Pharmacotherapy for Adults With Alcohol-Use Disorders in

447 Pages·2014·3.27 MB·English

Comparative Effectiveness Review
Number 134
Pharmacotherapy
for Adults
With Alcohol-
Use Disorders in
Outpatient Settings
Comparative Effectiveness Review
Number 134

Pharmacotherapy for Adults With Alcohol-Use
Disorders in Outpatient Settings

Prepared for:
Agency for Healthcare Research and Quality
U.S. Department of Health and Human Services
540 Gaither Road
Rockville, MD 20850
www.ahrq.gov

Contract No. 290-2012-00008-I

Prepared by:
RTI International–University of North Carolina Evidence-based Practice Center
Research Triangle Park, NC

Investigators:
Daniel E. Jonas, M.D., M.P.H.
Halle R. Amick, M.S.P.H.
Cynthia Feltner, M.D., M.P.H.
Georgiy Bobashev, Ph.D.
Kathleen Thomas, Ph.D.
Roberta Wines, M.P.H.
Mimi M. Kim, Ph.D.
Ellen Shanahan, M.A.
C. Elizabeth Gass, M.P.H.
Cassandra J. Rowe, B.A.
James C. Garbutt, M.D.

AHRQ Publication No. 14-EHC029-EF
May 2014
This report is based on research conducted by the RTI International–University of North
Carolina Evidence-based Practice Center (EPC) under contract to the Agency for Healthcare
Research and Quality (AHRQ), Rockville, MD (Contract No. 290-2012-00008-I). The findings
and conclusions in this document are those of the authors, who are responsible for its contents;
the findings and conclusions do not necessarily represent the views of AHRQ. Therefore, no
statement in this report should be construed as an official position of AHRQ or of the U.S.
Department of Health and Human Services.

The information in this report is intended to help health care decisionmakers—patients and
clinicians, health system leaders, and policymakers, among others—make well informed
decisions and thereby improve the quality of health care services. This report is not intended to
be a substitute for the application of clinical judgment. Anyone who makes decisions concerning
the provision of clinical care should consider this report in the same way as any medical
reference and in conjunction with all other pertinent information, i.e., in the context of available
resources and circumstances presented by individual patients.

This report may be used, in whole or in part, as the basis for development of clinical practice
guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage
policies. AHRQ or U.S. Department of Health and Human Services endorsement of such
derivative products may not be stated or implied.

This report may periodically be assessed for the urgency to update. If an assessment is done, the
resulting surveillance report describing the methodology and findings will be found on the
Effective Health Care Program Web site at: www.effectivehealthcare.ahrq.gov. Search on the
title of the report.

This document is in the public domain and may be used and reprinted without permission except
those copyrighted materials that are clearly noted in the document. Further reproduction of those
copyrighted materials is prohibited without the specific permission of copyright holders.

Persons using assistive technology may not be able to fully access information in this report. For
assistance contact [email protected].

None of the investigators have any affiliations or financial involvement that conflicts with the
material presented in this report.

Suggested citation: Jonas DE, Amick HR, Feltner C, Bobashev G, Thomas K, Wines R, Kim
MM, Shanahan E, Gass CE, Rowe CJ, Garbutt JC. Pharmacotherapy for Adults With Alcohol-
Use Disorders in Outpatient Settings. Comparative Effectiveness Review No. 134. (Prepared by
the RTI International–University of North Carolina Evidence-based Practice Center under
Contract No. 290-2012-00008-I.) AHRQ Publication No. 14-EHC029-EF. Rockville, MD:
Agency for Healthcare Research and Quality; May 2014.
www.effectivehealthcare.ahrq.gov/reports/final.cfm.

ii
Preface
The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-based
Practice Centers (EPCs), sponsors the development of systematic reviews to assist public- and
private-sector organizations in their efforts to improve the quality of health care in the United
States. These reviews provide comprehensive, science-based information on common, costly
medical conditions, and new health care technologies and strategies.
Systematic reviews are the building blocks underlying evidence-based practice; they focus
attention on the strength and limits of evidence from research studies about the effectiveness and
safety of a clinical intervention. In the context of developing recommendations for practice,
systematic reviews can help clarify whether assertions about the value of the intervention are
based on strong evidence from clinical studies. For more information about AHRQ EPC
systematic reviews, see www.effectivehealthcare.ahrq.gov/reference/purpose.cfm.
AHRQ expects that these systematic reviews will be helpful to health plans, providers,
purchasers, government programs, and the health care system as a whole. Transparency and
stakeholder input are essential to the Effective Health Care Program. Please visit the Web site
(www.effectivehealthcare.ahrq.gov) to see draft research questions and reports or to join an
email list to learn about new program products and opportunities for input.
We welcome comments on this systematic review. They may be sent by mail to Aysegul
Gozu, M.D., M.P.H., at: Agency for Healthcare Research and Quality, 540 Gaither Road,
Rockville, MD 20850, or by email to [email protected].

