty So-
`ciety Clinical Guidelines of the Council of Medical Specialty Societies (2012), and the requirements of
`the Agency for Healthcare Research and Quality (AHRQ) for inclusion of a guideline in the National
`Guidelines Clearinghouse. Parameters used for the guideline’s systematic review are included with the
`full text of the guideline; the development process is fully described in the following document available
`at the American Psychiatric Association (APA) Web site: http://www.psychiatry.org/File%20Library/
`Psychiatrists/Practice/Clinical%20Practice%20Guidelines/Guideline-Development-Process.pdf.
`
`Rating the Strength of Research Evidence
`and Recommendations
`
`Development of guideline statements entails weighing the potential benefits and harms of the
`statement and then identifying the level of confidence in that determination. This concept of
`balancing benefits and harms to determine guideline recommendations and strength of
`recommendations is a hallmark of GRADE (Grading of Recommend ations Assessment,
`Development and Evaluation), which is used by multiple professional organizations around the
`world to develop practice guideline recommendations (Guyatt et al. 2013). With the GRADE
`approach, recommendations are rated by assessing the confidence that the benefits of the statement
`outweigh the harms and burdens of the statement, determining the confidence in estimates of effect
`as reflected by the quality of evidence, estimating patient values and preferences (including whether
`they are similar across the patient population), and identifying whether resource expenditures are
`worth the expected net benefit of following the recommendation (Andrews et al. 2013).
`In weighing the balance of benefits and harms for each statement in this guideline, our level of con-
`fidence is informed by available evidence, which includes evidence from clinical trials as well as ex-
`pert opinion and patient values and preferences. Evidence for the benefit of a particular intervention
`within a specific clinical context is identified through systematic review and is then balanced against
`the evidence for harms. In this regard, harms are broadly defined and may include serious adverse
`events, less serious adverse events that affect tolerability, minor adverse events, negative effects of the
`intervention on quality of life, barriers and inconveniences associated with treatment, direct and in-
`direct costs of the intervention (including opportunity costs), and other negative aspects of the treat-
`ment that may influence decision making by the patient, the clinician, or both.
`Many topics covered in this guideline have relied on forms of evidence such as consensus opinions
`of experienced clinicians or indirect findings from observational studies rather than research from ran-
`domized trials. It is well recognized that there are guideline topics and clinical circumstances for which
`
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`high-quality evidence from clinical trials is not possible or is unethical to obtain (Council of Medical
`Specialty Societies 2012). For example, many questions need to be asked as part of an assessment,
`and inquiring about a particular symptom or element of the history cannot be separated out for
`study as a discrete intervention. It would also be impossible to separate changes in outcomes due
`to assessment from changes in outcomes due to ensuing treatment. Research on psychiatric assess-
`ments and some psychiatric interventions can also be complicated by multiple confounding factors
`such as the interaction between the clinician and the patient or the patient’s unique circumstances
`and experiences. The GRADE working group and guidelines developed by other professional or-
`ganizations have noted that a strong recommendation or “good practice statement” may be appro-
`priate even in the absence of research evidence when sensible alternatives do not exist (Andrews et
`al. 2013; Brito et al. 2013; Djulbegovic et al. 2009; Hazlehurst et al. 2013). For each guideline statement,
`we have described the type and strength of the available evidence as well as the factors, including pa-
`tient preferences, that were used in determining the balance of benefits and harms.
`The authors of the guideline determined each final rating, as described in the section “Guideline
`Development Process,” and is endorsed by the APA Board of Trustees. A recommendation (denoted
`by the numeral 1 after the guideline statement) indicates confidence that the benefits of the
`intervention clearly outweigh harms. A suggestion (denoted by the numeral 2 after the guideline
`statement) indicates greater uncertainty. Although the benefits of the statement are still viewed as
`outweighing the harms, the balance of benefits and harms is more difficult to judge, or either the
`benefits or the harms may be less clear. With a suggestion, patient values and preferences may be
`more variable, and this can influence the clinical decision that is ultimately made. Each guideline
`statement also has an associated rating for the strength of supporting research evidence. Three ratings
`are used: high, moderate, and low (denoted by the letters A, B, and C, respectively) and reflect the
`level of confidence that the evidence for a guideline statement reflects a true effect based on
`consistency of findings across studies, directness of the effect on a specific health outcome,
`precision of the estimate of effect, and risk of bias in available studies (Agency for Healthcare
`Research and Quality 2014; Balshem et al. 2011; Guyatt et al. 2006).
`
`Proper Use of Guidelines
`
`The APA Practice Guidelines are assessments of current scientific and clinical information provided
`as an educational service. The guidelines 1) should not be considered as a statement of the standard
`of care or inclusive of all proper treatments or methods of care; 2) are not continually updated and
`may not reflect the most recent evidence, as new evidence may emerge between the time information
`is developed and when the guidelines are published or read; 3) address only the question(s) or is-
`sue(s) specifically identified; 4) do not mandate any particular course of medical care; 5) are not in-
`tended to substitute for the independent professional judgment of the treating provider; and 6) do not
`account for individual variation among patients. As such, it is not possible to draw conclusions about
`the effects of omitting a particular recommendation, either in general or for a specific patient. Further-
`more, adherence to these guidelines will not ensure a successful outcome for every individual, nor
`should these guidelines be interpreted as including all proper methods of evaluation and care or ex-
`cluding other acceptable methods of evaluation and care aimed at the same results. The ultimate rec-
`ommendation regarding a particular assessment, clinical procedure, or treatment plan must be made
`by the clinician in light of the psychiatric evaluation, other clinical data, and the diagnostic and treat-
`ment options available. Such recommendations should be made in collaboration with the patient,
`whenever possible, and incorporate the patient’s personal and sociocultural preferences and values
`in order to enhance the therapeutic alliance, adherence to treatment, and treatment outcomes. For all
`of these reasons, the APA cautions against the use of guidelines in litigation. Use of these guidelines
`is voluntary. APA provides the guidelines on an “as is” basis and makes no warranty, expressed or
`implied, regarding them. APA assumes no responsibility for any injury or damage to persons or prop-
`erty arising out of or related to any use of the guidelines or for any errors or omissions.