Richard G.Kronick, Ph.D. Yen-pin Chiang, Ph.D.
Director, Agency for Healthcare Research and Acting Director, Center for Outcomes and
Quality Evidence
Agency for Healthcare Research and Quality

Stephanie Chang, M.D., M.P.H. Aysegul Gozu, M.D., M.P.H.
Director, EPC Program Task Order Officer
Center for Outcomes and Evidence Center for Outcomes and Evidence
Agency for Healthcare Research and Quality Agency for Healthcare Research and Quality

Carmen Kelly, Pharm.D., R.Ph.
Task Order Officer
Center for Outcomes and Evidence
Agency for Healthcare Research and Quality

iii
Acknowledgments
The authors gratefully acknowledge the continuing support of our AHRQ Task Order
Officers, Carmen Kelly, Pharm.D., R.Ph., and Aysegul Gozu, M.D., M.P.H., and our Associate
Editor, Melissa McPheeters, M.P.H., Ph.D., as well as the continued guidance of Christine
Chang, M.D., M.P.H. We extend our appreciation to our Key Informants and members of our
Technical Expert Panel (listed below), all of whom provided thoughtful advice and input during
our research process.
The investigators deeply appreciate the considerable support, commitment, and contributions
of the EPC team staff at RTI International and the University of North Carolina (UNC) at Chapel
Hill. We express our gratitude to the following individuals for their contributions to this project:
Carol Woodell, B.S.P.H., our Project Manager; Meera Viswanathan, Ph.D., Director of the RTI-
UNC EPC; Timothy S. Carey, M.D., M.P.H., Director of the Cecil G. Sheps Center for Health
Services Research at UNC; Christiane Voisin, M.S.L.S., our EPC Librarian; Claire Baker, our
Research Assistant; Jennifer Drolet, M.A., Editor; and Loraine Monroe and Judy Cannada, our
EPC Publications Specialists.

iv
Key Informants
Key Informants are the end-users of research, including patients and caregivers, practicing
clinicians, relevant professional and consumer organizations, purchasers of health care, and
others with experience in making health care decisions. Within the EPC program, the Key
Informant role is to provide input into identifying the Key Questions for research that will inform
health care decisions. The EPC solicits input from Key Informants when developing questions
for systematic review or when identifying high-priority research gaps and needed new research.
Key Informants are not involved in analyzing the evidence or writing the report and have not
reviewed the report, except as given the opportunity to do so through the peer or public review
mechanism.
Key Informants must disclose any financial conflicts of interest greater than $10,000 and any
other relevant business or professional conflicts of interest. Because of their role as end-users,
individuals are invited to serve as Key Informants and those who present with potential conflicts
may be retained. The Task Order Officer and the EPC work to balance, manage, or mitigate any
potential conflicts of interest identified.
The list of Key Informants who participated in developing this report follows:

Raymond Anton, M.D.
Medical University of South Carolina
Charleston, SC

David Fiellin, M.D.
Yale University
New Haven, CT

Joshua Lee, M.D., M.Sc.
New York University
New York, NY

Sandrine Pirard, M.D., Ph.D., M.P.H.
National Institute on Drug Abuse, National Institutes of Health
Baltimore, MD

v
Technical Expert Panel
Technical Experts comprise a multidisciplinary group of clinical, content, and methodologic
experts who provide input in defining populations, interventions, comparisons, or outcomes as
well as identifying particular studies or databases to search. They are selected to provide broad
expertise and perspectives specific to the topic under development. Divergent and conflicted
opinions are common and perceived as healthy scientific discourse that results in a thoughtful,
relevant systematic review. Therefore, study questions, design, and methodological approaches
do not necessarily represent the views of individual technical and content experts. Technical
Experts provide information to the EPC to identify literature search strategies and recommend
approaches to specific issues as requested by the EPC. Technical Experts do not do analysis of
any kind or contribute to the writing of the report and have not reviewed the report, except as
given the opportunity to do so through the peer or public review mechanism.
Technical Experts must disclose any financial conflicts of interest greater than $10,000 and
any other relevant business or professional conflicts of interest. Because of their unique clinical
or content expertise, individuals are invited to serve as Technical Experts and those who present
with potential conflicts may be retained. The Task Order Officer and the EPC work to balance,
manage, or mitigate any potential conflicts of interest identified.
The list of Technical Experts who participated in developing this report follows:

Raymond Anton, M.D. Raye Litten, Ph.D.
Medical University of South Carolina National Institute on Alcohol Abuse and
Charleston, SC Alcoholism
Bethesda, MD
David Fiellin, M.D.
Yale University Robert Lubran, M.S., M.P.A.
New Haven, CT Substance Abuse and Mental Health
Services Administration
Marc Fishman, M.D. Rockville, MD
Johns Hopkins University
Baltimore, MD Sandrine Pirard, M.D., Ph.D., M.P.H.
National Institute on Drug Abuse
Joshua Lee, M.D., M.Sc. National Institutes of Health
New York University Baltimore, MD
New York, NY

vi
Peer Reviewers
Peer Reviewers are invited to provide written comments on the draft report based on their
clinical, content, or methodologic expertise. Peer review comments on the preliminary draft of
the report are considered by the EPC in preparation of the final draft of the report. Peer
Reviewers do not participate in writing or editing the final report or other products. The synthesis
of the scientific literature presented in the final report does not necessarily represent the views of
individual reviewers. The dispositions of the peer review comments are documented and will, for
Comparative Effectiveness Reviews and Technical Briefs, be published 3 months after the
publication of the evidence report.
Potential reviewers must disclose any financial conflicts of interest greater than $10,000 and
any other relevant business or professional conflicts of interest. Invited Peer Reviewers may not
have any financial conflict of interest greater than $10,000. Peer Reviewers who disclose
potential business or professional conflicts of interest may submit comments on draft reports
through the public comment mechanism.
The list of Peer Reviewers follows:

Raymond Anton, M.D. David Oslin, M.D.
Medical University of South Carolina University of Pennsylvania
Charleston, SC Philadelphia, PA

Katharine Bradley, M.D., M.P.H. Ismene Petrakis, M.D.
Group Health Research Institute Yale University; U.S. Department of
U.S. Department of Veterans Affairs Puget Veterans Affairs Connecticut Healthcare
Sound Health Care System System
University of Washington West Haven, CT
Seattle, WA
Sandrine Pirard, M.D., Ph.D., M.P.H.
Jonathan Chick, M.A., M.Phil., M.B.Ch.B., National Institute on Drug Abuse,
D.Sc., FRCPsych, FRCPE National Institutes of Health
Queen Margaret University Baltimore, MD
Edinburgh, Scotland
Elizabeth Ralevski, Ph.D.
Raye Litten, Ph.D. Yale University
National Institute on Alcohol Abuse and New Haven, CT
Alcoholism
Bethesda, MD Joseph Volpicelli, M.D., Ph.D.
Institute of Addiction Medicine
Plymouth Meeting, PA

vii
Pharmacotherapy for Adults With Alcohol-Use Disorders in
Outpatient Settings
Structured Abstract
Objectives. To conduct a systematic review and meta-analysis of the efficacy, comparative
effectiveness, and harms of medications (both FDA approved and others) for adults with alcohol-
use disorders, and to evaluate the evidence from primary care settings.
Data sources. PubMed®, Cochrane Library, PsycINFO®, CINAHL®, Embase®, U.S. Food and
Drug Administration Web site, ClinicalTrials.gov, and World Health Organization International
Clinical Trials Registry Platform (January 1, 1970, to October 11, 2013).
Review methods. Two investigators independently selected, extracted data from, and rated risk
of bias of studies. We conducted meta-analyses using random-effects models. We graded
strength of evidence (SOE) based on established guidance.
Results. We included 135 studies. Most patients met criteria for alcohol dependence; mean ages
were in the 40s. Studies typically included psychosocial cointerventions; effect sizes reflect the
added benefits of medications.For acamprosate and oral naltrexone (50 mg per day), numbers
needed to treat (NNTs) to prevent 1 person from returning to any drinking were 12 and 20,
respectively (moderate SOE); NNT to prevent 1 person from returning to heavy drinking was 12
for oral naltrexone (50 mg per day) (moderate SOE). Our meta-analyses of four head-to-head
trials found no statistically significant difference between the two medications for consumption
outcomes (moderate SOE). For injectable naltrexone, meta-analyses found no significant benefit
for return to any or heavy drinking, but found a reduction in heavy drinking days (low SOE).
Evidence from well-controlled trials does not support efficacy of disulfiram, except possibly for
patients with excellent adherence. Among medications used off label, moderate evidence
supports the efficacy of nalmefene and topiramate for improving some consumption outcomes,
and limited evidence supports the efficacy of valproic acid. Evidence from primary care settings
was scant. We found insufficient direct evidence to conclude whether medications for alcohol-
use disorders are effective for improving health outcomes.
Compared with placebo, patients treated with acamprosate had a higher risk of anxiety, diarrhea,
and vomiting; those treated with naltrexone had a higher risk of dizziness, nausea, and vomiting.
In head-to-head studies, the risks of headache and vomiting were slightly higher for naltrexone
than for acamprosate. Individual trials of topiramate reported a significantly increased risk of
paresthesias, anorexia, difficulty concentrating, dizziness, psychomotor slowing, and other
adverse effects.
Our meta-analyses for variation in naltrexone response related to OPRM1 polymorphisms found
no statistically significant difference between A-allele homozygotes and those with at least one
G allele, but confidence intervals were wide and additional studies are needed.
Conclusions. Acamprosate and oral naltrexone have the best evidence for improving alcohol
consumption outcomes for patients with alcohol-use disorders. Head-to-head trials have not
consistently established the superiority of one medication. Thus, other factors may guide
viii
medication choices, such as frequency of administration, potential adverse events, coexisting
symptoms, and availability of treatments.
ix