`
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`Rationale
`
`The goal of this guideline is to improve the quality of care and treatment outcomes for patients with
`alcohol use disorder (AUD), as defined by DSM-5 (American Psychiatric Association 2013). The
`guideline focuses specifically on evidence-based pharmacological treatments for AUD but also
`includes statements related to assessment and treatment planning that are an integral part of using
`pharmacotherapy to treat AUD. AUD pharmacotherapy is a topic of increasing interest given the
`burden of AUD in the population and the availability of several U.S. Food and Drug Administra-
`tion (FDA)–approved medications for this disorder. For these reasons, the AHRQ undertook a sys-
`tematic review of AUD pharmacotherapy in outpatients (Jonas et al. 2014), which serves as the
`foundation of the systematic review for this practice guideline. The guideline does not apply to the
`use of these same medications for indications other than AUD. It also does not address the manage-
`ment of individuals who are intoxicated with alcohol, who require pharmacotherapy for the acute
`treatment of alcohol withdrawal, or who are experiencing other acute medical problems related to
`alcohol use. Evidence-based psychotherapeutic treatments for AUD, including cognitive-behavioral
`therapy (CBT), twelve-step facilitation (TSF), and motivational enhancement therapy (MET)
`(Anton et al. 2006; Martin and Rehm 2012; Project MATCH Research Group 1998b), also play a
`major role in the treatment of AUD, but specific recommendations related to these modalities are
`outside the scope of this guideline.
`Worldwide, the estimated 12-month adult prevalence of AUD is 8.5%, with an estimated lifetime
`prevalence of 20% (Slade et al. 2016a). In the United States, AUD has estimated values for 12-month
`and lifetime prevalence of 13.9% and 29.1%, respectively, with approximately half of individuals
`with lifetime AUD having a severe disorder (Grant et al. 2015). Rates of AUD in U.S. adults vary by
`race/ethnicity (Delker et al. 2016; Grant et al. 2015), with 12-month prevalence rates being highest
`among American Indians and Alaska Natives (19.2%) as compared with whites (14.0%), Hispanics
`(13.6%), African Americans (14.4%), and Asian Americans and Pacific Islanders (10.6%). Onset of
`AUD is most commonly between ages 18 and 29, and men are more likely to be diagnosed with the
`disorder as compared to women (12-month prevalence in the United States 17.6% vs. 10.4%; Grant
`et al. 2015). However, in recent decades, differences between men and women in patterns of alcohol
`use have become less pronounced (Slade et al. 2016b; White et al. 2015), and overall rates of AUD
`appear to be increasing (Grant et al. 2015).
`AUD places a significant strain on both the personal and public health of the U.S. population.
`According to a 2006 Centers for Disease Control and Prevention–sponsored study (Bouchery et al.
`2011), AUD and its sequelae cost the United States $223.5 billion annually and account for signifi-
`cant excess mortality (Kendler et al. 2016). Globally, AUD is associated with a substantial burden of
`disease in terms of years of life lost to premature mortality, disability-adjusted life years, and years
`lived with disability (Whiteford et al. 2013). Additionally, problematic alcohol use has been linked
`to motor vehicle accidents (Kelly et al. 2004); poor academic performance (Williams et al. 2003;
`Wolaver 2002); increased risk of suicide (American Psychiatric Association 2016; Darvishi et al.
`2015); increased criminal activity, including intimate partner violence perpetration (Okuda et al.
`2015); increased risk for death by overdose (Jones et al. 2014); and increased transmission risks for
`human immunodeficiency virus (HIV) and other sexually transmitted infections (Monroe et al.
`2016; Rashad and Kaestner 2004; Williams et al. 2016). Additionally, many symptoms of AUD relate
`to the inability to regulate alcohol use, and relapse of AUD is common (Dawson et al. 2007; Moos
`and Moos 2006; Tuithof et al. 2014). Associated impairments in insight often lead to delays in ac-
`
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`cessing care (Chapman et al. 2015). Access to care can also be challenging because AUD often co-
`occurs with other psychiatric disorders (Grant et al. 2015), and each disorder will need to be treated.
`Furthermore, the co-occurrence of AUD and other psychiatric disorders reduces treatment out-
`comes for both types of disorders (Drake et al. 2001) and can be an unrecognized source of treat-
`ment resistance.
`Despite its high prevalence and numerous negative consequences, AUD remains undertreated.
`Effective and evidence-based interventions are available, and treatment is associated with reduc-
`tions in the risk of relapse (Dawson et al. 2006) and AUD-associated mortality (Timko et al. 2006).
`Nevertheless, fewer than 1 in 10 individuals in the United States with a 12-month diagnosis of AUD
`receive any treatment (Grant et al. 2015; Substance Abuse and Mental Health Services Administra-
`tion 2014). Receipt of evidence-based care is even less common. For example, one study found that
`of the 11 million people in the United States with AUD, only 674,000 received psychopharmacolog-
`ical treatment (Mark et al. 2009). Furthermore, treatment availability and the type of treatment pro-
`vided can vary based on geography and, in the United States, insurance coverage (Hagedorn et al.
`2016; Mark et al. 2015), including formulary restrictions (Harris et al. 2013). In a systematic litera-
`ture review focused on this disparity, Hagedorn et al. (2016) identified contributing factors at the
`level of patients (e.g., lack of awareness of treatment options) and cl